Obicetrapib and ezetimibe combination therapy and fixed-dose pharmaceutical compositions

Abstract

The present disclosure relates to stable pharmaceutical compositions comprising a fixed-dose combination of obicetrapib and ezetimibe, or salts, solvates, or derivatives thereof. The present disclosure further describes the use of ezetimibe and obicetrapib, e.g., in the form of a fixed-dose combination as described above, for the preparation of medicaments and methods of treatment of subjects in need of LDL cholesterol reduction or suffering from hyperlipidemia or mixed dyslipidemia.

Description

[Technical Field]

[0001] The present disclosure relates to fixed-dose pharmaceutical compositions comprising obicetrapib and ezetimibe, and their use for the preparation and treatment of medicaments in subjects in need of LDL cholesterol reduction or in patients with heterozygous familial hypercholesterolemia (HeFH) and / or pre-existing atherosclerotic cardiovascular disease (ASCVD). [Background technology]

[0002] Despite advances in treatment, cardiovascular disease (CVD) remains a leading cause of death worldwide, accounting for more than 17 million deaths annually. It has long been known that abnormal cholesterol levels are associated with an increased risk of CVD, including cardiomyopathy, atherosclerosis, and myocardial infarction. In particular, individuals with elevated levels of low-density lipoprotein (LDL) cholesterol and very-low-density lipoprotein (VLDL) cholesterol, combined with low levels of high-density lipoprotein (HDL) cholesterol, have been observed to be at highest risk for developing cardiovascular disease.

[0003] Lowering low-density lipoprotein cholesterol (LDL-C) is a major goal of treatment in the primary and secondary prevention of cardiovascular events. Statin therapy is the mainstay of LDL-C reduction, but a significant proportion of patients prescribed these drugs fail to achieve target blood lipid levels with statin therapy or demonstrate partial or complete intolerance to statin therapy. To reduce the risk of recurrent nonfatal or fatal cardiovascular events, these patients are advised to use alternative lipid-lowering medications concomitantly.

[0004] One alternative therapeutic agent is cholesterol absorption inhibitors (CAIs). CAIs block cholesterol uptake from the small intestine by inhibiting the uptake of micellar cholesterol, reducing the incorporation of cholesterol esters into chylomicrons and chylomicron remnants. CAIs reduce the amount of circulating cholesterol returning to the liver, which in turn increases hepatic LDL receptor activity and enhances the clearance of LDL cholesterol particles from the bloodstream.

[0005] A well-known example of a CAI is ezetimibe, formerly known as Schering-Plough's compound "Sch-58235," which is marketed under the trade names Ezetrol and Zetia (Merck Sharp & Dohme / Merck), among others. The IUPAC name for ezetimibe is (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one. Ezetimibe is often administered as monotherapy or as an add-on combination therapy. Typical dosage forms of ezetimibe are tablets containing 10 mg of ezetimibe for oral administration.

[0006] Another therapeutic agent is an inhibitor of cholesteryl ester transfer protein (CETP). CETP is a plasma protein secreted primarily by the liver and adipose tissue. CETP transfers cholesteryl esters from HDL to apolipoprotein B (ApoB)-containing particles (mainly LDL and VLDL) in exchange for triglycerides (TG), thereby favoring cholesterol in (V)LDL and reducing the cholesterol content of HDL. Therefore, it has been hypothesized that CETP inhibition would preserve cholesteryl esters in HDL-C and reduce the cholesterol content of the atherogenic ApoB fraction.

[0007] Despite evidence supporting the potential of CETP inhibition to reduce cardiovascular morbidity, clinical development of CETP inhibitors has been challenging, with several CETP inhibitors stalling at various stages of clinical development. Obicetrapib (also known as TA-8995) is currently undergoing clinical evaluation.

[0008] There remains a need for improved therapies, including combination therapies, to reduce the risk of cardiovascular events in the treatment of subjects with hyperlipidemia or mixed dyslipidemia.

[0009] As described in more detail herein below, the inventors have found that combined treatment with obicetrapib and ezetimibe achieves significant improvement in blood lipid profiles, and therefore, in general, one aspect of the present invention provides a method of treatment comprising simultaneous administration of obicetrapib and ezetimibe.

[0010] Combination therapy requires the co-administration of multiple tablets under strict instructions from the physician who prescribes such treatment to the patient. Because each drug in the combination therapy may have its own instructions, it is often difficult for patients to comply with such instructions for a long period of time, which makes the treatment of chronic diseases such as those requiring lipid lowering, and even more difficult for patients or their caregivers. Such difficulties generally lead to non-compliance, resulting in reduced efficacy, increased risk of adverse reactions, and often changes in resistance or sensitivity of the target receptor / protein.

[0011] Preparing fixed-dose combinations of various drugs in a single pharmaceutical dosage form is often challenging due to multiple factors, including active pharmaceutical ingredient (API) physicochemical incompatibility, such as API-API interactions, excipient-excipient interactions, and drug-excipient interactions. Physicochemical incompatibility of active ingredients includes challenges arising from differences in API physicochemical properties and behavior, such as pKa, logP, solubility, hygroscopicity, light sensitivity, particle size, flowability, compressibility, melting point, or other parameters of one active ingredient that may be incompatible with the stability of another API in the formulation. Compared to preparing stable formulations of a single API, the need to control the size and shape of the dosage form within the range of routinely administered pill proportions limits the total amount of excipients that can be used to achieve the desired stability and dissolution of each API from a fixed-dose formulation. Excipient incompatibility with one or more drugs in a fixed-dose combination further limits the formulator's options. This becomes more difficult when one or both APIs are poorly water soluble and there are differences in their solubilities or dissolution patterns, such as one soluble and one insoluble or poorly soluble drug; or one lipophilic and the other hydrophilic. Interactions between one drug or its impurities and another drug or its impurities in the fixed dose combination can further affect the stability, solubility, efficacy, or dissolution of one or both drugs.

[0012] Ezetimibe is a practically insoluble drug and has poor solubility over the physiological pH range. Ezetimibe is also incompatible with many commonly used excipients and presents stability issues; for example, the presence of polyethylene glycol (PEG) in the coating layer can increase the tetrahydropyran impurity of ezetimibe. Furthermore, ezetimibe is an API that is inherently non-compressible and has poor flow properties (see, for example, European Patent Application No. 2168573A1), making it quite difficult to prepare tablet formulations of ezetimibe.

[0013] Obicetrapib is also poorly water soluble in the physiological pH range, which adversely affects the dissolution of ezetimibe (unpublished data). To Applicant's knowledge, there is no known compound that (i) can be stabilized for extended periods of time without a substantial increase in the levels of deleterious impurities, (ii) is free of significant API-API, API-excipient, or excipient-excipient interactions that would make such a composition unsuitable for human use, (iii) can consistently provide the desired dissolution profile of each of the two components with a shelf life equivalent to or superior to that of the single-drug formulations, (iv) is easy to formulate and does not present issues with regard to processability of the components during scale-up for formulation and manufacturing, and (v) exhibits the desired bioavailability upon oral administration to humans. There are no known fixed-dose combinations of ezetimibe and obicetrapib that can achieve efficacy and are bioequivalent to the same doses of both active ingredients when co-administered as two separate formulations for each drug, and (vi) provide improved patient compliance, thereby demonstrating comparable or superior long-term therapeutic results without the adverse effects of taking multiple tablets of a single drug formulation, e.g., the development of receptor / protein tolerance or hypersensitivity due to chronic and irregular exposure of the receptor / protein to subtherapeutic or toxic levels of the drug and its metabolites due to poor patient compliance. [Prior art documents] [Patent documents]

[0014] [Patent Document 1] European Patent Application Publication No. 2168573 Summary of the Invention [Problem to be solved by the invention]

[0015] Therefore, there remains a need for a fixed-dose combination of ezetimibe and obicetrapib that meets all of the aforementioned criteria for use in treating subjects with hyperlipidemia or mixed dyslipidemia to reduce the risk of cardiovascular events. [Means for solving the problem]

[0016] As previously mentioned, the inventors have found that combined treatment with obicetrapib and ezetimibe achieves significant improvements in blood lipid profiles, even in subjects who do not adequately respond to (high-intensity) statin treatment, such as high-intensity statin (HIS) low-responders. More specifically, as described in the experimental section of this document, a Phase 2b clinical trial ("ROSE2"; NCT05266586) has now demonstrated that the combination of obicetrapib (10 mg) and ezetimibe (10 mg) is well tolerated and achieved a median LDL-C reduction of 59%, clearly demonstrating synergistic effects. In particular, patients treated with obicetrapib achieved a median LDL-C reduction of 39%, meaning that the addition of ezetimibe to obicetrapib resulted in an additional / incremental LDL-C reduction of approximately 32%. This is significantly greater than the LDL-C reduction typically achieved with ezetimibe: with ezetimibe monotherapy, LDL-C levels are typically reduced by 15-22% (in hyperlipidemic patients), whereas in combination with statins, ezetimibe typically provides incremental LDL-C reductions of 15-20% (see, e.g., Catapano et al. European Heart Journal (2016) 37, 2999-3058). Studies also demonstrated significant improvements in ApoB and Lp(a) levels.

[0017] Accordingly, one aspect of the present invention relates to a fixed-dose pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof; ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and a pharmaceutically acceptable excipient, such as a fixed-dose pharmaceutical composition wherein the composition is a two-component composition, one component comprising ezetimibe and the other component comprising obicetrapib.

[0018] One embodiment relates to a fixed-dose pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate, or co-crystal thereof; ezetimibe or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and pharmaceutically acceptable excipients, wherein when the pharmaceutical composition is dissolved in 500 ml of a solution containing 0.45% SLS in 0.05 M sodium acetate buffer (pH 4.5) in a USP Type II apparatus at a rotation speed of about 75 rpm at 37±0.5°C, at least about 60%, preferably at least about 70%, and more preferably at least about 80% of the ezetimibe is dissolved within about 30 minutes.

[0019] One embodiment relates to a fixed-dose pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate, or co-crystal thereof; ezetimibe or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and pharmaceutically acceptable excipients, wherein upon oral administration of the composition to a subject, the 90% confidence interval of the geometric mean of the area under the curve (AUC0-∞ and / or AUC0-t) and / or Cmax of obicetrapib is greater than or equal to the area under the curve (AUC0-∞ and / or AUC0-t) of obicetrapib obtained upon oral administration of a reference pharmaceutical composition to a similar subject. and / or Cmax within 75% to 125%, preferably 80% to 125%, more preferably 90% to 110%, of each of the reference compositions, wherein said reference composition comprises an equivalent dose of obicetrapib or a pharmaceutically acceptable salt, solvate or cocrystal thereof, and the reference composition is administered alone or as simultaneous or sequential co-administration with another pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or cocrystal thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or cocrystal thereof.

[0020] Another embodiment relates to a fixed-dose pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate, or co-crystal thereof; ezetimibe or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and a pharmaceutically acceptable excipient, wherein upon oral administration of the composition to a subject, the area under the curve (AUC) of ezetimibe and / or ezetimibe glucoronide is 0-∞ and / or AUC0-t ) and / or the 90% confidence interval of the geometric mean of Cmax is the area under the curve (AUC 0-∞ and / or AUC 0-t ) and / or Cmax within 75% to 125%, preferably 80% to 125%, more preferably 90% to 110%, respectively, wherein said reference composition comprises an equivalent dose of ezetimibe or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and the reference composition is administered alone or as simultaneous or sequential co-administration with another pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

[0021] It has surprisingly been found that the fixed-dose pharmaceutical compositions of ezetimibe and obicetrapib can maintain stability for extended periods of time without a substantial increase in the levels of harmful impurities or the formation of substantial amounts of new impurities. It has also surprisingly been found that the fixed-dose pharmaceutical compositions of ezetimibe and obicetrapib are free of any significant API-API, drug-excipient, and / or excipient-excipient interactions that may render the formulation unsuitable for use.

[0022] Furthermore, it has been surprisingly found that the pharmaceutical compositions consistently provide dissolution profiles for ezetimibe as well as obicetrapib throughout their shelf life that are comparable to the dissolution achieved by formulations containing only a single drug. Because the stable compositions provide the desired dissolution profile in a single tablet, they surprisingly eliminate problems associated with co-administration of multiple tablets of a single drug formulation, such as poor patient compliance, suboptimal treatment outcomes, and an increased risk of undesirable adverse effects such as the development of receptor tolerance or hypersensitivity. This makes the fixed-dose compositions particularly relevant and therefore preferred for the long-term treatment of patients requiring lipid-lowering therapy.

[0023] A second aspect relates to a fixed-dose pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate, or co-crystal thereof; ezetimibe or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and pharmaceutically acceptable excipients for use in reducing LDL cholesterol in patients in need thereof, such as those with heterozygous familial hypercholesterolemia (HeFH) and / or those with pre-existing atherosclerotic cardiovascular disease (ASCVD).

[0024] The present invention also provides a method of treating a subject in need thereof, said method comprising combination treatment of said subject with obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, preferably in the form of a fixed-dose pharmaceutical composition as defined herein.

[0025] More specifically, the present invention relates to the following aspects:

[0026] One aspect of the present invention relates to a method for the prophylactic and / or therapeutic treatment of a subject suffering from or at risk of suffering from CVD, in particular ASCVD, said method comprising combination treatment of said subject with obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a preferred embodiment of the present invention, said method comprises administration of a fixed-dose pharmaceutical composition as defined herein.

[0027] Another aspect of the present invention relates to a pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and / or obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, for use in a method for prophylactic and / or therapeutic treatment of a subject suffering from or at risk of suffering from CVD, in particular ASCVD, said method comprising combination treatment of the subject with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof and obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a preferred embodiment of the invention, said pharmaceutical composition is a fixed-dose pharmaceutical composition as defined herein.

[0028] Yet another aspect of the present invention relates to a method of synergistically lowering LDL-C plasma levels in a subject in need thereof, said method comprising combination treatment of said subject with ezetimibe, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and obicetrapib, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof. In a preferred embodiment of the invention, said method comprises administration of a fixed-dose pharmaceutical composition as defined herein.

[0029] A further aspect of the present invention relates to a pharmaceutical composition comprising ezetimibe, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and / or obicetrapib, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, for use in a method for synergistically lowering LDL-C plasma levels in a subject in need thereof, said method comprising simultaneous administration of ezetimibe, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and / or obicetrapib, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof. In a preferred embodiment of the invention, said method comprises administration of a fixed-dose pharmaceutical composition as defined herein.

[0030] Another aspect of the present invention relates to a method of synergistically delaying the onset and / or progression of CVD, particularly ASCVD, and / or reducing the risk and / or occurrence of CVD-related events, particularly ASCVD-related events, in a subject in need thereof, said method comprising co-administration of ezetimibe, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and obicetrapib, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof. In a preferred embodiment of the present invention, said method comprises administration of a fixed-dose pharmaceutical composition as defined herein.

[0031] Yet another aspect of the present invention relates to a pharmaceutical composition comprising ezetimibe, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and / or obicetrapib, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, for use in a method for synergistically delaying the onset and / or progression of CVD, particularly ASCVD, and / or synergistically reducing the risk and / or occurrence of CVD-related events, particularly ASCVD-related events, said method comprising combination treatment of ezetimibe, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, with obicetrapib, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof. In a preferred embodiment, said method comprises the administration of a fixed-dose pharmaceutical composition as defined herein.

[0032] A further aspect of the present invention relates to a method of enhancing, preferably synergistically enhancing, the LDL-C lowering effect of obiscetrapib, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, in a subject in need thereof, said method comprising combination treatment of the subject with ezetimibe, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof. In a preferred embodiment of the present invention, said method comprises administration of a fixed-dose pharmaceutical composition as defined herein.

[0033] Another aspect of the present invention relates to a pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate, or co-crystal thereof for use in a method for enhancing, preferably synergistically enhancing, the LDL-C lowering effect of obicetrapib, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, in a subject in need thereof, said method comprising co-administration of ezetimibe or a pharmaceutically acceptable salt, solvate, or co-crystal thereof. In a preferred embodiment of the invention, said method comprises administration of a fixed-dose pharmaceutical composition as defined herein.

[0034] Yet another aspect of the present invention relates to a method of enhancing, preferably synergistically enhancing, the therapeutic effect of obiscetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, particularly in the treatment and / or prevention of CVD, especially ASCVD, in a subject in need thereof, said method comprising co-administration of ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a preferred embodiment of the invention, said method comprises administration of a fixed-dose pharmaceutical composition as defined herein.

[0035] A further aspect of the present invention relates to a pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof for use in a method for enhancing, preferably synergistically enhancing, the therapeutic effect of obicetrapib or a pharmaceutically acceptable salt or co-crystal thereof, particularly in the treatment and / or prevention of CVD, especially ASCVD, in a subject in need thereof, said method comprising co-administration of ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a preferred embodiment of the invention, said method comprises administration of a fixed-dose pharmaceutical composition as defined herein.

[0036] Also, another aspect of the present invention relates to the use of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and / or ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, in the manufacture of a medicament for use in any one of the methods defined above. In a preferred embodiment of the present invention, said medicament comprises the administration of a fixed-dose pharmaceutical composition as defined herein.

[0037] Another aspect of the present invention relates to a kit comprising a package containing a plurality of pharmaceutical unit dosage forms, e.g., fixed-dose pharmaceutical compositions as defined herein, comprising obicetrapib and ezetimibe, and pharmaceutically acceptable salts, hydrates or solvates thereof, for the treatment and / or prevention of CVD, particularly ASCVD, by combination therapy, and a leaflet containing printed instructions for repeated self-administration of said unit dosage forms.

[0038] It will be understood that these aspects of the invention all encompass the same compositions, the same methods of treatment, the same subjects, etc., unless otherwise indicated.

[0039] In certain preferred embodiments of the present invention, the salt of obicetrapib contained in the pharmaceutical compositions of the present invention, used in the methods of the present invention, contained in unit dosage forms (including in pharmaceutical kits), etc. is the amorphous calcium salt of obicetrapib.

[0040] Specific details and preferred embodiments of the aforementioned methods and compositions and pharmaceutical kits used therein will be apparent to those skilled in the art based on the following detailed description and accompanying experimental section.

[0041] definition Obicetrapib, also known as "TA-8995," has the following chemical name and structure: [ka] {4-[(2-{[3,5-bis(trifluoromethyl)benzyl][(2R,4S)-1-(ethoxycarbonyl)-2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4-yl]amino}pyrimidin-5-yl)oxy]butanoic acid}.

[0042] Ezetimibe, also known as "Sch-58235," has the following chemical name and structure: [ka] (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one.

[0043] Both obicetrapib and ezetimibe may also be used as various salt forms, solvates or co-crystals, and may also be formulated as prodrugs.

[0044] As used herein, the term "apolipoprotein" has its ordinary meaning and refers to a protein that combines with lipids to form lipoproteins.

[0045] As used herein, the term "apolipoprotein B" (ApoB) has its ordinary meaning and refers to the protein encoded by the ApoB gene.

[0046] As used herein, the term "pharmaceutical composition" has its ordinary meaning and refers to a pharmaceutically acceptable composition.

[0047] As used herein, the term "pharmaceutically acceptable" has its ordinary meaning and refers to compounds, substances, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for contact with the tissues of mammals, particularly humans, without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit / risk ratio.

[0048] As used herein, the term "carrier" has its ordinary meaning and refers to a pharmaceutically acceptable diluent, adjuvant, excipient, or vehicle with which a pharmaceutically active ingredient is administered.

[0049] As used herein, the term "excipient" has its ordinary meaning and refers to a pharmaceutically acceptable ingredient commonly used in the pharmaceutical arts to prepare granular, solid or liquid oral dosage formulations.

[0050] As used herein, the term "salt" has its ordinary meaning and includes acid addition and base salts of pharmaceutically active compounds.

[0051] The term "solvate" as used herein has its conventional meaning and refers to a compound formed by solvation, e.g., the combination of a molecule or ion of a solute with a solvent molecule. Known solvent molecules include water, alcohols, nitriles, and polar organic solvents.

[0052] As used herein, the term "subject" refers to a human suffering from or at risk of suffering from a particular disease or disorder. The terms "subject" and "patient" are used interchangeably herein.

[0053] The term "increased risk" has its ordinary meaning and refers to a situation where a subject, preferably a human subject, either male or female, based on their risk profile (such as an LDL-cholesterol level above 70 mg / dL, e.g., above 2.6 mmol / l [100.54 mg / dL]), is at increased risk of suffering a cardiovascular event compared to subjects with lower levels.

[0054] The term "treatment" as used herein has its ordinary meaning and refers to curative, palliative and prophylactic treatment.

[0055] The term "cardiovascular disease" as used herein has its ordinary meaning and includes the clinical manifestations of arteriosclerosis, peripheral vascular disease angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, cerebral infarction and stroke.

[0056] As used herein, the term "cardiovascular event" has its ordinary meaning and refers to the occurrence of myocardial infarction, stroke, coronary death, or the need to undergo coronary revascularization (Ference, 2017).

[0057] As used herein, the term "hypercholesterolemia" has its ordinary meaning and refers to the condition of having high levels of cholesterol in the blood.

[0058] As used herein, the term "hyperlipidemia" has its ordinary meaning and refers to a condition in which there are too many lipids in the blood.

[0059] As used herein, the term "mixed dyslipidemia" has its ordinary meaning and refers to a condition in which there are elevated LDL cholesterol and triglyceride levels with low levels of HDL cholesterol in the blood.

[0060] As used herein, the term "statin intolerance" has its ordinary meaning and refers to a patient's intolerance to two or more statins (one at a low dose) due to adverse safety effects that begin or increase during statin therapy and disappear or improve when the statin is discontinued.

[0061] As used herein, the term "cholesterol absorption inhibitor" (CAI) has its conventional meaning and refers to compounds used to lower LDL-C by inhibiting the intestinal and biliary absorption of cholesterol. A known cholesterol absorption inhibitor is ezetimibe.

[0062] As used herein, the term "cholesteryl ester transfer protein inhibitors" (CETP inhibitors) has its ordinary meaning and refers to a class of compounds that inhibit the CETP receptor in mammals. A known CETP inhibitor is obicetrapib.

[0063] The term "unit dosage form" has its ordinary meaning and refers to a dosage form that is capable of being administered to a subject, preferably a human, to produce an effect, and that can be easily handled and packaged and maintained as a physically and chemically stable unit dose containing a therapeutic agent, i.e., obicetrapib or a combination of therapeutic agents, such as obicetrapib and ezetimibe.

[0064] As used herein, the term "fixed dose combination" has its ordinary meaning and refers to a combination of two or more drugs or active ingredients in defined doses provided in a single dosage unit (e.g., tablet or capsule) and administered as is.

[0065] As used herein, the term "free dose combination" has its ordinary meaning and refers to a combination of two drugs or active ingredients that are administered simultaneously but as two different dosage units.

[0066] The term "effective amount" or "therapeutically effective amount" refers to an amount sufficient to effect treatment as defined herein when administered to a mammal in need of such treatment. The therapeutically effective amount varies depending on the patient to be treated, the patient's weight and age, the severity of the disease state, the method of administration, etc., but can be readily determined by one skilled in the art.

[0067] Unless otherwise specified, when a compound can take alternative tautomeric, regioisomeric, and / or stereoisomeric forms, all alternative isomers are intended to be encompassed within the scope of the claims. For example, if a compound is described as a particular optical isomer, D- or L-, both optical isomers are intended to be encompassed herein. For example, if a compound is described as having one of two tautomeric forms, both tautomers are intended to be encompassed herein. Thus, the compounds provided herein may be enantiomerically pure or may be stereoisomeric or diastereomeric mixtures. The compounds provided herein may have chiral centers. Such chiral centers may be in either the (R) or (S) configuration, or a mixture thereof. The chiral centers of the compounds provided herein may undergo epimerization in vivo. Therefore, one of skill in the art will recognize that, for compounds that undergo epimerization in vivo, administration of the (R) form of the compound is equivalent to administration of the (S) form of the compound.

[0068] The present disclosure also encompasses all suitable isotopic variants of the compounds according to the present disclosure, whether radioactive or not.Isotopic variants of the compounds according to the present disclosure are understood to mean compounds in which at least one atom in the compounds according to the present disclosure is replaced with another atom having the same atomic number but an atomic mass different from the atomic mass that is usually or predominantly present in nature.Examples of isotopes that can be incorporated into compounds according to the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, bromine and iodine, for example: 2 H (deuterium), 3 H (tritium), 13 C. 14 C. 15 N, 17 O. 18 O. 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131Certain isotopic variants of the compounds according to the present disclosure, particularly variants incorporating one or more radioisotopes, may be useful, for example, for examining the mechanism of action or biodistribution of the active compound. 3 H, 14 C and / or 18 Compounds labeled with F isotopes are suitable. Furthermore, the incorporation of isotopes, such as deuterium, can result in increased metabolic stability of the compounds, resulting in certain therapeutic advantages, such as increased half-life in the body or a reduced required active dose. In some embodiments, hydrogen atoms in the compounds described herein may be replaced with deuterium atoms. In certain embodiments, "deuterated," as applied to a chemical group, refers to a chemical group that is isotopically enriched with deuterium in amounts substantially greater than the natural abundance, unless otherwise indicated. Isotopic variants of compounds according to the present disclosure can be prepared by various methods, including, for example, those described below and in the Examples, by using corresponding isotopic modifications of specific reagents and / or starting compounds described therein.

[0069] Therefore, any of the embodiments described herein are meant to include single stereoisomers, mixtures of stereoisomers and / or isotopic forms of the compounds.

[0070] Unless otherwise specified, the term "about" or "approximately" refers to an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, or 3 standard deviations. In certain embodiments, the term "about" or "approximately" means within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.25%, 0.2%, 0.1%, or 0.05% of a given value or range. Unless otherwise specified, the term "about" means within plus or minus 10% of the recited value, rounded to the nearest whole number. [Brief explanation of the drawings]

[0071] [Figure 1] 1 shows the cumulative undersize curve of a small-scale batch of a fixed-dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib. [Figure 2] 1 shows the retention curve of a small-scale batch of a fixed-dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib. [Figure 3] 1 shows a comparison of the dissolution profiles of small scale batches of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib with discriminatory dissolution method-ezetimibe at pH 6.8. [Figure 4] 1 shows a comparison of the dissolution profile of obicetrapib by discriminatory dissolution method (pH 6.8) for small scale batches of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib. [Figure 5] 1 shows a comparison of the dissolution profiles of ezetimibe by discriminatory dissolution method-pH 4.5 for small scale batches of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib. [Figure 6] 1 shows a comparison of obicetrapib dissolution profiles from a stressed stability study of small scale batch a4459 / 05 / 05-pH 6.8 of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib. [Figure 7] 1 shows a comparison of obicetrapib dissolution profiles from a stressed stability study of small scale batch a4459 / 05 / 06-pH 6.8 of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib. [Figure 8] 1 shows a comparison of obicetrapib dissolution profiles from a stressed stability study of small scale batch a4459 / 05 / 07-pH 6.8 of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib. [Figure 9] 1 shows a comparison of obicetrapib dissolution profiles from a stressed stability study of small scale batch a4459 / 05 / 08-pH 6.8 of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib. [Figure 10]1 shows a comparison of ezetimibe dissolution profiles from a stressed stability study of small scale batch a4459 / 05 / 05-pH 6.8 of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib. [Figure 11] 1 shows a comparison of ezetimibe dissolution profiles from a stressed stability study of small scale batch a4459 / 05 / 06-pH 6.8 of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib. [Figure 12] 1 shows a comparison of ezetimibe dissolution profiles from a stressed stability study of small scale batch a4459 / 05 / 07-pH 6.8 of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib. [Figure 13] 1 shows a comparison of ezetimibe dissolution profiles from a stressed stability study of small scale batch a4459 / 05 / 08-pH 6.8 of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib. [Figure 14] 1 shows a comparison of ezetimibe dissolution profiles from a stressed stability study of small scale batch a4459 / 05 / 05-pH 4.5 of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib. [Figure 15] 1 shows a comparison of ezetimibe dissolution profiles from a stressed stability study of small scale batch a4459 / 05 / 06-pH 4.5 of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib. [Figure 16] 1 shows a comparison of ezetimibe dissolution profiles from a stressed stability study of small scale batch a4459 / 05 / 07-pH 4.5 of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib. [Figure 17] 1 shows a comparison of ezetimibe dissolution profiles from a stressed stability study of small scale batch a4459 / 05 / 08-pH 4.5 of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib. [Figure 18]1 shows the % cumulative undersize curve for a small scale batch of a fixed dose composition of 10 mg ezetimibe and 10 mg obicetrapib. [Figure 19] 1 shows the obicetrapib dissolution profile of small scale 10 mg ezetimibe and 10 mg obicetrapib (free acid) fixed dose compositions. [Figure 20] Figure 1 shows the ezetimibe dissolution profiles (50 rpm) of small scale 10 mg ezetimibe and 10 mg obicetrapib (free acid) fixed dose compositions. [Figure 21] Figure 1 shows the ezetimibe dissolution profiles (75 rpm) of small scale 10 mg ezetimibe and 10 mg obicetrapib (free acid) fixed dose compositions. [Figure 22] 1 shows obicetrapib prototype C 200 BN A4459 / 19 / 03 stress stability dissolution test results of a small scale 10 mg ezetimibe and 10 mg obicetrapib (free acid) fixed dose composition. [Figure 23] 1 shows the scale-up BN A4459 / 19 / 02 stress stability dissolution results of obicetrapib prototype C of small-scale 10 mg ezetimibe and 10 mg obicetrapib (free acid) fixed dose composition. [Figure 24] 1 shows scale-up BN A4459 / 19 / 02 stress stability dissolution results of ezetimibe prototype C of small-scale 10 mg ezetimibe and 10 mg obicetrapib (free acid) fixed dose compositions. [Figure 25] 1 shows scale-up BN A4459 / 19 / 02 stress stability dissolution results of ezetimibe prototype C of small-scale 10 mg ezetimibe and 10 mg obicetrapib (free acid) fixed dose compositions. [Figure 26] 1 shows the cumulative size reduction of the small scale FDC1 composition. [Figure 27] Figure 1 shows the obicetrapib dissolution profile of the FDC1 prototype. [Figure 28] Figure 1 shows the ezetimibe elution profile of the FDC1 prototype. [Figure 29]1 shows the cumulative size reduction of the small scale FDC2 composition. [Figure 30] 1 shows the dissolution profile of obicetrapib from small-scale FDC2 composition. [Figure 31] 1 shows the ezetimibe dissolution profile of the small-scale FDC2 composition. [Figure 32] 1 shows the dissolution profile of obicetrapib from small-scale FDC2 coated tablets by discrimination method. [Figure 33] 1 shows the dissolution profile of obicetrapib from small-scale FDC2 coated tablets by QC method. [Figure 34] 1 shows the dissolution profile of ezetimibe from small-scale FDC2 coated tablets by QC method. [Figure 35] 1 shows the dissolution profile of obicetrapib from FDC2 coated tablets from stress stability. [Figure 36] Figure 1 shows the ezetimibe dissolution profile of prototype 2 FDC2 coated tablets from stress stability. [Figure 37] The cumulative undersize curve for the scale-up batch is shown. [Figure 38] Figure 1 shows the dissolution profile of obicetrapib in FDC1 granules from a scaled-up batch. [Figure 39] Figure 1 shows the ezetimibe dissolution profile of FDC1 granules from a scaled-up batch. [Figure 40] Figure 1 shows the ezetimibe dissolution profile of FDC2 final blend from a scaled-up batch. [Figure 41] Figure 1 shows the dissolution profile of obicetrapib from uncoated tablets of FDC1 scale-up batch at various compression forces. [Figure 42] Figure 1 shows the ezetimibe dissolution profile of uncoated tablets of FDC1 scale-up batches at various compression forces. [Figure 43] Figure 1 shows the obicetrapib dissolution profile of uncoated tablets of FDC2 scale-up batch at various compression forces. [Figure 44] Figure 1 shows the ezetimibe dissolution profile of uncoated tablets of FDC2 scale-up batches at various compression forces. [Figure 45] The cumulative undersize curve for the technical batch is shown. [Figure 46] 1 shows the dissolution profiles of obicetrapib for FDC1 and FDC2 technical batches. [Figure 47] 1 shows the dissolution profiles of obicetrapib for FDC1 and FDC2 technical batches. [Figure 48] Figure 1 shows particle size distribution (PSD) data for granules from technical batches. [Figure 49] 1 shows the X-ray powder diffraction pattern of amorphous obicetrapib hemi-calcium. [Figure 50] 1 shows the X-ray powder diffraction pattern of amorphous obicetrapib hemi-calcium. [Figure 51] 1 shows the X-ray powder diffraction pattern of amorphous obicetrapib hemi-calcium. [Figure 52] 1 shows the infrared spectrum of amorphous obicetrapib hemi-calcium. [Figure 53] 1 shows the 1H-NMR spectrum of amorphous obicetrapib hemi-calcium. [Figure 54] 1 shows the X-ray powder diffraction pattern of crystalline obicetrapib hemi-calcium. [Figure 55] 1 shows a stack plot of X-ray powder diffraction patterns obtained from a stability study of crystalline obicetrapib hemi-calcium. [Figure 56] 1 shows a stack plot of X-ray powder diffraction patterns obtained from a stability study of amorphous obicetrapib hemi-calcium. [Figure 57] 1 shows a polarized light micrograph of amorphous obicetrapib hemi-calcium. [Figure 58] 1 shows a polarized light micrograph of crystalline obicetrapib hemi-calcium. [Figure 59] 1 shows a thermogravimetric analysis plot of amorphous obicetrapib hemi-calcium. [Figure 60]1 shows a modulated differential scanning calorimetry thermogram (with pinhole) of amorphous obicetrapib hemi-calcium. [Figure 61] 1 shows a modulated differential scanning calorimetry thermogram (with pinhole) of amorphous obicetrapib helicalcium. [Figure 62] 1 shows a modulated differential scanning calorimetry thermogram (with pinhole) of crystalline obiscetrapib hemi-calcium. [Figure 63] 1 shows the solid-state 13C-NMR spectra of amorphous and crystalline obicetrapib hemi-calcium. [Figure 64] 1 shows the solid-state 13C-NMR spectrum of crystalline obicetrapib hemi-calcium. [Figure 65] 1 shows the solid-state 13C-NMR spectrum of crystalline obicetrapib hemi-calcium. [Figure 66] 1 shows X-ray powder diffraction patterns of crystalline obicetrapib HCl and at least partially desolvated crystalline obicetrapib HCl. [Figure 67] 1 shows the X-ray powder diffraction pattern of crystalline obicetrapib HCl. [Figure 68] 1 shows the X-ray powder diffraction pattern of crystalline Compound 1D. [Figure 69] 1 shows the 1H-NMR spectrum of compound 1D. DETAILED DESCRIPTION OF THE INVENTION

[0072] Fixed-dose pharmaceutical compositions of the present invention One aspect of the present invention relates to a fixed-dose pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, ezetimibe or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and a pharmaceutically acceptable excipient.

[0073] In one embodiment, upon oral administration of the composition to a subject, the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or the 90% confidence interval of the geometric mean of Cmax is the area under the curve (AUC 0-∞ and / or AUC 0-t ) and / or Cmax within about 75% to 125%, preferably about 80% to 125%, more preferably about 90% to 110%, respectively, wherein said reference composition comprises an equivalent dose of obicetrapib or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, and the reference composition is administered alone or as simultaneous or sequential co-administration with another pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof.

[0074] In another embodiment, the area under the curve (AUC) of ezetimibe and / or ezetimibe glucoronide upon oral administration of the composition to a subject 0-∞ and / or AUC 0-t ) and / or the 90% confidence interval of the geometric mean Cmax is the area under the curve (AUC 0-∞ and / or AUC 0-t ) and / or Cmax within about 75% to 125%, preferably about 80% to 125%, more preferably about 90% to 110%, respectively, wherein said reference composition comprises an equivalent dose of ezetimibe or a pharmaceutically acceptable salt, solvate or cocrystal thereof, and the reference composition is administered alone or as simultaneous or sequential co-administration with another pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or cocrystal thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or cocrystal thereof.

[0075] Ezetimibe is a practically insoluble drug and has low solubility over the physiological pH range. It is quite difficult to achieve desirable dissolution, and therefore bioavailability, for ezetimibe under in vivo conditions. This problem is exacerbated by the fact that obicetrapib reduces the dissolution rate and the total amount of ezetimibe that can be dissolved (unpublished data). Surprisingly, it has been found that when the pharmaceutical composition is dissolved in a 500 ml solution containing 0.45% SLS in 0.05 M sodium acetate buffer at pH 4.5 in a USP Type II apparatus at a rotation speed of about 75 rpm at 37±0.5°C, at least about 60%, preferably at least about 70%, and more preferably at least about 80% of the ezetimibe from the fixed-dose pharmaceutical composition dissolves within about 30 minutes. In a preferred embodiment, it has been surprisingly found that when the pharmaceutical composition is dissolved in 500 ml of a solution containing 0.45% SLS in 0.05 M sodium acetate buffer, pH 4.5, in a USP Type II apparatus at a rotation speed of about 75 rpm at 37±0.5° C., at least about 60%, preferably at least about 70%, and more preferably at least about 80% of the ezetimibe from the fixed dose pharmaceutical composition dissolves within about 20 minutes.

[0076] Even more surprisingly, it has been found that when the pharmaceutical composition is dissolved in 1000 ml of a solution containing pH 6.8 phosphate buffer plus 0.2% w / v polysorbate 80 in a USP Type II apparatus at a rotation speed of about 75 rpm at 37±0.5° C., at least about 70%, preferably at least about 80%, more preferably at least about 85%, and even more preferably at least about 90% of the obicetrapib from the fixed-dose pharmaceutical composition dissolves within about 30 minutes. In a preferred embodiment, it has been unexpectedly found that when the pharmaceutical composition is dissolved in 1000 ml of a solution containing pH 6.8 phosphate buffer plus 0.2% w / v polysorbate 80 in a USP Type II apparatus at a rotation speed of about 75 rpm at 37±0.5° C., at least about 70%, preferably at least about 80%, and more preferably at least about 85% of the obicetrapib from the fixed-dose pharmaceutical composition dissolves within about 15 minutes.

[0077] Ezetimibe is an inherently difficult / non-compressible API (see, e.g., European Patent Application No. 2168573A1) and has poor flowability. Therefore, it is very challenging for formulators to prepare tablet formulations that not only meet the requirements for hardness, disintegration time, friability, shape, and size of ezetimibe, but also provide the desired stability and dissolution properties. Surprisingly, it has been found that the present composition not only meets the requirements for solubility and stability that make it suitable for the required application, but also meets the criteria for processability parameters, i.e., flowability, compressibility, disintegration time, friability, hardness, shape, and size.

[0078] The fixed-dose pharmaceutical composition may comprise a combination of 1-10 mg of obicetrapib and 5-20 mg of ezetimibe. In a preferred embodiment, the composition comprises 5 mg of obicetrapib and 10 mg of ezetimibe. In a more preferred embodiment, the composition comprises 10 mg of obicetrapib and 10 mg of ezetimibe.

[0079] In a preferred embodiment, the pharmaceutical composition is provided in a unit dosage form containing 5 mg of obicetrapib and 10 mg of ezetimibe. In a more preferred embodiment, the composition is provided in a unit dosage form containing 10 mg of obicetrapib and 10 mg of ezetimibe.

[0080] In the present disclosure, when a dose of either obicetrapib or ezetimibe is stated in mg and / or relative amount (by weight), it means obicetrapib or ezetimibe in free form. When a salt, solvate or co-crystal of ezetimibe or obicetrapib is used, for the purposes, said dose shall mean the dose corresponding to the weight of ezetimibe or obicetrapib, respectively, in free form.

[0081] In certain embodiments, the pharmaceutical composition is provided in a solid oral dosage form selected from caplets, mini-tablets, lozenges, granules, beads, pellets, tablets, capsules, pills, etc., or liquid oral dosage forms that may be used in the pharmaceutical formulation include, but are not limited to, drinks, solutions, suspensions, syrups, beverages, and emulsions.

[0082] In one embodiment, the solid oral dosage form is provided as a two-component pharmaceutical composition. In a preferred embodiment, one component of the two-component pharmaceutical composition contains ezetimibe and the other component contains obicetrapib. In another preferred embodiment, only one of the components of the two-component pharmaceutical composition contains both ezetimibe and obicetrapib.

[0083] In certain embodiments, the binary composition is a bilayer tablet formulation. In a preferred embodiment, ezetimibe is present in one of the two layers and obicetrapib is present in the other layer of the bilayer tablet.

[0084] In another embodiment, the two-component system is a capsule formulation. In a preferred embodiment, the capsule can contain two types of granules, where one granule type contains ezetimibe and the other granule type contains obicetrapib. In yet another preferred embodiment, the capsule can contain two different types of blends or mini-tablets, each containing ezetimibe or obicetrapib, and optionally, such blends or mini-tablets can be filled into two parts of the capsule, which are separated from each other. In a specific embodiment, each blend or mini-tablet is filled into a smaller capsule, or such blends are compressed into tablets / caplets / mini-tablets, and then these tablets / caplets / mini-tablets are filled into a capsule formulation.

[0085] In another embodiment, the fixed dose pharmaceutical composition is a compressed tablet formulation comprising an extragranular component and an intragranular component. In a preferred embodiment, the intragranular component comprises ezetimibe and the extragranular component comprises obicetrapib. In a more preferred embodiment, the intragranular component comprises both ezetimibe and obicetrapib. In another embodiment, the intragranular component comprises obicetrapib and the extragranular component comprises ezetimibe. In yet another embodiment, the extragranular component comprises both ezetimibe and obicetrapib.

[0086] The intragranular component and the extragranular component are present in a ratio of about 1:99 to about 99:1, preferably about 3:97 to about 97:3, and more preferably about 5:95 to about 95:5. In another embodiment, the intragranular component and the extragranular component are present in a ratio of about 10:90 to about 90:10, preferably about 20:80 to about 80:20 or about 30:70 to about 70:30, and more preferably about 40:60 to about 60:40 or about 50:50.

[0087] The term "intragranular" refers to being or being present within a granule of the composition, i.e., a granule that includes, but is not limited to, a first set of pharmaceutically acceptable excipients (such as, but not limited to, binders, disintegrants, diluents, lubricants and solvents), and optionally one or more pharmaceutically acceptable active ingredients, in this case ezetimibe and / or obicetrapib.

[0088] The term "extragranular" refers to the addition of pharmaceutically acceptable ingredients to the material after granulation, i.e., the extragranular fraction containing a second set of pharmaceutically acceptable excipients (including but not limited to disintegrants, diluents, lubricants, glidants, etc.). Optionally, the extragranular component may contain one or more pharmaceutically acceptable active ingredients, in this case ezetimibe and / or obicetrapib.

[0089] The pharmaceutical compositions can be obtained by known conventional methods such as dry granulation, wet granulation, direct compression, roller compaction, fluidized bed granulation, rapid mixer granulation, solvent evaporation, hot melt extrusion, etc. In a preferred embodiment, the composition is obtained by wet granulation followed by compressing the granules into a tablet formulation or filling such granules into capsules.

[0090] In one embodiment, the pharmaceutical composition comprises ezetimibe as anhydrous ezetimibe. In another embodiment, the pharmaceutical composition comprises ezetimibe as ezetimibe hydrate, preferably ezetimibe monohydrate. In yet another embodiment, the pharmaceutical composition comprises a mixture of anhydrous ezetimibe and ezetimibe hydrate, preferably ezetimibe monohydrate. The molar ratio of anhydrous ezetimibe to ezetimibe hydrate, preferably ezetimibe monohydrate, in the pharmaceutical composition may be 100:0-0:100, 99.09:0.01-0.01:99.09, 99.08:0.02-0.02:99.08, 99.07:0.03-0.03:99.07, 99.06:0.04-0.04:99.06, 99.05:0.05 99.04:0.06-0.06:99.04, 99.03:0.07-0.07:99.03, 99.02:0.08-0.02:99.02, 99.01:0.09-0.09:99.01, 99:1-1:99, 98:2-2:98, 90:10-10:90, 70:30-30:70 or 50:50. In a preferred embodiment, the composition is substantially free of ezetimibe hydrate, with about 100% of the ezetimibe being in the form of anhydrous ezetimibe. In another preferred embodiment, about 99.5% of ezetimibe is present in the form of anhydrous ezetimibe and about 0.5% of ezetimibe is present in the form of ezetimibe hydrate, preferably ezetimibe monohydrate. In a more preferred embodiment, the composition is substantially free of anhydrous ezetimibe and about 100% of ezetimibe is present in the form of ezetimibe hydrate, preferably ezetimibe monohydrate.

[0091] Ezetimibe or obicetrapib, or both, may exist in the form of a pharmaceutically acceptable salt, solvate, or co-crystal. Solvates include, but are not limited to, hydrates. Furthermore, "salt" refers to a compound prepared by the reaction of an organic acid or base with a pharmaceutically acceptable inorganic or organic acid or base; as used herein, "salt" includes hydrates and solvates of salts. Exemplary pharmaceutically acceptable inorganic or organic acids or bases are listed in Tables 1-8 of "Handbook of Pharmaceutical Salts," P.H. Stahl and C.G. Wermuth (eds.), VHCA, Zurich, 2002, pp. 334-345. Pharmaceutically acceptable salts of obicetrapib or ezetimibe can be readily prepared by mixing a solution of such a compound with the desired acid or base, as needed. The salt may precipitate from solution and be collected by filtration, or it may be recovered by evaporation of the solvent. In one embodiment, salts include, but are not limited to, hydrochloride, phosphate, sulfate, mesylate, esylate, and besylate salt forms. In a preferred embodiment, the composition comprises obicetrapib as an alkali metal or alkaline earth metal salt, preferably obicetrapib sodium, obicetrapib potassium, or obicetrapib calcium, more preferably obicetrapib calcium salt. As used herein, the term "cocrystal" refers to a crystalline substance consisting of two or more unique solids at room temperature, each containing unique physical properties such as structure, melting point, and heat of fusion, except that, if otherwise specified, the active pharmaceutical ingredient may be a liquid at room temperature. Cocrystals may include a cocrystal former H-bonded to obicetrapib and / or ezetimibe. The cocrystal former may be H-bonded directly to the active pharmaceutical ingredient or to an additional molecule bound to obicetrapib and / or ezetimibe. In one embodiment, a co-crystal can be formed between obicetrapib and ezetimibe, or a salt or solvate thereof. A solvate of an active compound without a co-crystal former is not a co-crystal. The co-crystal can also be a co-crystal between a co-crystal former and a salt of ezetimibe or obicetrapib, or both.Other modes of molecular recognition may also exist, such as π-stacking, guest-host complexation, and van der Waals interactions. Of the interactions listed above, hydrogen bonding is the dominant interaction in the formation of cocrystals, resulting in the formation of non-covalent bonds between a hydrogen bond donor on one moiety and a hydrogen bond acceptor on the other moiety. In another embodiment, the cocrystal comprises two cocrystal formers. Co-crystal formers include, but are not limited to, free acids, free bases, or zwitterions; inorganic base addition salts such as sodium, potassium, lithium, calcium, magnesium, ammonium, or aluminum salts, or organic base addition salts; inorganic acid addition salts such as HBr, HCl, sulfuric acid, nitric acid, or phosphoric acid addition salts; or organic acid addition salts such as acetic acid, propionic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, stearic acid, or lactic acid; anhydrous or hydrated forms of the free forms or salts, more specifically, for example, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, or pentahydrate; or solvates of the free forms or salts. The ratio of the active ingredient to the co-crystal former can be stoichiometric or non-stoichiometric, depending on the purpose. For example, 1:1, 1:1.5, 1:2 and 2:1 ratios of active ingredient (including obicetrapib or ezetimibe or both, salts or solvates thereof):co-crystal former are acceptable.

[0092] In one embodiment, the fixed dose pharmaceutical composition comprises either ezetimibe or obicetrapib, or both, as the micronized API. The particle size distribution of such micronized APIs can be determined by one skilled in the art using methods well known in the art, including, but not limited to, laser diffraction (LD), dynamic light scattering (DLS), dynamic image analysis (DIA), or sieve analysis. Preferably, the method used is the laser diffraction dry powder dispersion method, which provides particle size distribution by measuring the angular change in the intensity of light scattered as a laser beam passes through a dispersed particulate sample. Large particles scatter light at small angles relative to the laser beam, and small particles scatter light at large angles. The angular scattering intensity data is then analyzed to calculate particle sizes, which contribute to creating a cumulative undersize distribution curve that represents the particle size distribution by volume. Particle sizes from this method are typically reported as equivalent sphere diameters (Dv). The most commonly reported percentiles are Dv10, Dv50, and Dv90 (X 10 , X 50 and X 90 Dv90 means that 90% of the particles by volume are below a particular size and 10% are above it, Dv50 means that 50% of the particles by volume are below a particular size and 50% are above it, and Dv10 means that 10% of the particles by volume are below this size and 90% are above it.

[0093] In one preferred embodiment, the composition comprises micronized ezetimibe having a Dv90 of 10 μm or less, preferably in the range of 4-10 μm, more preferably 8.5 μm or less; a Dv50 of 4 μm or less, preferably in the range of about 1-4 μm, more preferably 3.8 μm or less, and a Dv10 of 1 μm or less.

[0094] In another preferred embodiment, the composition comprises micronized obicetrapib having a Dv90 of 14 μm or less, preferably in the range of about 5-14 μm; a Dv50 of 5 μm or less, preferably in the range of about 3-5 μm; and a Dv10 of 3 μm or less.

[0095] The pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients. Excipients include, but are not limited to, one or more binders, surfactants, disintegrants, glidants, lubricants, diluents, chelating agents, desiccants, or absorbents. The following references disclose techniques and excipients used in formulating oral dosage forms. See: "The Handbook of Pharmaceutical Excipients", 9th edition, Rowe et al., Eds., American Pharmaceuticals Association (2020); and "Remington: The Science and Practice of Pharmacy", 22nd edition, Gennaro, Ed., Lippincott Williams & Wilkins (2013).

[0096] The one or more binders used in the pharmaceutical composition are preferably selected from the following: cellulose derivatives such as methylcellulose and carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, and hydroxyethylcellulose, gelatin, glucose, sucrose, lactose, dextrose, xylitol, sorbitol, maltitol, polymethacrylates, polyvinylpyrrolidone and its copolymers, starch paste, pregelatinized starch, tragacanth gum, alginic acid and its salts, such as sodium alginate, magnesium aluminum silicate, polyethylene glycol, guar gum, and bentonite. In a preferred embodiment, the binder is polyvinylpyrrolidone or a copolymer of polyvinylpyrrolidone. In a more preferred embodiment, the binder is copovidone. In an even more preferred embodiment, the binder is Kollidon 30.

[0097] The binder may typically be present in an amount of about 0.2% to about 10%, about 0.5% to about 5%, about 0.5% to about 2%, or about 0.5% to about 1%, preferably about 1.0±0.5%, by weight of the granule composition, and in another embodiment, by weight of the entire tablet.

[0098] The one or more surfactants used in the composition preferably have an HLB value selected from at least about 15, at least about 20, at least about 30, or at least about 40. One or more such surfactants are selected from the following: lauric acid, palmitic acid, stearic acid, and oleic acid or salts thereof, polyethylene glycol glycerides, polyoxyethylene monoesters, polyoxyethylene monostearate, polyoxyethylene monolaurate, polyoxyethylene sorbitan monooleate, polyethoxylated castor oil, polyethylene glycols having molecular weights ranging from about 2,000 to 10,000, propylene glycol caprylate, glycerol oleic acid and caprylate, and esters of glycerol and fatty acids. In a preferred embodiment, the one or more surfactants are selected from the following: dioctyl sodium sulfosuccinate, Capmul PG-8, Capryol 90, Capmul MCM, polysorbate 20, polysorbate 40, or polysorbate 80, or sodium lauryl sulfate. In a more preferred embodiment, the surfactant is sodium lauryl sulfate, such as Kolliphor SLS.

[0099] The surfactant may typically be present in an amount of about 0.2% to about 10%, about 0.5% to about 5%, about 0.5% to about 2%, or about 0.5% to about 1%, preferably about 1.0±0.5%, by weight of the granule composition in one embodiment, and by weight of the entire tablet in another embodiment.

[0100] In one embodiment, the composition comprises a binder:surfactant ratio ranging from about 0.05:5.0 to about 5.0:0.05, preferably from about 0.5:4.5 to about 4.5:0.5, more preferably from about 1:4 to about 4:1, even more preferably from about 1:2 to about 2:1, and most preferably about 1:1. Such a binder:surfactant ratio may be for a granular composition, such as an intragranular or extragranular composition, or for the entire composition of a tablet.

[0101] The pharmaceutical composition typically further comprises one or more disintegrants selected from cross-linked polyvinylpyrrolidone, croscarmellose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, alginic acid, sodium alginate, microcrystalline cellulose, sodium starch glycolate, or pregelatinized starch. In a preferred embodiment, the disintegrant is croscarmellose sodium or sodium starch glycolate. In a more preferred embodiment, the disintegrant is sodium starch glycolate.

[0102] In one embodiment, the disintegrant may be present in an amount of about 0.5% to about 10%, about 1% to about 8%, about 2% to about 5%, preferably about 2% to about 3%, about 4% to about 5%, or about 7% to about 8% by weight of the granular composition, and in another embodiment, of the total tablet weight.

[0103] The one or more diluents used in the pharmaceutical composition are preferably selected from the group consisting of inorganic phosphates such as dibasic calcium phosphate, or sugars or sugar analogs and derivatives thereof, particularly lactose, e.g., lactose monohydrate or anhydrous lactose, dextrose, sorbitol, mannitol, sucrose, maltodextrin, isomaltose, or cellulose, such as microcrystalline cellulose or powdered cellulose. In a preferred embodiment, the diluent is selected from lactose, e.g., lactose monohydrate, microcrystalline cellulose, and mannitol, or a mixture thereof. In a more preferred embodiment, the intragranular component contains microcrystalline cellulose and lactose monohydrate as diluents. In another preferred embodiment, microcrystalline cellulose and mannitol are present as diluents in the extragranular component. In one embodiment, the diluent may be present in an amount of about 10% to about 95%, preferably about 40% to about 90%, more preferably about 60% to about 85%, and even more preferably about 70% to about 85% by weight of the granular composition, or in another embodiment, of the weight of the entire tablet.

[0104] The pharmaceutical composition can optionally be film-coated using techniques well known in the art, such as spray coating or dip coating in a conventional coating pan or fluidized bed processor. Alternatively, it can be coated using hot-melt techniques. The film coat comprises a film-forming polymer, one or more pharmaceutically acceptable excipients, and a pharmaceutically acceptable solvent. Examples of film-forming agents include, but are not limited to, cellulose derivatives such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxymethylethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and ethylcellulose; polyvinyl alcohol; waxes; fatty substances; or mixtures thereof. Alternatively, commercially available coating compositions containing film-forming polymers, such as those sold under various trade names, such as Opadry®, can be used for coating.

[0105] Examples of solvents used to prepare the coating solution are selected from the following: methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, or mixtures thereof. In a preferred embodiment, the film coating is a primary alcohol-free coating. Preferably, the primary alcohol-free coating is a coating prepared using water.

[0106] The lubricant present in the pharmaceutical dosage form is preferably selected from silicon dioxide, talc, magnesium stearate, etc. Preferred lubricants are silicon dioxide such as Aerosil® or magnesium stearate such as Ligamed MF 2V, or mixtures thereof. The lubricant may typically be present in an amount of about 0.1% to about 10%, about 0.1% to about 5%, or about 1% to about 2% by weight of the granule composition in one embodiment, and about 1% to about 2% by weight of the entire tablet in another embodiment.

[0107] The lubricant present in the pharmaceutical composition is preferably selected from the following: fatty acids or fatty acid derivatives, such as the alkali and earth alkali salts of stearic acid, lauric acid, and / or palmitic acid. A preferred lubricant is magnesium stearate, which may typically be present in an amount of about 0.1% to about 10%, about 0.1% to about 5%, or about 1% to about 2% by weight of the granule composition in one embodiment, and about 1% to about 2% by weight of the entire tablet in another embodiment.

[0108] Stability is an essential quality attribute of a pharmaceutical formulation, determining the shelf life of the composition, during which the composition is suitable for its intended use in terms of both efficacy and safety. The term stability of a pharmaceutical composition means that one or more parameters governing the physical and chemical integrity of the active pharmaceutical ingredient (API) remain within pharmaceutically acceptable standards throughout the product's shelf life. Typically, one or more such parameters are selected from the following: identification of the active ingredient in the composition by methods such as HPLC and / or UV spectroscopy; visual appearance of the composition; assay percentage of the active ingredient in the composition; individual and / or total percentages of related substances and / or impurities in the composition; content uniformity of the composition with respect to the active ingredient; dissolution rate; microbial limits; etc.

[0109] Pharmaceutical compositions often lose their efficacy and / or safety over time due to loss or degradation of the active ingredient or its conversion to impurities, commonly known as related substances. The stable fixed-dose pharmaceutical composition retains up to at least about 90% (w / w) of the desired potency for ezetimibe, as well as for obicetrapib.

[0110] Ezetimibe has been found to cause stability problems associated with its formulation due to interactions with excipients and / or formulation partners. Surprisingly, it has been found that fixed-dose pharmaceutical compositions effectively control the levels of individual and total related substances of ezetimibe during preparation and storage of the fixed-dose composition. In one embodiment, the stable fixed-dose pharmaceutical composition comprises an individual related substance of ezetimibe of about 5% (w / w) or less, preferably about 2% (w / w) or less, more preferably about 1% (w / w) or less, and even more preferably about 0.2% (w / w) or less; and a total related substance of ezetimibe of about 5% (w / w) or less, preferably about 2% (w / w) or less, more preferably about 1% (w / w) or less, and even more preferably about 0.5% (w / w) or less. In a preferred embodiment, the fixed-dose pharmaceutical composition comprises ezetimibe and obicetrapib, wherein the tetrahydropyran analog impurity of ezetimibe is less than or equal to about 2% (w / w), preferably less than or equal to about 0.5% (w / w), more preferably less than or equal to about 0.3% (w / w), and even more preferably less than or equal to about 0.2% (w / w).

[0111] In another embodiment, the stable fixed dose pharmaceutical composition comprises no more than about 5% (w / w), preferably no more than about 2% (w / w), more preferably no more than about 0.5% (w / w), even more preferably no more than about 0.3% (w / w), and most preferably no more than about 0.2% (w / w) of unspecified individual obicetrapib-related substances; and no more than about 5% (w / w), preferably no more than about 2% (w / w), more preferably no more than about 1% (w / w), and even more preferably no more than about 0.5% (w / w) of total obicetrapib-related substances.

[0112] Surprisingly, it has been found that under stability conditions of 40°C and 75% relative humidity, the pharmaceutical composition is stable for at least 1 month, preferably at least 3 months, and more preferably at least 6 months. In a preferred embodiment, the composition is stable under stability conditions of 40°C and 75% relative humidity for at least 3 months, preferably at least 6 months. In another preferred embodiment, the composition is stable under stability conditions of 25°C and 60% relative humidity for at least 3 months, 6 months, or 12 months. In yet another preferred embodiment, the composition is stable at room temperature for at least 6 months, 12 months, 18 months, or 24 months.

[0113] In one preferred embodiment, the pharmaceutical composition comprises: a. Below: i. Obicetrapib calcium equivalent to 10 mg of obicetrapib free acid; ii. anhydrous ezetimibe or a mixture of anhydrous ezetimibe and ezetimibe monohydrate equivalent to 10 mg of ezetimibe; iii. a 1:1 ratio of binder and surfactant (preferably, the binder and surfactant each comprise about 1±0.5% w / w of the intragranular component granules; more preferably, the binder is 1±0.5% w / w of polyvidone or polyvinylpyrrolidone and the surfactant is 1±0.5% w / w of sodium lauryl sulfate); iv. a disintegrant selected from croscarmellose sodium, pregelatinized starch, or sodium starch glycolate, more preferably sodium starch glycolate (preferably, the disintegrant is about 2-8% w / w, preferably 3-6% w / w, more preferably about 4.5±0.5% w / w of the intragranular component granules); v. one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol, or mannitol. and an intragranular component containing; b. Below: i. a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate, even more preferably about 4% to 6% w / w sodium starch glycolate; ii. optionally, a lubricant, preferably magnesium stearate, more preferably about 1%-2% w / w magnesium stearate; iii. optionally, a lubricant, preferably colloidal silicon dioxide or talc or both, more preferably about 1% to 2% w / w colloidal silicon dioxide or talc or both; iv. Optionally, one or more diluents selected from a disaccharide, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; a polysaccharide, preferably cellulose, more preferably microcrystalline cellulose; a sugar alcohol, preferably sorbitol, xylitol, or mannitol; more preferably mannitol or microcrystalline cellulose, even more preferably about 20% to about 50% w / w microcrystalline cellulose and about 1% to about 20% mannitol. Extragranular components containing A tablet formulation comprising or consisting of: c. Optionally, the composition comprises a film coating, preferably the film coating is free of primary alcohols, more preferably the film coating is free of polyethylene glycol.

[0114] In another preferred embodiment, the pharmaceutical composition comprises: a. Below: i. anhydrous ezetimibe or a mixture of anhydrous ezetimibe and ezetimibe hydrate equivalent to 10 mg of ezetimibe; ii. a 1:1 ratio of binder and surfactant (preferably, the binder and surfactant each comprise about 1±0.5% w / w of the intragranular component granules; more preferably, the binder is 1±0.5% w / w of polyvidone or polyvinylpyrrolidone and the surfactant is 1±0.5% w / w of sodium lauryl sulfate); iii. a disintegrant selected from croscarmellose sodium, pregelatinized starch, or sodium starch glycolate, more preferably sodium starch glycolate (preferably, the disintegrant is about 2-8% w / w, preferably 3-6% w / w, more preferably about 4.5±0.5% w / w of the intragranular component granules); iv. one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol, or mannitol. and an intragranular component containing; b. Below: i. Obicetrapib calcium equivalent to 10 mg of obicetrapib free acid; ii. a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate, even more preferably about 4% to 6% w / w of sodium starch glycolate; iii. optionally, a lubricant, preferably magnesium stearate, more preferably about 1% w / w magnesium stearate; iv. optionally, a lubricant, preferably colloidal silicon dioxide or talc or both, more preferably about 1% to 2% w / w colloidal silicon dioxide or talc or both; v. Optionally, one or more diluents selected from a disaccharide, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; a polysaccharide, preferably cellulose, more preferably microcrystalline cellulose; a sugar alcohol, preferably sorbitol, xylitol, or mannitol; more preferably mannitol or microcrystalline cellulose, even more preferably about 20% to about 50% w / w microcrystalline cellulose and about 1% to about 20% mannitol. Extragranular components containing A tablet formulation comprising or consisting of: c. Optionally, the composition comprises a film coating, preferably the film coating is free of primary alcohols, more preferably the film coating is free of polyethylene glycol.

[0115] In yet another preferred embodiment, the pharmaceutical composition comprises: a. Below: i. Obicetrapib calcium equivalent to 10 mg of obicetrapib free acid; ii. a 1:1 ratio of binder and surfactant (preferably, the binder and surfactant each comprise about 1±0.5% w / w of the intragranular component granules; more preferably, the binder is 1±0.5% w / w of polyvidone or polyvinylpyrrolidone and the surfactant is 1±0.5% w / w of sodium lauryl sulfate); iii. a disintegrant selected from croscarmellose sodium, pregelatinized starch, or sodium starch glycolate, more preferably sodium starch glycolate (preferably, the disintegrant is about 2-8% w / w, preferably 3-6% w / w, more preferably about 4.5±0.5% w / w of the intragranular component granules); iv. one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol, or mannitol. and an intragranular component containing; b. Below: i. anhydrous ezetimibe or a mixture of anhydrous ezetimibe and ezetimibe hydrate equivalent to 10 mg of ezetimibe; ii. a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate, even more preferably about 4% to 6% w / w of sodium starch glycolate; iii. optionally, a lubricant, preferably magnesium stearate, more preferably about 1%-2% w / w magnesium stearate; iv. optionally, a lubricant, preferably colloidal silicon dioxide or talc or both, more preferably about 1-2% w / w colloidal silicon dioxide or talc or both; v. Optionally, one or more diluents selected from a disaccharide, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; a polysaccharide, preferably cellulose, more preferably microcrystalline cellulose; a sugar alcohol, preferably sorbitol, xylitol, or mannitol; more preferably mannitol or microcrystalline cellulose, even more preferably about 20% to about 50% w / w microcrystalline cellulose and about 1% to about 20% mannitol. Extragranular components containing A tablet formulation comprising or consisting of: c. Optionally, the composition comprises a film coating, preferably the film coating is free of primary alcohols, more preferably the film coating is free of polyethylene glycol.

[0116] Another aspect relates to a pharmaceutical composition comprising obicetrapib and ezetimibe, or pharmaceutically acceptable salts, solvates, or co-crystals thereof, and a pharmaceutically acceptable carrier for use in treating adults with heterozygous familial hypercholesterolemia (HeFH) or pre-existing atherosclerotic cardiovascular (CV) disease (ASCVD) in a subject in need of further lowering of low-density lipoprotein cholesterol as an adjunct to diet and / or maximal tolerated lipid-lowering therapy.

[0117] A second aspect relates to the use of a fixed-dose pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the treatment of a subject in need of lowering LDL cholesterol and / or increasing HDL cholesterol.

[0118] In one embodiment, the subject has or has a history of hyperlipidemia or mixed dyslipidemia, heterozygous familial hypercholesterolemia (HeFH), or atherosclerotic cardiovascular disease (ASCVD).

[0119] In one embodiment, the subject is partially or completely intolerant to statins.

[0120] In one embodiment, the use of the pharmaceutical composition is for the treatment of subjects in need of further lowering of low-density lipoprotein cholesterol as an adjunct to dietary and / or maximally tolerated lipid-lowering therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or pre-existing atherosclerotic cardiovascular (CV) disease (ASCVD).

[0121] A third aspect relates to a method of treating a subject in need of lowering LDL cholesterol and / or increasing HDL cholesterol, said method comprising administering to said subject a therapeutically effective amount of a fixed-dose pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and one or more pharmaceutically acceptable excipients.

[0122] In one embodiment, the method is for treating a subject suffering from or having hyperlipidemia or mixed dyslipidemia, heterozygous familial hypercholesterolemia (HeFH), or pre-existing atherosclerotic cardiovascular disease (ASCVD).

[0123] In one embodiment, the subject is in need of further lowering of low-density lipoprotein cholesterol as an adjunct to diet and / or as maximal tolerated lipid-lowering therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or pre-existing atherosclerotic cardiovascular (CV) disease (ASCVD).

[0124] In one embodiment, the subject is partially or completely intolerant to statins.

[0125] A fourth aspect relates to a fixed-dose combination pharmaceutical composition of obicetrapib and ezetimibe, said pharmaceutical composition being considered suitable for said use according to the second aspect or said method of treatment according to the third aspect if: a. When the fixed dose pharmaceutical composition is orally administered to a subject; b. The subject's blood obicetrapib concentration is measured at one or more time points after administration to obtain a set of obicetrapib concentration / time data points to obtain the area under the curve (AUC); and c. The 90% confidence intervals of the geometric means of the area under the curve (AUC0-∞ and / or AUC0-t) and / or Cmax of obicetrapib are within 75% to 125%, preferably 80% to 125%, more preferably 90% to 110%, of the area under the curve (AUC0-∞ and / or AUC0-t) and / or Cmax of obicetrapib obtained upon oral administration of a reference pharmaceutical composition to similar subjects; wherein said reference composition comprises an equivalent dose of obicetrapib or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, and the reference composition is administered alone or as simultaneous or sequential co-administration with another pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate, or cocrystal thereof.

[0126] A fifth aspect relates to a fixed-dose combination pharmaceutical composition of obicetrapib and ezetimibe, said pharmaceutical composition being considered suitable for said use according to the second aspect or said method of treatment according to the third aspect if: a. the fixed-dose pharmaceutical composition is orally administered to a subject, and ezetimibe and / or ezetimibe glucoronide in the subject's blood is measured at one or more time points after administration to obtain a set of ezetimibe and / or ezetimibe glucoronide concentration / time data points, respectively, for determining the area under the curve (AUC) for ezetimibe and / or ezetimibe glucoronide, respectively; and b. Area under the curve (AUC) of ezetimibe and / or ezetimibe glucoronide 0-∞ and / or AUC 0-t ) and / or the 90% confidence interval of the geometric mean of Cmax is the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax within 75% to 125%, preferably 80% to 125%, more preferably 90% to 110%, respectively; wherein said reference composition comprises an equivalent dose of ezetimibe or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and the reference composition is administered alone or as simultaneous or sequential co-administration with another pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

[0127] In one embodiment for the use according to the above aspect, the t of AUC is selected from 48 hours (AUC), 72 hours (AUC), 96 hours (AUC), 144 hours (AUC), 192 hours (AUC), 240 hours (AUC), 336 hours (AUC) or AUC, preferably 48 hours (AUC), more preferably 72 hours (AUC) or AUC.

[0128] In one embodiment, the subject is a healthy human subject, preferably a tobacco-free, non-nicotine-using adult male or female human, more preferably a human between 18 and 65 years of age, and optionally, the human has a body weight of between 18.5 and 29.9 Kg / m 2 have a body mass index of

[0129] In another embodiment, the subject is a human in need of LDL cholesterol reduction and / or HDL cholesterol increase. In a preferred embodiment, the human suffers from or has a history of hyperlipidemia or mixed dyslipidemia, heterozygous familial hypercholesterolemia (HeFH), or atherosclerotic cardiovascular disease (ASCVD).

[0130] In one embodiment, the human is partially or completely intolerant to statins.

[0131] Preferably, said human subject has an LDL-cholesterol level of ≧70 mg / d, and optionally said human is not adequately controlled by current lipid-modifying therapy.

[0132] For use in the pharmaceutical composition or method of treatment according to other embodiments, the composition may be administered to a subject in need thereof to deliver a total daily oral dose of 5 mg obicetrapib and 10 mg ezetimibe, 10 mg obicetrapib and 10 mg ezetimibe, or 20 mg obicetrapib and 20 mg ezetimibe, preferably the subject is administered the composition to deliver a daily oral dose of 10 mg obicetrapib and 10 mg ezetimibe.

[0133] Unexpectedly, the dissolution profiles of ezetimibe from the fixed-dose combinations were found to be non-inferior, or in some cases superior, to the marketed ezetimibe formulation (Zetia®), as detailed in the Examples section. Surprisingly, the fixed-dose combination compositions disclosed herein were also found to be bioequivalent to the monotherapeutic combinations co-administered to human subjects. The 90% confidence intervals for the geometric mean ratios of AUC0-t, AUC0-∞, and Cmax for obicetrapib, ezetimibe, and ezetimibe glucoronide from two of the representative compositions (FDC1 and FDC2) were found to be 75% to 125%, preferably 80% to 125%, and more preferably 90% to 110%, of those obtained from co-administration of identical doses of monotherapeutic formulations of ezetimibe and obicetrapib, respectively, as detailed in the Examples section below.

[0134] The fixed-dose combination pharmaceutical compositions of obicetrapib and ezetimibe are further illustrated in detail by the following non-limiting examples.

[0135] Therapeutic Methods of the Present Invention As explained hereinabove, the present invention provides methods for the curative and / or prophylactic treatment of a subject in need thereof. More particularly, the present invention provides methods for the treatment and / or prevention of cardiovascular disease, in particular atherosclerotic cardiovascular disease, in such a subject using a composition as defined herein. The present invention further provides methods for the treatment and / or prevention of one or more symptoms associated with (atherosclerotic) cardiovascular disease in such a subject using a composition as defined herein. The present invention further provides methods for the treatment and / or prevention of one or more pathologies associated with and / or caused by (atherosclerotic) cardiovascular disease in such a subject using a composition as defined herein. The present invention further provides methods for the treatment and / or prevention of one or more etiologic factors associated with (atherosclerotic) cardiovascular disease, e.g., elevated LDL-C levels and / or elevated ApoB levels, in such a subject using a composition as defined herein. The present invention further provides methods for alleviating and / or ameliorating resistance or hyporesponsiveness to statin therapy, particularly high-intensity statin therapy, in such subjects using the compositions defined herein.

[0136] The terms "treat," "treating," or "treatment," when used in connection with a particular disease or condition (e.g., "methods of treating a disease"), refer to curing, alleviating, or eliminating the disease and / or associated symptoms, reducing the extent of the disease, stabilizing the condition (i.e., not worsening), delaying or slowing the progression of the disease, ameliorating the condition, prolonging survival (compared to expected survival in the absence of treatment), and the like. As used herein, the terms "prevent," "preventing," or "prevention" refer to reducing a subject's risk of acquiring the disease and / or associated symptoms, delaying the time by which a subject acquires the disease, and the like. The terms "treat," "treating," or "treatment," when used in reference to a patient or subject (e.g., "methods of treating a subject"), typically refer to the act of administering a therapeutic compound to the patient or subject, whether for therapeutic and / or prophylactic purposes.

[0137] As used herein, the term "cardiovascular disease" has its conventional meaning as referring to a disease or condition in which the function of a subject's cardiovascular system is impaired. Examples of cardiovascular diseases include: thromboembolic disease (e.g., arterial, venous, or ventricular thromboembolic disorders); atherosclerosis; hypertensive heart disease; coronary artery disease; carotid artery disease; stroke; peripheral artery disease with atherosclerosis; restenosis; arteritis; myocarditis; cardiovascular inflammation; vascular inflammation; coronary heart disease (CHD); unstable angina (UA); unstable angina (UA). These include refractory angina, stable angina (SA), chronic stable angina, acute coronary syndrome (ACS), myocardial infarction (first or recurrent), acute myocardial infarction (AMI), myocardial infarction, ischemic heart disease, cardiac ischemia, ischemia, sudden ischemic death, transient ischemic attack, stroke, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary artery thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, etc.

[0138] As used herein, the term "atherosclerotic cardiovascular disease" refers to a specific subset of cardiovascular diseases that include atherosclerosis as a component or precursor of a specific type of cardiovascular disease. Atherosclerosis is a chronic inflammatory reaction that occurs in the walls of arterial blood vessels associated with the accumulation of LDL-C. This leads to arterial narrowing ("stenosis") and is accompanied by the formation of atheromatous plaques, which may ultimately lead to partial or complete closure of the arterial opening and / or plaque rupture. Thus, atherosclerotic diseases or disorders include the consequences of atheromatous plaque formation and rupture, including, but not limited to, arterial stenosis or narrowing, heart failure, aneurysm formation, including aortic aneurysm, aortic dissection, and ischemic events such as myocardial infarction and stroke.

[0139] In particularly preferred embodiments, the atherosclerotic cardiovascular disease and / or conditions associated with atherosclerotic cardiovascular disease that may be advantageously treated and / or prevented in accordance with the present invention are selected from the group consisting of arteriosclerosis, peripheral vascular disease, hyperlipidemia, mixed dyslipidemia, abetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, angina pectoris, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, cerebral infarction and stroke.

[0140] As will be apparent from the present teachings, the methods of the present invention are effective and / or intended to reduce and / or normalize LDL-C plasma levels. In particular, the methods of the present invention are effective and / or intended to reduce LDL-C plasma levels by at least 5%, more preferably at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% from baseline (baseline defined as the start of treatment with obicetrapib and ezetimibe). In another embodiment, the method is effective in and / or is intended to reduce LDL-C plasma levels by at least 5 mg / dL, more preferably at least 10 mg / dL, at least 15 mg / dL, at least 20 mg / dL, at least 25 mg / dL, at least 30 mg / dL, at least 35 mg / dL, or at least 40 mg / dL from baseline (baseline being defined as the start of treatment with obicetrapib and ezetimibe). In yet another embodiment, the method is effective in and / or is intended to reduce LDL-C plasma levels to levels below 85 mg / dL, preferably below 80 mg / dL, below 75 mg / dL, below 70 mg / dL, below 65 mg / dL, below 60 mg / dL, below 55 mg / dL, or below 50 mg / dL.

[0141] As will become apparent from the present teachings, administering ezetimibe (or a pharmaceutically acceptable salt, solvate, or cocrystal thereof) in addition to obicetrapib (or a pharmaceutically acceptable salt, solvate, or cocrystal thereof) results in a significant enhancement of LDL-C lowering, in particular a supra-additive or synergistic enhancement. More particularly, the present methods of administering ezetimibe (or a pharmaceutically acceptable salt, solvate, or cocrystal thereof) to enhance the LDL-C lowering effect of obicetrapib as defined herein are intended to be effective and / or further reduce LDL-C plasma levels by at least 20%, more preferably at least 22.5%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, or at least 30%, compared to methods based on treatment with obicetrapib or a pharmaceutically acceptable salt, solvate, or cocrystal thereof alone (or at least, without ezetimibe). In another embodiment, these methods are effective in and / or are intended to further reduce LDL-C plasma levels by at least 20 mg / dL, more preferably at least 22.5 mg / dL, at least 25 mg / dL, at least 27.5 mg / dL, at least 30 mg / dL, at least 32.5 mg / dL, or at least 35 mg / dL, compared to methods based on treatment with obicetrapib, or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, alone (or at least, without ezetimibe).

[0142] In a preferred embodiment of the present invention, the method is effective and / or intended to reduce and / or normalize ApoB plasma levels. In particular, the method is effective and / or intended to reduce ApoB plasma levels by at least 5%, more preferably at least 10%, at least 15%, at least 20%, at least 22.5%, at least 25%, or at least 27.5% from baseline (wherein baseline is defined as the start of treatment with obicetrapib and ezetimibe). In another embodiment, the method is effective and / or intended to reduce ApoB plasma levels by at least 5 mg / dL, more preferably at least 5 mg / dL, at least 10 mg / dL, at least 15 mg / dL, at least 20 mg / dL, at least 22.5 mg / dL, at least 25 mg / dL, or at least 27.5 mg / dL from baseline (wherein baseline is defined as the start of treatment with obicetrapib and ezetimibe). In yet another embodiment, the method is effective in and / or is intended to reduce ApoB plasma levels to levels below 80 mg / dL, preferably below 75 mg / dL, below 70 mg / dL, below 65 mg / dL, below 60 mg / dL, below 57.5 mg / dL, or below 55 mg / dL.

[0143] In preferred embodiments of the present invention, the methods are effective in and / or are intended to reduce and / or normalize Lp(a) plasma levels. In particular, the methods are effective in and / or are intended to reduce Lp(a) plasma levels by at least 5%, more preferably at least 7.5%, at least 10%, at least 12.5%, at least 15%, at least 17.5%, or at least 20% from baseline (baseline defined as the start of treatment with obicetrapib and ezetimibe). In another embodiment, the method is effective in and / or is intended to reduce Lp(a) plasma levels by at least 5 nmol / L, more preferably at least 10 nmol / L, at least 15 nmol / L, at least 20 nmol / L, at least 25 nmol / L, at least 30 nmol / L, at least 35 nmol / L, or at least 40 nmol / L from baseline (baseline being defined as the start of treatment with obicetrapib and ezetimibe). In yet another embodiment, the method is effective in and / or is intended to reduce Lp(a) plasma levels to levels below 110 nmol / L, preferably below 105 nmol / L, below 100 nmol / L, below 95 nmol / L, below 90 nmol / L, below 85 nmol / L, or below 80 nmol / L.

[0144] In some embodiments of the present invention, the method is effective and / or intended to alleviate and / or improve resistance or hyporesponsiveness to statin therapy, particularly high-intensity statin therapy. High-intensity statin therapy is a term commonly used in the art and refers to a regimen based on the maximum tolerated dose of a statin that has the highest efficacy in lowering LDL-C, particularly a regimen that typically shows an LDL-C reduction of ≥ 50% in normally responsive subjects. Among the statins currently in clinical use, only 20 mg (daily) or 40 mg (daily) rosuvastatin and 40 mg (daily) or 80 mg (daily) atorvastatin meet this criterion. In the context of the present invention, hyporesponsiveness to HIS therapy means that a subject receiving HIS therapy does not achieve a 35% LDL-C reduction; preferably, it means that a subject receiving HIS therapy does not achieve a 30%, 25%, 20%, 15%, or 10% LDL-C reduction. Alleviating and / or improving hyporesponsiveness to HIS therapy means that the difference between the subject's response (LDL-C reduction) and the (average) response of normal-responding subjects is reduced. In a further embodiment of the present invention, the method is effective and / or intended to normalize responsiveness to statin therapy.

[0145] As previously described herein, the methods of the present invention are directed to the treatment and / or prevention of subjects suffering from or at risk of suffering from CVD, particularly ASCVD.

[0146] The term "subject" refers to an organism, typically a mammal, particularly a human subject, suffering from or susceptible to a disease or condition that can be treated using the compositions provided herein.

[0147] In a particularly preferred embodiment of the present invention, the subject is a subject diagnosed with CVD, particularly ASCVD.

[0148] In a further preferred embodiment of the invention, the subject is one who is considered to be at risk, typically above average risk, of developing CVD, particularly ASCVD, as can be determined, for example, by a medical professional.

[0149] In a preferred embodiment of the present invention, the subject is a subject suffering from one or more conditions known to have a causal and / or epidemiological correlation with the occurrence of (AS)CVD, such as diabetes, hypertension, hypercholesterolemia, including overweight / obesity, metabolic syndrome, etc. In another preferred embodiment of the present invention, the subject is a subject with a genetic predisposition to developing (AS)CVD. In yet another preferred embodiment of the present invention, the subject is a subject who is susceptible to developing (AS)CVD as a result of lifestyle / habitual factors, such as an unhealthy diet, lack of exercise, alcohol consumption, smoking, etc.

[0150] According to a preferred embodiment of the present invention, the subject to be treated has an elevated LDL-C plasma level, typically at least 70 mg / dL, more preferably at least 75 mg / dL, at least 80 mg / dL, at least 85 mg / dL, at least 90 mg / dL, at least 95 mg / dL, or at least 100 mg / dL. Furthermore, according to a preferred embodiment of the present invention, the subject has an LDL-C plasma level that is at least 125%, e.g., at least 150%, at least 175%, or at least 200% of the average LDL-C plasma level in healthy subjects. Normal LDL-C (reference) values ​​typically vary depending on gender and age.

[0151] According to a preferred embodiment of the present invention, the subject to be treated has an elevated ApoB plasma level, typically at least 70 mg / dL, more preferably at least 75 mg / dL, at least 80 mg / dL, at least 85 mg / dL, at least 90 mg / dL, at least 95 mg / dL, or at least 100 mg / dL. Furthermore, according to a preferred embodiment of the present invention, the subject has an ApoB plasma level that is at least 125%, e.g., at least 150%, at least 175%, or at least 200% of the average ApoB plasma level in healthy subjects. Normal ApoB (reference) values ​​typically vary depending on gender and age.

[0152] According to a preferred embodiment of the present invention, the subject to be treated has an elevated plasma level of non-HDL-C, typically at least 100 mg / dL, more preferably at least 105 mg / dL, at least 110 mg / dL, at least 115 mg / dL, at least 120 mg / dL, at least 125 mg / dL, or at least 130 mg / dL. Furthermore, according to a preferred embodiment of the present invention, the subject has a non-HDL-C plasma level that is at least 125%, e.g., at least 150%, at least 175%, or at least 200% of the average non-HDL-C plasma level in healthy subjects. Normal non-HDL-C (reference) values ​​typically vary depending on gender and age.

[0153] In one embodiment of the invention, the subject is a male human. In another embodiment of the invention, the subject is a female human.

[0154] In further preferred embodiments of the invention, the subject is at increased risk based on age, for example, the subject is 35 years of age or older, 40 years of age or older, 45 years of age or older, 50 years of age or older, 55 years of age or older, 60 years of age or older, 65 years of age or older, or 70 years of age or older; typically in combination with one or more other risk factors defined herein.

[0155] According to certain embodiments of the present invention, the subject being treated exhibits poor response to statin therapy, particularly HIS therapy. High-intensity statin therapy is a term commonly used in the art and refers to a regimen based on the maximum tolerated dose of a statin that is most effective in lowering LDL-C, particularly a regimen that typically shows a ≥ 50% LDL-C reduction in normally responsive subjects. In current clinical practice, only 20 mg / day or 40 mg / day of rosuvastatin and 40 mg / day or 80 mg / day of atorvastatin are considered HIS therapy. In a preferred embodiment of the present invention, the subject is receiving HIS therapy and has not achieved a 35% LDL-C reduction, preferably a 30%, 25%, 20%, 15%, or 10% LDL-C reduction. In a preferred embodiment of the present invention, the subject's hyporesponsiveness to statin therapy, in particular HIS therapy, is confirmed after at least 1 month (continuously) of HIS therapy, more preferably after at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months.

[0156] The various aspects of the invention defined herein all relate to methods of treatment involving the administration, typically repeated administration, of a composition comprising obicetrapib or a salt or solvate / hydrate thereof, preferably any of the compositions defined herein above.

[0157] Thus, in particularly preferred embodiments of the invention, the method comprises administering a dose of at least 1 mg, preferably at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 7 mg, at least 8 mg, or at least 9 mg, e.g., about 10 mg, of obicetrapib; or an equiconcentrated dose of a salt, solvate, or cocrystal of obicetrapib. According to various aspects of the invention, the method comprises administering a dose of obicetrapib of 100 mg or less, more preferably 75 mg or less, 50 mg or less, 40 mg or less, 30 mg or less, 20 mg or less, 15 mg or less, 12.5 mg or less, 12 mg or less, or 11 mg, or an equiconcentrated dose of a salt, solvate, or cocrystal of obicetrapib. According to various aspects of the invention, the methods comprise administering a dose of obicetrapib in the range of 1 to 100 mg, 2 to 50 mg, 3 to 50 mg, 4 to 25 mg, 4.5 to 15 mg, or 5 to 10 mg; or an equiconcentrated dose of a salt, solvate, or cocrystal of obicetrapib. In certain preferred embodiments, the methods comprise administering a dose of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg of obicetrapib; or an equiconcentrated dose of a salt, solvate, or cocrystal of obicetrapib. In certain particularly preferred embodiments, the methods comprise administering a dose of 5, 7.5, 10, 12.5, or 15 mg of obicetrapib; or an equiconcentrated dose of a salt, solvate, or cocrystal of obicetrapib.

[0158] In a particularly preferred embodiment of the present invention, the treatment comprises the repeated administration of a composition containing obicetrapib or a salt, hydrate or solvate thereof, preferably at a dose within the ranges already defined herein. In a particularly preferred embodiment of the present invention, the treatment comprises the repeated administration of a composition at a frequency of at least once every two days or at least once a day, preferably at a dose within the ranges already defined herein. In a particularly preferred embodiment of the present invention, the treatment comprises the repeated administration of a composition at a frequency of 1 to 4 times a day, preferably at a dose within the ranges already defined herein. In a particularly preferred embodiment of the present invention, the method comprises the administration of a composition containing obicetrapib or a salt, hydrate or solvate thereof, once or twice a day, most preferably twice a day, at a dose range as defined above.

[0159] Thus, in particularly preferred embodiments of the invention, the methods comprise administering a daily dose of at least 1 mg, preferably at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 7 mg, at least 8 mg, or at least 9 mg, e.g., about 10 mg, of obicetrapib; or an equiconcentrated dose of a salt, solvate, or cocrystal of obicetrapib. According to various aspects of the invention, the methods comprise administering a daily dose of obicetrapib of 100 mg or less, more preferably 75 mg or less, 50 mg or less, 40 mg or less, 30 mg or less, 20 mg or less, 15 mg or less, 12.5 mg or less, 12 mg or less, or 11 mg; or an equiconcentrated dose of a salt, solvate, or cocrystal of obicetrapib. According to various aspects of the invention, the methods comprise administering a daily dose of obicetrapib in the range of 1 to 100 mg, 2 to 50 mg, 3 to 50 mg, 4 to 25 mg, 4.5 to 15 mg, or 5 to 10 mg; or an equiconcentrated dose of a salt, solvate, or cocrystal of obicetrapib. In certain preferred embodiments, the methods comprise administering a daily dose of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg of obicetrapib; or an equiconcentrated dose of a salt, solvate, or cocrystal of obicetrapib. In certain particularly preferred embodiments, the methods comprise administering a daily dose of 4, 5, 7.5, 10, 12.5, or 15 mg of obicetrapib; or an equiconcentrated dose of a salt, solvate, or cocrystal of obicetrapib.

[0160] Based on the teachings of the present invention, it will be clear to those skilled in the art that the method of the present invention further includes simultaneous treatment with ezetimibe. To this end, ezetimibe and obicetrapib (or a therapeutically acceptable salt, solvate, or cocrystal thereof) may be administered simultaneously, before or after each other, sequentially or simultaneously, or at different times. In a preferred embodiment of the present invention, obicetrapib and ezetimibe are administered at equal frequencies and intervals, more preferably once a day, even more preferably at the same time each day, as two separate unit dosage forms, preferably in the form of a fixed-dose combination formulation as defined herein, sequentially or simultaneously. In preferred embodiments, the methods of the invention comprise the administration of a daily dose of ezetimibe of 1 to 30 mg, 2 to 25 mg, 3 to 20 mg, 4 to 17.5 mg, or 5 to 15 mg, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg, most preferably about 10 mg; or an equipotent dose of a salt, solvate, or co-crystal of ezetimibe.

[0161] Based on the teachings of the present invention, it will be apparent to those skilled in the art that, in some embodiments, the method of the present invention further comprises simultaneous treatment with an HMG-CoA reductase inhibitor, preferably simultaneous treatment with a concomitant HIS therapy. To this end, the HMG-CoA reductase inhibitor and obicetrapib (or a therapeutically acceptable salt, solvate, or cocrystal thereof) may be administered simultaneously, before or after each other, sequentially or simultaneously, or at different times. In a preferred embodiment of the present invention, the administration frequency and intervals of obicetrapib and the HMG-CoA reductase inhibitor are equal, more preferably once a day, even more preferably at the same time each day, sequentially or simultaneously, as two separate unit dosage forms or in the form of a fixed-dose combination preparation. In preferred embodiments, the methods of the present invention comprise the administration of a daily dose of 10 to 50 mg, 15 to 45 mg, 17.5 to 42.5 mg, or 20 to 40 mg, e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45 mg, most preferably about 20 mg or 40 mg; or an equiconcentrated dose of a salt, solvate, or co-crystal of rosuvastatin. In preferred embodiments, the methods of the present invention involve administration of a daily dose of atorvastatin of 30 to 90 mg, 35 to 85 mg, 37.5 to 82.5 mg, or 40 to 80 mg, e.g., 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, or 85 mg, most preferably about 40 mg or 80 mg; or an equipotent dose of a salt, solvate, or cocrystal of atorvastatin. In certain preferred embodiments, the methods of the present invention do not include concomitant treatment with an HMG-CoA reductase inhibitor.

[0162] Based on the present teachings, it will be clear to those skilled in the art that the daily doses set forth herein may be contained not only in a single unit dosage form, but also in multiple unit dosage forms. In the most preferred embodiment of the present invention, the method comprises a single daily administration of obicetrapib (or a salt, hydrate, or solvate thereof) at the dose set forth herein. However, a method is also contemplated that comprises administering two unit dosage forms, each containing approximately half of the daily dose set forth above, at predetermined scheduled times during the day, for example, once in the morning, such as immediately after the subject wakes up, and once in the evening, such as at dinnertime or around bedtime. Embodiments are also contemplated in which unit dosage forms containing greater amounts of obicetrapib and / or ezetimibe than the daily doses set forth herein are used. This may involve, for example, using sustained-release dosage forms that remain in the body and continue to release the active ingredients for a sufficiently long period of time.

[0163] In embodiments, methods and / or compositions for use according to the invention are provided, wherein said methods and / or uses comprise administering, preferably repeatedly administering, obicetrapib and ezetimibe (or salts, hydrates or solvates thereof), preferably in the form of a fixed-dose pharmaceutical composition as defined herein, to a subject at a dose and frequency effective to reduce the subject's LDL-C plasma level, the subject's ApoB plasma level and / or the subject's Lp(a) plasma level, more preferably to achieve a reduction in one or more of the subject's LDL-C plasma level, the subject's ApoB plasma level and / or the subject's Lp(a) plasma level within the ranges described elsewhere herein. In particularly preferred embodiments of the invention, these treatments comprise the repeated administration of obicetrapib and ezetimibe (or salts, hydrates or solvates of obicetrapib and / or ezetimibe), preferably in the form of a fixed-dose pharmaceutical composition as defined herein, according to the regimen defined above, over a period of at least 1 month, at least 3 months, at least 4 months, at least 6 months, at least 9 months, at least 1 year, at least 2 years, at least 3 years, at least 5 years, at least 10 years, at least 20 years, at least 30 years. There is no particular upper limit; treatment can continue for as long as is considered beneficial to the subject's overall health and well-being (as determined by an appropriately qualified medical professional), e.g., for the duration of the subject's life.

[0164] The pharmaceutical kit of the present invention Another aspect of the present invention relates to a pharmaceutical kit comprising a package containing a plurality of unit dosage forms and a leaflet, wherein said unit dosage forms comprise a pharmaceutical composition according to the present invention and said leaflet comprises printed instructions for repeated self-administration of said unit dosage forms to achieve any of the therapeutic objectives defined herein, for example to treat and / or prevent any cardiac disease or dysfunction as defined herein.

[0165] According to an embodiment of the present invention, the pharmaceutical kit comprises a container, such as a cardboard box, holding one or more blister packs, said one or more blister packs comprising a plurality of solid unit dosage forms as previously defined herein, preferably a plurality of tablets as previously defined herein. In particularly preferred embodiments of the present invention, the pharmaceutical kit comprises at least 5, at least 8, at least 10, at least 12, or at least 15 of said unit dosage forms, such as 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 of said unit dosage forms. In one embodiment of the present invention, the pharmaceutical kit comprises only unit dosage forms, as defined herein, comprising obicetrapib as the sole active ingredient. In one embodiment of the present invention, the pharmaceutical kit comprises a plurality of unit dosage forms as defined herein comprising obicetrapib (or a salt, hydrate, or solvate thereof) as the sole active ingredient, and a plurality, preferably an equal number, of unit dosage forms comprising ezetimibe as the sole active ingredient, typically in the dosage amounts described elsewhere herein. In one embodiment of the present invention, the pharmaceutical kit comprises only a plurality of unit dosage forms as defined, each unit dosage form comprising obicetrapib (or a salt, hydrate, or solvate thereof) and ezetimibe (or a salt, hydrate, or solvate thereof), more preferably a plurality of fixed-dose pharmaceutical compositions as defined herein. In some embodiments, the pharmaceutical kit as defined herein may further comprise a plurality of unit dosage forms comprising an HMG CoA reductase inhibitor, preferably atorvastatin or rosuvastatin (or a salt, hydrate, or solvate thereof), as the sole active ingredient, typically in the dosage amounts described elsewhere herein.

[0166] In accordance with the present invention, the pharmaceutical kit includes a leaflet, typically a patient information leaflet containing printed information, to be inserted into the container, which may include a description of the form and composition of the unit dosage forms included in the kit, an indication of the therapeutic indication for which the formulation is intended, instructions on how to use the formulation, and information and warnings regarding side effects and contraindications associated with use. Based on the information provided herein, those skilled in the art will understand that the leaflet that is part of the kit according to the present invention will typically contain information regarding the therapeutic indications, uses, treatment regimens, etc., as described above in connection with the treatment methods of the present invention. In particularly preferred embodiments of the present invention, the leaflet includes printed instructions for repeated (self-)administration of the unit dosage forms to treat and / or prevent CVD, particularly ASCVD.

[0167] The treatment methods of the present invention based on the combination therapy of obicetrapib and ezetimibe are further illustrated by the non-limiting examples set forth herein below.

[0168] Amorphous calcium salt form of obicetrapib In certain preferred embodiments of the present invention, the obicetrapib contained in the pharmaceutical composition used in the present methods, such as in a unit dosage form (included in a pharmaceutical kit), is a salt form of obicetrapib, more particularly amorphous obicetrapib calcium salt, and especially amorphous obicetrapib hemi-calcium.

[0169] The amorphous obicetrapib hemi-calcium of the present disclosure is different from and distinguishable from the crystalline obicetrapib hemi-calcium disclosed in U.S. Patent No. 7,872,126. X-ray powder diffraction is a common technique used to distinguish crystalline from amorphous materials. However, this technique has limitations, especially when the crystalline material is disordered. In the case of amorphous obicetrapib hemi-calcium, X-ray powder diffraction patterns of two different lots of amorphous obicetrapib hemi-calcium are shown in Figures 49 and 50. These patterns exhibit the well-known "halo" characteristic associated with amorphous materials. The X-ray powder diffraction pattern in Figure 50 exhibits peaks at approximately 3.4° 2θ, approximately 7.0° 2θ, and approximately 9.2° 2θ. Similarly, another sample in Figure 51 exhibits X-ray powder diffraction peaks at approximately 3.4° 2θ, approximately 7.0° 2θ, and approximately 9.2° 2θ. The X-ray powder diffraction pattern of any of Figures 49, 50, or 51 can be used to characterize amorphous obicetrapib hemi-calcium, although occasionally there is a sharper higher angle peak, such as that seen at approximately 31.7°2θ (e.g., Figure 50), which, when present, is due to sodium chloride. In Figure 51, peaks at approximately 3.4°2θ, approximately 7.0°2θ, and approximately 9.2°2θ were observed in another sample of amorphous obicetrapib hemi-calcium. The peak at approximately 5.6°2θ in Figure 51 was determined to be due to the Kapton foil used in the measurement setup described in Example 11.20. The X-ray powder pattern of crystalline obicetrapib hemi-calcium prepared in Example 11.16 is shown in Figure 54. This also shows halo-like behavior, which would be indicative of disorder in a crystalline compound.

[0170] Examples 11.18, 11.19, 11.20, and 11.21 illustrate various X-ray powder diffraction procedures. The procedure of Example 11.18 was generally used to collect the data shown in Figures 49, 54, 55, and 56; Example 11.19 was generally used for Figure 50; Example 11.20 was generally used for Figure 51; and Example 11.21 was generally used for Figures 66, 67, and 68 (Figure 68 relates to Compound 1D, not crystalline obicetrapib hydrochloride).

[0171] The use of the term "amorphous" in "amorphous obicetrapib hemi-calcium" does not mean that there is no order in the material. There is still order in the sample, as evidenced by the presence of peaks in the X-ray powder diffraction pattern. Thus, as used herein, the term "amorphous" in "amorphous obicetrapib helicalcium" does not mean that the X-ray powder diffraction pattern must contain a purely amorphous halo (although it may contain halo-like features). Rather, it means that there is disorder, but that the amorphous phase is distinguishable from the crystalline phase, as described below.

[0172] Another technique that can be used to distinguish crystalline from amorphous materials is polarized light microscopy ("PLM"). In PLM, anisotropic (e.g., crystalline) or isotropic (e.g., amorphous compounds) materials can be distinguished by viewing the material through polarized light and then viewing the material through crossed polarizers. Anisotropic materials exhibit birefringence when exposed to polarized light through crossed polarizers, which indicates a change in color through the crossed polarizers. On the other hand, isotropic materials do not exhibit birefringence and do not show a change in color when exposed to polarized light.

[0173] In Figure 57, amorphous obicetrapib hemi-calcium was analyzed by polarized light microscopy, as described in Example 11.17. As Figure 57 shows, the material under test does not exhibit birefringence, indicating that the material is amorphous. In comparison, Figure 58 is a polarized light micrograph of crystalline obicetrapib hemi-calcium prepared according to Example 11.16. Notably, the particles shown in Figure 58 (which is black and white) exhibit much brighter contrast. In the corresponding color version, the image is multicolored. Thus, Figure 58 demonstrates crystallinity. Furthermore, the crystals in Figure 58 are larger than the particles provided in the polarized light micrograph of amorphous obicetrapib hemi-calcium in Figure 57. Therefore, PLM and / or the lack of birefringence can be used to characterize amorphous obicetrapib hemi-calcium.

[0174] Additionally, other techniques can be used to distinguish amorphous obicetrapib hemi-calcium from crystalline obicetrapib hemi-calcium and therefore characterize it. One such technique is modulated differential scanning calorimetry, also known as "mDSC." The difference in the amount of heat required to raise the temperature of a sample compared to a reference is measured as a function of temperature and can be measured using modulated differential scanning calorimetry (mDSC). mDSC thermograms can also measure glass transition temperatures, which can be used to characterize amorphous materials. In Figure 60, the procedure for which is described in Example 11.25, an mDSC thermogram of amorphous obicetrapib hemi-calcium was measured using an open sample holder that allowed volatile gases to escape during the measurement. In Figure 60, the opening was created by drilling a hole in the pan lid. A glass transition temperature of approximately 110°C was reported for this sample.

[0175] With respect to thermal measurements, the term "about" generally refers to a variation of plus or minus 1°C. In comparison, crystalline obicetrapib hemi-calcium has a higher glass transition temperature under the same conditions, with the three measurements in Figure 62 showing a range of about 118°C to about 125.5°C. In some embodiments, the glass transition temperature of amorphous obicetrapib hemi-calcium is about 109°C to 112°C, as measured by pinhole. In one sample from Example 11.26, the glass transition temperature of amorphous obicetrapib hemi-calcium was found to be about 111°C (111.32°C midpoint), as shown in Figure 61. The onset temperature was measured to be about 102°C (101.62°C) and the endpoint temperature was measured to be about 118°C (117.58°C).

[0176] The glass transition temperature of amorphous obiscetrapib hemi-calcium can also be measured using a DSC with a sealed pan. The type of sample preparation can affect the measured glass transition temperature. In such cases, the glass transition temperature may decrease to temperatures below about 100°C, particularly from about 70°C to about 92°C, depending on humidity.

[0177] Other thermal techniques, such as thermogravimetric analysis (TGA), can also be used to analyze and characterize amorphous obicetrapib hemi-calcium. Figure 59 is a thermogravimetric analysis thermogram of amorphous obicetrapib hemi-calcium, showing a weight loss of less than 1% when heated to about 200°C. Such weight loss can be, for example, about 0.8% to about 0.95%, including about 0.84% ​​to about 0.92%. In Figure 59, the weight loss was determined to be about 0.85%. The moisture content of this particular material was about 1.5%. In some embodiments, the moisture content may be higher, including in the range of about 0% to about 5% by weight, such as up to about 4% by weight, up to about 3% by weight, and between about 0.5% and 1.5% by weight.

[0178] solid 13 C-NMR spectroscopy is another technique that can be used to characterize amorphous materials. Figure 63 shows the solid state images of crystalline and amorphous obiscetrapib hemi-calcium. 13Figures 64 and 65 show the C-NMR spectra of crystalline and amorphous obicetrapib hemi-calcium, respectively. There are at least two differences in the spectra. The crystalline phase has a peak at about 22.1 ppm that is absent in the amorphous phase. Furthermore, the peak at about 29.5 ppm is prominent in the crystalline phase, but not at all in the amorphous phase. Therefore, the solid peak at about 22.1 ppm is 13 The absence of C-NMR peaks and / or the absence of a prominent peak at about 29.5 ppm can be used to characterize amorphous obicetrapib hemicaltrium. In addition, the solid obicetrapib hemicaltrium spectrum is substantially the same as that of Figure 65. 13 Amorphous obicetrapib hemi-calcium can be characterized using C-NMR spectroscopy. In this context, the absence of a peak does not necessarily mean that there is no intensity at, for example, 22.1 ppm or 29.5 ppm, but rather that there is no intensity at all at, for example, 22.1 ppm or 29.5 ppm, as in crystalline obicetrapib hemi-calcium. 13 This means that the intensity is not as pronounced as in the C-NMR spectrum.

[0179] The properties of crystalline materials also generally differ from those of amorphous materials. Thermodynamically, crystalline materials are more physically stable than amorphous materials. Therefore, there is a thermodynamic driving force to convert amorphous compounds to crystalline compounds. Under accelerated stress conditions, if there is a physical transformation of a solid form, it is generally expected to be from amorphous to crystalline. However, in the case of obiscetrapib hemi-calcium, the opposite is true.

[0180] Figure 54 is a plot of the X-ray powder diffraction pattern of crystalline obicetrapib hemi-calcium, and Figure 55 is a plot of the X-ray powder diffraction pattern of crystalline obicetrapib hemi-calcium under stress conditions. Figure 55 shows four diffraction patterns based on the stability study described in Example 11.27. Pattern 1 is the X-ray powder diffraction pattern of an amorphous obicetrapib hemi-calcium sample. Pattern 2 is the X-ray powder diffraction pattern of a crystalline obicetrapib hemi-calcium sample. In Pattern 3, a sample of crystalline obicetrapib hemi-calcium was exposed to 70°C at 75% relative humidity for one day. As can be seen from Pattern 3, the X-ray powder diffraction pattern shows almost complete loss of crystallinity within that day. After 7 days under the same conditions, the results remain the same as observed in Pattern 4. A similar experiment was performed with amorphous obicetrapib hemi-calcium, shown in Figure 56. Pattern 1 was obtained before the sample was subjected to stability testing. When this sample was exposed to the same conditions of 70°C and 75% relative humidity, no crystallization occurred and the material remained amorphous after 7 days (pattern 2) and 14 days (pattern 3). Thus, these experiments suggest that, contrary to expectations, the amorphous form of obicetrapib hemi-calcium is more stable than crystalline obicetrapib hemi-calcium.

[0181] In some embodiments of the present disclosure, stable amorphous obicetrapib hemi-calcium is provided herein, which in these embodiments is more physically stable than crystalline obicetrapib hemi-calcium under typical pharmaceutical use and processing conditions.

[0182] Without wishing to be bound by theory, it is possible that the kinetics in this case is such that the amorphous phase is kinetically stabilized relative to the thermodynamically more stable crystalline phase, at least under pharmaceutically relevant processing and use conditions. The results of this stability profile indicate that amorphous obicetrapib hemi-calcium is more suitable for pharmaceutical development and use than the corresponding crystalline phase. Despite being more physically resilient, amorphous obicetrapib hemi-calcium is more soluble than the highly insoluble crystalline obicetrapib hemi-calcium.

[0183] The solubility of obicetrapib is particularly challenging. For example, at 20° C., the solubility of obicetrapib in water has been measured to be substantially below 0.1 mg / mL. It would be desirable to have a solid form of obicetrapib that can deliver higher amounts of obicetrapib.

[0184] Although solubility is a thermodynamic quantity of a substance, the kinetic solubility of a substance can be measured without necessarily reaching thermodynamic equilibrium. Such measurements provide solubility under metastable conditions, e.g., providing information on the amount of substance dissolving as a function of time.

[0185] The amorphous form has a higher kinetic solubility and dissolution rate than the crystalline form (and even than obicetrapib itself). Kinetic solubility measurements of both crystalline and amorphous obicetrapib hemi-calcium were performed in biorelevant media at different pHs, i.e., about 5.0 (FeSSIF conditions) and about 6.5 (FaSSIF conditions), as shown in Example 11.28.

[0186] Table W shows the solubility of two different batches of amorphous obicetrapib hemi-calcium versus crystalline obicetrapib hemi-calcium measured over a 2-hour period in FeSSIF medium at 37°C. In both cases, the amorphous obicetrapib hemi-calcium was at a higher concentration in solution than the corresponding crystalline material at all time points measured. The concentrations in Table W are those of obicetrapib (i.e., the free acid).

[0187] [Table 1]

[0188] Table X shows a similar experiment at 37°C, but in FaSSIF medium at pH 6.5. As with Table W, in both batches, amorphous obicetrapib hemi-calcium was at a higher concentration in solution than the corresponding crystalline material at all measured time points. The concentrations in Table X are those of obicetrapib (i.e., the free acid).

[0189] [Table 2]

[0190] Amorphous obicetrapib hemi-calcium dissolves faster than the corresponding crystalline phase, so more drug is available for immediate use in the amorphous phase than in the crystalline phase, potentially resulting in greater bioavailability.

[0191] Amorphous obicetrapib hemi-calcium also has the advantage of being less prone to absorbing moisture than many amorphous organic compounds. For example, when exposed to relative humidity approaching 90%, moisture uptake is typically measured at about 5% or less. This lack of hygroscopicity is advantageous because it does not require special handling or storage conditions. Similarly, other drawbacks typically associated with the production and use of amorphous materials are also absent. For example, amorphous materials are often difficult to make chemically pure. However, the present disclosure allows for routine production of amorphous obicetrapib hemi-calcium with chemical purity of 99.9% or greater.

[0192] In some embodiments of the present disclosure, substantially pure amorphous obicetrapib hemi-calcium is provided. In these and other embodiments, the substantially pure amorphous obicetrapib hemi-calcium has a chemical purity of 99.9% or greater.

[0193] In many aspects of the present disclosure, there is provided a method for preparing an amorphous calcium salt of obicetrapib, such as amorphous obicetrapib hemi-calcium, comprising: treating obicetrapib with an acid to form a salt, solvate, or composition; isolating the resulting salt, solvate, or composition; and treating the salt, solvate, or composition with a calcium source to produce an amorphous obicetrapib calcium salt, such as amorphous obicetrapib hemi-calcium. The resulting salt can then be isolated.

[0194] Examples of calcium sources include calcium salts, such as calcium halide salts and soluble calcium salts. In many embodiments, the calcium source is calcium chloride.

[0195] It has been found that the preparation of amorphous salts of obicetrapib calcium, such as amorphous obicetrapib hemi-calcium, occurs in the presence of intermediate salts, solvates, or compositions (such compositions include the corresponding acid used to prepare the salt). Direct treatment of obicetrapib with a calcium base, such as calcium hydroxide, has been found to be an unfeasible method for preparing amorphous salts of obicetrapib calcium due to low solubility, the weakness of available bases, or both. Rather, the use of intermediate salts, such as sodium salts, has been found to enable the preparation of amorphous obicetrapib calcium. However, even with sodium salts, the use of additional salts or salt type exchanges (e.g., the use of compositions or solvates rather than actual salts) in conjunction with the sodium salt of obicetrapib is preferred from the standpoint of purity and yield. In particular, the use of salts, solvates, or compositions allows for the preparation of highly pure amorphous calcium salts of obicetrapib, such as amorphous obicetrapib hemi-calcium.

[0196] Exemplary salts that can be prepared as intermediates include those from sulfonates (e.g., besylate, tosylate, napsylate, camsylate, esylate, edisylate, or mesylate), sulfates (e.g., methylsulfate), halides (e.g., chloride, iodide, or bromide), acetate, aspartate, benzoate, bicarbonate, acid tartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate, or teoclate salts. When the intermediate is a solvate or a compound, the corresponding acid may be used, or a salt thereof may exist. Furthermore, when the intermediate is a solvate, the intermediate may further contain a solvent such as an organic solvent or water, in which case the solvate becomes a hydrate. One such organic solvent is CPME (cyclopentyl methyl ether).

[0197] In some embodiments, the intermediate is a solvate of an acid. In these and other embodiments, the intermediate is a solvate of an acid and an organic solvent. In certain embodiments, the intermediate is a solvate comprising an acid and a solvent. In some of these embodiments, the acid is hydrochloric acid and the solvent is CPME.

[0198] In many embodiments of the present disclosure, the present disclosure includes methods for preparing amorphous obicetrapib calcium salts, such as amorphous obicetrapib hemi-calcium. The present disclosure also includes amorphous obicetrapib calcium salts, such as amorphous obicetrapib hemi-calcium, so prepared. In one such preparation, an intermediate referred to herein as crystalline obicetrapib HCl is used in a process for preparing amorphous obicetrapib calcium, such as amorphous obicetrapib hemi-calcium.

[0199] In many embodiments of the present disclosure, amorphous obicetrapib hemi-calcium is prepared by reacting an intermediate having the formula: [ka] It is prepared by chemical synthesis as used and shown by

[0200] wherein y varies such that the mass % of HCl varies from 0.01% to 8% by weight, and may further include associated organic solvents, such as through solvates. In some embodiments, y varies from 0.002 to 1.5. In some embodiments, y varies from 0.3 to 1. In some embodiments, y varies from 0.4 to 0.6, including 0.5-0.6. In some embodiments, Formula (IH) as a solvate is isolated in its crystalline form. In many embodiments, the solvent is CPME. Other solvents that may form solvates include toluene and heptane.

[0201] The obicetrapib HCl typically prepared herein is crystalline. Furthermore, the term crystalline obicetrapib HCl may include CPME as a solvate when CPME is used in the preparation of crystalline obicetrapib HCl. In formula (IH), the solvate is of an organic solvent, and in many embodiments, the solvent is CPME. In some embodiments, the present disclosure provides a composition comprising crystalline obicetrapib HCl.

[0202] Formula (IH) is referred to as obicetrapib HCl, and when crystalline it is referred to as crystalline obicetrapib HCl.

[0203] Without being bound by theory, crystalline obicetrapib HCl is believed to be a mixed salt solvate. When CPME is used to deliver HCl to the reaction to produce Formula (IH), the chloride content of Formula (IH) has been found to be about 2.5% to 3.0% by weight, which is below that expected for the neutral salt, i.e., about 4.8% by weight.

[0204] In many embodiments, when CPME is used in this manner, it is found in the material upon crystallization. When CPME is used in the reaction to deliver dry HCl and is therefore present in the crystallized material, the resulting crystalline Formula (IH) material is referred to as crystalline obicetrapib HCl, and its X-ray powder diffraction pattern can be seen in Figure 66. An advantage of using crystalline obicetrapib hydrochloride as an intermediate is that the resulting amorphous obicetrapib hemi-calcium always has a chemical purity of 99.9% or greater. Chemical purity quantitatively describes the presence of chemical entities other than the compound being measured. For example, amorphous obicetrapib hemi-calcium with a chemical purity of 99.9% means that 0.1% or more of the compound in a sample of amorphous obicetrapib hemi-calcium is free of other entities. Physical purity, in the case of amorphous obicetrapib hemi-calcium, refers to the amount of other solid forms of the same compound present, where the other solid form is crystalline obicetrapib hemi-calcium. The present disclosure provides physically pure amorphous obicetrapib hemi-calcium, meaning free or substantially free of crystalline obicetrapib hemi-calcium. Unless otherwise specified herein, the purity measurements provided herein are measurements of chemical purity.

[0205] As used herein, obicetrapib hydrochloride is not limited to crystalline obicetrapib hydrochloride, and indeed, upon desolvation, crystalline obicetrapib hydrochloride may become amorphous.

[0206] Under stress, crystalline obicetrapib hydrochloride loses its crystallinity. In Figure 66, pattern 2 represents crystalline obicetrapib hydrochloride that has been subjected to a mild drying treatment, thereby removing the surface solvent, demonstrating that the compound is crystalline. In comparison, the sample measured for X-ray powder diffraction in pattern 1 was subjected to a strong drying treatment at 55°C and 2 mbar pressure for 48 hours. Apparently, this drying transformed the material from crystalline to amorphous, likely due to the loss of HCl and desolvation of CPME. For example, 1Using H-NMR spectroscopy, the presence of CPME was shown in the upper pattern, but was substantially absent from the lower amorphous pattern. Thus, the amorphous pattern represents obicetrapib HCl, not crystalline obicetrapib. While it may be obicetrapib, it is believed to be HCl combined with obicetrapib as a solvate, and thus is obicetrapib HCl, but with a lower chloride content than typically found in the range found for crystalline obicetrapib HCl. In some embodiments, the chloride content is less than 0.1 wt%, such as about 0.01 wt% to 0.1 wt%.

[0207] Crystalline obicetrapib HCl may be characterized by an X-ray powder diffraction pattern comprising a peak at about 9.8°2θ. In some embodiments, crystalline obicetrapib HCl may be characterized by an X-ray powder diffraction pattern comprising one or more peaks at about 8.1°2θ, about 9.8°2θ, about 13.8°2θ, about 16.7°2θ, or about 19.5°2θ. Table Y provides exemplary peaks that may be present in crystalline obicetrapib HCl. In some embodiments, crystalline obicetrapib HCl may be characterized by an X-ray powder diffraction pattern substantially the same as that in Figure 67, although the material analyzed in Figure 67 is believed to have been measured such that no peaks between about 4.3°2θ and about 4.7°2θ are observed.

[0208] [Table 3]

[0209] Another intermediate used in the preparation of obicetrapib is represented by formula (VI) [ka] (In the formula, Y 1 is a protecting group (e.g., as described herein); A n- is an anion; and n is an integer from 1 to 3. It is of the type.

[0210] In one embodiment, the compound of formula (VI) is 1 is t-butyl, compound 1D: [ka] It is a mesylate salt having the structure:

[0211] Compound 1D 1 The H-NMR spectrum (in solution) can be found in Figure 69. Crystalline Compound 1D may be characterized by an X-ray powder diffraction pattern comprising one or more peaks at about 5.2°2θ or about 9.1°2θ. In some embodiments, crystalline Compound 1D may be characterized by an X-ray powder diffraction pattern comprising one or more peaks at about 5.2°2θ, about 9.1°2θ, about 15.9°2θ, about 16.5°2θ, about 17.2°2θ, about 18.6°2θ, and about 19.2°2θ. Table Z shows exemplary peaks that may be present in crystalline Compound 1D (the peak at about 5.2°2θ was not measured due to instrument limitations in reflectance mode). In some embodiments, crystalline Compound 1D may be characterized by an X-ray powder diffraction pattern substantially the same as Figure 68.

[0212] [Table 4]

[0213] For example, crystalline compounds such as crystalline Compound 1D and crystalline obicetrapib HCl can be characterized by X-ray powder diffraction. An X-ray powder diffraction pattern is an XY graph with °2θ (diffraction angle) on the X-axis and intensity on the Y-axis. Typically, peaks are represented and referenced by their position on the X-axis rather than their intensity on the Y-axis because peak intensity is particularly sensitive to sample orientation (see Pharmaceutical Analysis, Lee & Web, pp. 255-257 (2003)). Therefore, intensity is not typically used to characterize solid forms. X-ray powder diffraction data can be used in several ways to characterize crystalline forms. For example, the entire X-ray powder diffraction pattern output from a diffractometer can be used to characterize crystalline obicetrapib HCl or crystalline Compound 1D. However, smaller subsets of such data can also be, and typically are, suitable for characterizing such compounds. For example, a collection of one or more peaks from such a pattern can be used to characterize these compounds in this way. The reference to "one or more peaks" in a list of peaks from an X-ray powder diffraction pattern generally means that any combination of the listed peaks can be used for characterization. Furthermore, the presence of other peaks in the X-ray powder diffraction pattern generally does not negate or limit the characterization.

[0214] In addition to variations in peak intensity, there may also be variations in the position of the peaks on the X-axis. However, this variation can usually be accounted for when reporting peak positions for characterization purposes. Such variations in peak positions along the X-axis can result from several sources (e.g., sample preparation, particle size, water content, solvent content, instrument parameters, data analysis software, and sample orientation). For example, samples of the same crystalline material prepared under different conditions may produce slightly different diffractograms, and various X-ray instruments may operate using different parameters, which may result in slightly different diffraction patterns from the same crystalline solid. Due to such sources of variation, it is common to refer to X-ray diffraction peaks using the term "about" before the peak value (°2θ). For purposes of the data reported herein, it is intended that the value be generally reported with such variation whenever disclosed herein, regardless of whether the term "about" is present. The variability may be greater in some cases depending on the condition of the instrumentation, such as how well the instrument is maintained.

[0215] In some embodiments, crystalline Compound 1D may be further characterized by an X-ray powder diffraction pattern substantially the same as the X-ray powder pattern of FIG.

[0216] In many embodiments of the present disclosure, there is provided a method for preparing an amorphous calcium salt of obicetrapib, e.g., amorphous obicetrapib hemicaltrium, comprising the steps of: i. treating obicetrapib with HCl to obtain crystalline obicetrapib HCl; ii. isolating the crystalline obicetrapib HCl; iii. Preparing an amorphous calcium salt of obicetrapib, e.g., amorphous obicetrapib hemi-calcium, from the crystalline obicetrapib HCl isolated in step (ii); and iv. Isolating the amorphous calcium salt of obicetrapib, e.g., amorphous obicetrapib hemi-calcium. Includes:

[0217] In another aspect of the present disclosure, there is provided a method for preparing obicetrapib, the method comprising: (a) preparing a compound of formula (IV) by coupling a compound of formula (II) or a salt thereof with a compound of formula (III): [ka] (In the formula, X 1 is a leaving group, and Y 1 is a protecting group); (b) preparing a carbamate salt of formula (V) from a compound of formula (IV) and isolating it as a solid salt form of formula (VI): [ka] (In the formula, Y 1 is a protecting group, and A n- is an anion, and n is an integer from 1 to 3; (c) optionally desalting the compound of formula (VI) and alkylating it with a compound of formula (VII) to provide a compound of formula (VIII): [ka] (In the formula, X 2 is a leaving group, and Y 1 is a protecting group); and (d) converting the compound of formula (VIII) to obicetrapib wherein reaction steps (a) to (d) are carried out in an organic solvent, and compounds (IV), (V) and (VIII) are optionally not isolated from the organic solvent, and the process need not include chromatography.

[0218] The reactions of steps (a)-(d) of the subject method are carried out in a solvent, and the intermediate compounds of formulas (IV), (V), and (VIII) do not need to be isolated from their respective solvents if they are further processed into the final product. That is, any solvent exchange between reaction steps (x) and (x+1) is carried out by evaporating at least a portion of the solvent used in step (x) and gradually adding the solvent of step (x+1), with the compound remaining in solution during the solvent exchange. The intermediate compound of formula (VI) can be isolated from the solvent as a solid salt so that it can be washed to remove impurities. This isolation step ensures sufficient purity of the downstream product. The subject process does not need to include a purification step using chromatography, such as column chromatography, to achieve the chemical purity levels described herein.

[0219] Method for preparing amorphous calcium salts such as amorphous obicetrapib hemi-calcium (Steps (i)-(ii) from aspects (i)-(iv)) In some embodiments of the method for preparing an amorphous calcium salt of obicetrapib, such as amorphous obicetrapib hemi-calcium, the method comprises step (i) of treating obicetrapib with HCl in an organic solvent to obtain crystalline obicetrapib HCl.

[0220] In some embodiments, the crystalline obicetrapib HCl has a purity of 98% or greater, such as 98.5% or greater, 99% or greater, 99.5% or greater, or greater.

[0221] In some embodiments, the HCl in step (i) is in a suitable solvent. Such a solvent can be an aqueous solvent or an organic solvent. In some embodiments, the organic solvent used in step (i) comprises a mixture of a solvent and an anti-solvent. In some embodiments, the solvent is selected from methanol, ethanol, isopropanol, acetic acid, acetonitrile, acetone, methyl isobutyl ketone, isopropyl acetate, tetrahydrofuran, methyl t-butyl ether, cyclopentyl methyl ether, N-methyl-2-pyrrolidone, dimethyl sulfoxide, dimethylformamide, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, 1,2-difluorobenzene, toluene, hexafluoroisopropanol, and water. In some embodiments, the anti-solvent is selected from n-heptane, n-hexane, n-pentane, and cyclohexane.

[0222] In some embodiments, HCl has sufficient solubility in the anti-solvent so that it can be used as a suitable solvent. In some embodiments, the organic solvent used in step (i) comprises a mixture of cyclopentyl methyl ether and n-heptane. In some embodiments, the organic solvent used in step (i) further comprises toluene. In some embodiments, toluene is the major component of the organic solvent.

[0223] In some embodiments, step (i) involves providing obicetrapib in a mixture of cyclopentyl methyl ether and n-heptane, raising the temperature to 35°C-40°C under stirring, adding dry HCl in cyclopentyl methyl ether, raising the temperature again to 50°C-55°C, and then adding n-heptane as an anti-solvent. At this point, a small portion of the reaction mixture can be optionally extracted and cooled to a temperature of 10°C-15°C to obtain a slurry of crystalline obicetrapib HCl crystals in a mixture of cyclopentyl methyl ether and n-heptane (referred to herein as a "seed slurry"). Optionally, all or a portion of the crystalline obicetrapib HCl seed slurry can then be returned to the reaction mixture. Seed crystals aid in nucleation, but are not required. The resulting reaction mixture is then cooled to a temperature of 5°C-15°C (e.g., 10°C-15°C), after which crystalline obicetrapib HCl is crystallized from the system under stirring. In some embodiments, the crystalline obicetrapib HCl is crystallized over a period of 12 hours or more, followed by filtration (e.g., through a filter drier), one or more optional washing steps, such as with a mixture of cyclopentyl methyl ether and n-heptane, and drying. In some aspects, the wet filter cake of crystalline obicetrapib HCl is dried under vacuum using temperatures of 25°C to 30°C, 30°C to 40°C, 40°C to 50°C, then 50°C to 55°C, e.g., 25°C, 35°C, 46°C, and 54°C.

[0224] In some embodiments, the method for preparing crystalline obicetrapib HCl includes adding seed crystals (e.g., as a seed slurry). Seed crystals of the HCl compound can be formed as a slurry by carrying out step (i) as described above and adding dry HCl in cyclopentyl methyl ether and an anti-solvent, n-heptane, followed by extraction of a small portion of the reaction mixture and cooling to a temperature of 10°C to 15°C to provide a slurry of crystals of crystalline obicetrapib HCl in cyclopentyl methyl ether and n-heptane.

[0225] Thus, in one embodiment, step (i) comprises providing obicetrapib in a mixture of cyclopentyl methyl ether and n-heptane, increasing the temperature to 35°C-45°C under stirring, adding dry HCl in cyclopentyl methyl ether, again increasing the temperature to 50°C-55°C, adding more n-heptane as an anti-solvent, optionally adding seeds of crystalline obicetrapib HCl (e.g., as a seed slurry prepared as described herein), cooling to a temperature of 5°C-15°C (e.g., 10°C-15°C), and then crystallizing crystalline obicetrapib HCl from the system under stirring. In some embodiments, the crystalline obicetrapib HCl is crystallized for a period of 12 hours or more, followed by filtration, one or more optional washing steps, such as with a mixture of cyclopentyl methyl ether and n-heptane, and drying. In some embodiments, the crystalline obicetrapib HCl is dried under vacuum. In some embodiments, the crystalline obicetrapib HCl is subjected to drying in a vacuum drying cabinet at a pressure of 25 mbar and a temperature of 55° C. for 10 hours or more. In some embodiments, after the drying procedure, the crystalline obicetrapib HCl contains less than 0.1% by weight of residual cyclopentyl methyl ether.

[0226] In some embodiments, step (i) includes providing a solution of obicetrapib in cyclopentyl methyl ether having a concentration of 30-40 wt %, for example 33-37 wt %, based on the weight of the solution, less than 1 wt % of the first organic solvent (e.g., toluene) used in step (d), and less than 1 wt % of n-heptane based on the weight of the solution, adding n-heptane, increasing the temperature to 35° C.-45° C. under stirring, adding dry HCl in cyclopentyl methyl ether, and again increasing the temperature to 50° C.-55° C. , further adding n-heptane as an anti-solvent, optionally adding seed crystals of crystalline obicetrapib HCl (e.g., as a seed slurry prepared as described herein), and after cooling to a temperature of 10°C to 15°C, crystallizing crystalline obicetrapib HCl from the system under stirring, for example, for a period of at least 12 hours, followed by filtration, one or more washing steps with a mixture of cyclopentyl methyl ether and n-heptane, and drying, for example, under vacuum. In some embodiments, the amount of toluene is substantially higher.

[0227] In some embodiments, the crystalline obicetrapib HCl from step (i) is isolated in step (ii). In some embodiments, the isolated crystalline obicetrapib HCl has a purity of 98% or greater, e.g., 98.5% or greater, 99% or greater, 99.5% or greater, 99.7% or greater, or greater.

[0228] Another embodiment of the present disclosure relates to crystalline obicetrapib HCl obtained by or obtainable by the process defined herein.

[0229] Yet another embodiment of the present disclosure relates to obicetrapib HCl, such as crystalline obicetrapib HCl.

[0230] In some embodiments, the crystalline obicetrapib HCl is stored at controlled room temperature and under a nitrogen atmosphere and protected from moisture to prevent the formation of amorphous solids, such as by desolvation.

[0231] Method for preparing amorphous calcium salt of obicetrapib, such as amorphous obicetrapib hemi-calcium - steps (iii)-(iv) from aspects (i)-(iv) In some embodiments of the method for preparing an amorphous calcium salt of obicetrapib, such as amorphous obicetrapib hemi-calcium, the method includes steps (iii)-(iv) of preparing an amorphous calcium salt of obicetrapib from the crystalline obicetrapib HCl isolated in step (ii), and isolating the amorphous calcium salt of obicetrapib, such as amorphous obicetrapib hemi-calcium.

[0232] In some embodiments of the method for isolating the amorphous calcium salt of obicetrapib according to step (iv), the amorphous calcium salt of obicetrapib is amorphous obicetrapib hemi-calcium: [ka] It is in the form of:

[0233] In some embodiments of the method for preparing obicetrapib, step (iii) comprises: (iii-1) converting the crystalline obicetrapib HCl of step (ii) to provide obicetrapib in an organic solvent; (iii-2) treating obicetrapib in an organic solvent with aqueous sodium hydroxide to form a sodium salt of obicetrapib; and (iii-3) treating the sodium salt of obicetrapib with aqueous calcium chloride to form amorphous obicetrapib hemi-calcium wherein the compounds of steps (iii-1) and (iii-2) are not isolated.

[0234] Thus, in some embodiments, step (iii-1) comprises: (aa) providing the crystalline obicetrapib HCl isolated in step (ii); (bb) dissolving crystalline obicetrapib HCl in a mixture of water and isopropyl acetate under stirring (in some embodiments, step (bb) is carried out at a temperature between 15°C and 25°C); (cc) subjecting the resulting organic phase to one or more subsequent washing steps with water, separating the aqueous phase after each washing step to obtain a washed organic phase; and (dd) subjecting the washed organic phase obtained from step (cc) to two or more distillations at a temperature of 50° C. or less (e.g., 30° C. or less) with the addition of ethanol therebetween to obtain a solution of obicetrapib in ethanol. Includes:

[0235] In some embodiments, step (iii-2) comprises: (ee) adding aqueous NaOH to the solution obtained in step (dd) and stirring the resulting mixture, for example, at a temperature of 20°C to 25°C for at least 4 hours, to obtain a solution of the sodium salt of obicetrapib; and (ff) optionally filtering the solution obtained in step (ee). Includes:

[0236] In some embodiments, step (iii-3) comprises: (gg) preparing a CaCl2 solution by adding deionized water to CaCl2 under stirring, followed by adding ethyl acetate as a co-solvent, and stirring the resulting mixture for 10 to 30 minutes; (hh) cooling the CaCl2 solution obtained in step (gg) to a temperature of 8°C to 12°C and adding it through a filter to the solution obtained in step (ff) or (ee) at said temperature under stirring; (ii) stirring the slurry resulting from step (hh) for about 1 to about 10 hours (in some embodiments of step (ii), the stirring is carried out at a temperature of 8°C to 12°C); (jj) isolating the solids from the slurry obtained in step (ii) by filtration (in some embodiments of step (jj), the isolation is carried out at a temperature of 8°C to 12°C); (kk) washing the filter cake obtained in step (jj) with water in one or more washing steps (in some embodiments of step (kk), the washing is carried out at a temperature of 8°C to 12°C); and (ll) drying the washed residue obtained in step (kk) under vacuum at a temperature of 40°C to 50°C for 16 hours or more (e.g., 50 hours, 100 hours, 150 hours, or 200 hours or more) to obtain amorphous obicetrapib hemi-calcium (sometimes referred to herein as Compound 3). Includes:

[0237] In some embodiments, the amorphous obicetrapib hemi-calcium is subjected to a subsequent reprocessing procedure by dissolving the amorphous obicetrapib hemi-calcium in ethanol (e.g., twice the weight of ethanol relative to the amorphous obicetrapib hemi-calcium) at a temperature of 25°C to 50°C, cooling to 10°C to 15°C, filtering the solution into a mixture of aqueous calcium chloride and ethyl acetate, again cooling to 10°C to 15°C, filtering, washing with water, and vacuum drying at 45°C or below for 20 hours or more, followed by further reprocessing.

[0238] In some embodiments of step (iv), the amorphous obicetrapib hemi-calcium is isolated to a purity of 95% or greater, such as 95.5% or greater, 96% or greater, 96.5% or greater, 97% or greater, 97.5% or greater, 98% or greater, 98.5% or greater, 99% or greater, 99.1% or greater, 99.2% or greater, 99.3% or greater, 99.4% or greater, 99.5% or greater, 99.6% or greater, 99.7% or greater, 99.8% or greater, or 99.9% or greater.

[0239] In some embodiments, the amorphous obicetrapib hemi-calcium is subjected to a milling process, which in some embodiments is adapted (e.g., parameters such as feed rate, venturi pressure, and mill pressure are adapted) to allow for the production of finely divided amorphous obicetrapib hemi-calcium.

[0240] Preparation method of obicetrapib - Step (a) from side (a) to (d) In step (a) of the process for preparing obicetrapib according to the present disclosure, a compound of formula (II) or a salt thereof is coupled with a compound of formula (III) to provide a compound of formula (IV) (e.g., wherein X is an integer from 1 to 3, e.g., as described herein). 1 is a leaving group, and Y 1 is a protecting group). [ka]

[0241] Step (a) of the subject method comprises preparing a compound of formula (II) (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline), or a salt thereof: [ka] Start from.

[0242] The compound of formula (II) can be obtained, for example, using the process disclosed in WO 2016 / 024858 A1 or WO 2007 / 116922 A1 (both of which are incorporated herein by reference in their entirety). In some embodiments, the compound of formula (II) can be obtained from a stable corresponding salt and can be obtained in pure and solid form. The solid form can be amorphous or crystalline. In some embodiments, the compound of formula (II) can be obtained from a corresponding crystalline salt.

[0243] In some embodiments, the compound of Formula (II) provided in step (a) has Formula (IIA) or (IIB): [ka] (In the formula, A m- is an anion, and n is an integer of 1 to 3. It is salt of.

[0244] In some embodiments, the compound of Formula (II) provided in step (a) is a salt of Formula (IIA). In some embodiments, the compound of Formula (IIA) is used directly in the coupling reaction with the compound of Formula (III) without performing a desalting step.

[0245] In some embodiments, the compound of Formula (II) provided in step (a) is a salt of Formula (IIB). In some embodiments, the compound of Formula (IIB) is used directly in the coupling reaction with the compound of Formula (III) without performing a desalting step.

[0246] In some embodiments, the compound of formula (II) in step (a) is obtained from a salt of formula (IIA) or (IIB). In some embodiments, prior to the coupling reaction in step (a), the compound of formula (II) is obtained from a salt of formula (IIA) or (IIB): (Pre-a1) Formula (IIA) or (IIB): [ka] providing a compound of the formula: (Pre-a2) A step of desalting a compound of formula (IIA) or (IIB) to obtain a compound of formula (II), wherein the reaction of step (Pre-a2) is carried out in an organic solvent, the compound of formula (II) is not isolated from the organic solvent, and the process does not involve chromatography.

[0247] In some embodiments, the compound of formula (II) in step (a) is obtained from a salt of formula (IIA). In some embodiments, the compound of formula (II) in step (a) is obtained from a salt of formula (IIB).

[0248] In some embodiments, the salt of Formula (IIA) or (IIB) is selected from a sulfonate (e.g., besylate, tosylate, napsylate, camsylate, esylate, edisylate, or mesylate), sulfate (e.g., methylsulfate), halogen (e.g., chloride, iodide, or bromide), acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate, and teoclate salt.

[0249] In some embodiments, the salt of Formula (IIA) or (IIB) comprises an anion A selected from chloride, bromide, acid tartrate, sulfate, and sulfonate. m- The salt is selected from salts having the formula:

[0250] In some embodiments, the salt of Formula (IIA) or (IIB) comprises an anion A selected from chloride, bromide, tartrate, and mesylate. m- The salt is selected from salts having the formula:

[0251] In some embodiments of the salt of Formula (IIA) or (IIB), m is 1.

[0252] In some embodiments, the salt is of formula (IIA) and the anion A m- is mesylate and m is 1. The mesylate (MSA) salt (also referred to herein as compound 1A shown below) can be obtained by a process such as that disclosed in WO 2016 / 024858 A1 or WO 2007 / 116922 A1, the disclosures of which are incorporated herein by reference in their entireties. [ka]

[0253] In some embodiments, the desalting of the compound of Formula (IIA) or (IIB) in step (pre-a2) is carried out in a mixture of aqueous sodium hydroxide and an organic solvent selected from toluene, dichloromethane, cyclopentyl methyl ether, isopropyl ether, t-butyl methyl ether, ethyl acetate, isopropyl acetate, methyl ethyl ketone, methyl isobutyl ketone, chlorobenzene, and combinations thereof, followed by heating the mixture, then cooling the mixture, allowing the system to phase separate, and then separating the aqueous phase. In some embodiments, the solvent is toluene. In some embodiments, the reaction mixture is heated to a temperature of 45°C to 60°C, then cooled to a temperature of 15°C to 40°C.

[0254] In some embodiments, the organic phase obtained after separating the aqueous phase is subjected to one or more aqueous washing steps, and after each aqueous washing step, separation of the aqueous phase is performed, for example, one or more washing steps with aqueous sodium chloride solution, followed by separation of the aqueous phase, then one or more washing steps with deionized water, and then separation of the aqueous phase again.The resulting washed organic phase is then optionally distilled to reduce the water content to less than 1000 ppm by weight of the solution.Alternatively, in some embodiments, a small amount of water remains in the organic phase together with the compound of formula (II), and the subsequent coupling with the compound of formula (III) proceeds in the presence of this small amount of water.

[0255] In some embodiments, the desalting reaction in step (Pre-2a) is carried out on the mesylate salt (Compound 1A) in a mixture of aqueous sodium hydroxide and toluene at a temperature of 45°C to 60°C. The mixture is then cooled to a temperature of 15°C to 25°C, allowing the system to undergo phase separation and separating the aqueous phase. The toluene phase obtained after separating the aqueous phase is then optionally subjected to one or more washing steps with aqueous sodium chloride, followed by separation of the aqueous phase and then one or more washing steps with deionized water, after which the aqueous phase is again separated. The resulting washed toluene phase is then distilled under reduced pressure at a temperature of 50°C to 65°C to reduce the water content to less than 1000 ppm by weight of the total solution. Alternatively, a small amount of water remains in the toluene with the compound of Formula (II), and the subsequent coupling reaction with the compound of Formula (III) proceeds in the presence of this small amount of water.

[0256] As outlined above, in step (a), a compound of formula (II) or a salt thereof (e.g., a compound of formula (IIA) or (IIB), such as mesylate 1A) is coupled with a compound of formula (III) to provide a compound of formula (IV). In some embodiments, this step is carried out in an organic solvent.

[0257] The coupling partner of formula (III) in step (a) is a leaving group (X 1 ) X 1 It will be understood that any convenient leaving group may be useful in the present disclosure. In some embodiments, the leaving group (X 1 ) is selected from halogen, carbamate, and a substituted sulfonyloxy group. In some embodiments, the leaving group (X) in the compound of formula (III) 1 ) is a sulfonyloxy group selected from a methanesulfonyloxy group, a p-toluenesulfonyloxy group, or a trifluoromethanesulfonyloxy group. In some embodiments, the leaving group (X 1 ) is a carbamate. In some embodiments, the leaving group (X 1) is a halogen. In certain embodiments, the halogen is chloride. The coupling partner of formula (III) in step (a) may also contain a protecting group (Y 1 ). The term "protecting group" refers to any group that, when attached to a functional group, such as a carboxylic acid moiety, of a compound (including intermediates thereof), prevents reaction from occurring at that functional group, and the protecting group can be removed by a conventional chemical or enzymatic step to restore the functional group, e.g., the carboxylic acid moiety. The particular removable protecting group used is not critical; examples of carboxylic acid protecting groups include t-butyl esters, methyl esters, ethyl esters, benzyl esters, allyl esters, 1,1-diethylallyl esters, 2,2,2-trifluoroethyl esters, phenyl esters, 4-methoxybenzyl esters, silyl esters, orthoesters, esters of 2,6-disubstituted phenols (e.g., 2,6-dimethylphenol), and any other group that is chemically introduced into a carboxylic acid group or similar functional group and can be subsequently selectively removed by either chemical or enzymatic methods under mild conditions compatible with the properties of the product. Y 1 It will be understood that any convenient protecting group for the carboxylic acid moiety (e.g., an ester group) may be useful in the present disclosure, and that the selection of an appropriate protecting group can be readily determined by one of ordinary skill in the art. Suitable groups for this purpose can be found in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis, 4 by T.W. Greene and P.G.M.Wuts. th Ed., (John Wiley & Sons, New York, 1999), Protecting Group Chemistry, 1st Edition by Jeremy Robertson (Oxford University Press, 2000); and March's Advanced Organic Chemistry: Reactions Mechanisms, and Structure, 8th Edition, by Michael B. Smith (Wiley-Interscience Publication, 2001). In some embodiments, the protecting group (Y1 ) is selected from alkyl groups, substituted alkyl groups, aryl groups, substituted aryl groups, allyl groups, substituted allyl groups, and silyl groups. 1 ) is selected from t-butyl, methyl, ethyl, benzyl, allyl, substituted allyl, 2,2,2-trifluoroethyl, phenyl, 4-methoxybenzyl ester, 2,6-disubstituted phenol, and silyl groups. 1 ) is a t-butyl group. In some embodiments, the compound of Formula (III) has the following structure 1B: [ka] It is of the type.

[0258] In some embodiments of the coupling reaction of step (a), the solvent is selected from toluene, t-butanol, 1,4-dioxane, xylene, N-methyl-2-pyrrolidone, dimethylformamide, water, tetrahydrofuran, and combinations thereof. In some embodiments, the solvent is a mixture of the organic solvent toluene and the organic co-solvent t-butanol.

[0259] When steps (pre-a1) and (pre-a2) are performed before step (a), the compound of formula (II) is already present in the required solvent because the same organic solvent is used in steps (pre-a2) and (a), or because of a solvent exchange in step (pre-a2). If necessary, more organic solvent and, for example, an organic co-solvent can be added in step (a). As will be understood by those skilled in the art, an organic co-solvent can also be added during the solvent exchange in step (pre-a2). In some embodiments, steps (pre-a1) and (pre-a2) are performed before step (a), and the compound of formula (II) is present in toluene.

[0260] The coupling reaction of step (a) is typically a catalytic reaction. In some embodiments, the reaction is a palladium-catalyzed coupling reaction in the presence of a base. Suitable examples of palladium catalysts include, for example, tris(dibenzylideneacetone)dipalladium and Pd(II) acetate. Suitable bases include organic bases (e.g., sodium t-butoxide and potassium t-butoxide) and inorganic bases (e.g., K3PO4, K3PO4·H2O, sodium carbonate, potassium carbonate, cesium carbonate, LiHMDS, NaHMDS, KOH, and NaOH).

[0261] In many embodiments, anhydrous KPO is used as the base. In many such embodiments, the particle size distribution is such that 90% of the particles are smaller than about 140 microns to about 307 microns, including about 140 microns to about 170 microns, such as about 160 microns to about 290 microns, and about 180 microns to about 220 microns, and about 200 microns to about 210 microns. In some embodiments, 90% of the particles are less than 205 microns.

[0262] In these and other embodiments, 50% of the particles are no larger than about 35 microns to about 173 microns, including about 35 microns to about 40 microns.

[0263] In these and other embodiments, 10% of the particles are from about 7 to about 74 microns, such as from about 7 to about 10 microns.

[0264] In some embodiments, in step (a), the compound of Formula (II) is reacted with the compound of Formula (III) in a solvent (e.g., an organic solvent) using a palladium catalyst and a base. In some embodiments, the reaction mixture further comprises a ligand.

[0265] In some embodiments, in step (a), a compound of Formula (IIA) or (IIB) is reacted with a compound of Formula (III) in a solvent (e.g., an organic solvent) using a palladium catalyst and a base. In some embodiments, the reaction mixture further comprises a ligand.

[0266] In some embodiments, in step (a), the desalted compound of Formula (II) is reacted with a compound of Formula (III) in a solvent (e.g., an organic solvent) using Pd(II) acetate and either (S)-BINAP [(S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl] or rac-BINAP as the ligand. In some embodiments, (S)-BINAP is used as the ligand and the base is selected from sodium t-butoxide, potassium t-butoxide, anhydrous K3PO4, K3PO4·H2O, sodium carbonate, potassium carbonate, cesium carbonate, LiHMDS, NaHMDS, KOH, and NaOH.

[0267] In some embodiments, in step (a), the salt of Formula (IIA) or (IIB) is reacted with a compound of Formula (III) in a solvent (e.g., an organic solvent) using Pd(II) acetate and either (S)-BINAP [(S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl], (R)-BINAP [(S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl], or rac-BINAP as a ligand. In some embodiments, (S)-BINAP is used as the ligand, and a base selected from sodium t-butoxide, potassium t-butoxide, anhydrous KPO, KPO·HO, sodium carbonate, potassium carbonate, cesium carbonate, LiHMDS, NaHMDS, KOH, and NaOH is used. In some embodiments, the salt of Formula (IIA) is the mesylate salt, Compound 1A.

[0268] In some embodiments, the reaction in step (a) is carried out at a temperature between 70° C. and 80° C., optionally under a nitrogen atmosphere, for 2 hours or more.

[0269] In some embodiments, in step (a), the compound of Formula (II) or the salt of Formula (IIA) is reacted with a compound of Formula (III) (X) in a mixture of the organic solvent toluene and the organic co-solvent t-butanol. 1 is Cl and Y 1is t-butyl) with palladium(II) acetate as a catalyst, (S)-BINAP as a ligand, and anhydrous K3PO4 or K3PO4·H2O as a base, under a nitrogen atmosphere at a temperature of 70-80°C for at least 2 hours.

[0270] In some embodiments, the one or more aqueous washing steps include one or more washing steps with water, preferably deionized water, followed by separating the aqueous phase, then one or more washing steps with aqueous HCl, followed by separating the aqueous phase, then one or more washing steps with aqueous sodium chloride, followed by separating the aqueous phase, and finally one or more washing steps with deionized water again, followed by separating the aqueous phase.

[0271] If t-butanol is used as the organic co-solvent in step (a), this organic co-solvent is removed from the organic phase during the washing process.

[0272] If step (a) is carried out in an organic solvent different from the solvent used in step (b), the organic solvent used in step (a) is exchanged in step (a) for the organic solvent used in step (b), such that the compound of formula (IV) remains in solution.

[0273] In some embodiments in which the (organic) solvents used in steps (a) and (b) are different, at least a portion of the (organic) solvent used in step (a) is evaporated, for example, by distillation under reduced pressure, followed by the addition of the organic solvent in step (b), such that the compound of formula (IV) remains in solution during the solvent exchange. This process can be carried out by continuously evaporating the (organic) solvent used in step (a) and continuously adding the organic solvent in step (b), for example, until the amount of the (organic) solvent used in step (a) falls below a certain threshold, based on the total amount of solvent. Alternatively, this process can be carried out in two or more batchwise steps, by evaporating a portion of the (organic) solvent used in step (a) and then adding a portion of the organic solvent used in step (b), for example, until the amount of the (organic) solvent used in step (a) falls below a certain threshold, based on the total amount of solvent.

[0274] In some embodiments, the solvent used in step (a) is a mixture of the organic solvent toluene and the organic co-solvent t-butanol, which is removed from the organic phase containing the compound of Formula (IV) during a washing step.

[0275] In some embodiments of step (a), the remaining organic solvent, toluene, is exchanged for acetonitrile by distilling off a portion of the toluene, with intermediate additions of acetonitrile, in two or more steps at a temperature between 50° C. and 65° C. under reduced pressure in an amount that results in a solvent mixture containing less than about 20% by weight toluene, based on the total weight of the solvents, while the compound of Formula (IV) remains in solution. 1 is t-butyl.

[0276] Method for preparing obicetrapib—step (b) from aspects (a) to (d) In step (b) of the method for preparing a compound of formula (I) according to the present disclosure, a compound of formula (IV) is converted into a carbamate salt of formula (V) in an organic solvent, followed by the addition of a compound of formula (VI) (wherein Y 1is isolated as a solid salt of a protecting group, eg, as described herein. [ka]

[0277] In some embodiments, the organic solvent used in step (b) is selected from acetonitrile, chlorobenzene, toluene, N-methyl-2-pyrrolidone, xylene, 1,4-dioxane, ethyl acetate, isopropyl acetate, methyl ethyl ketone, methyl isobutyl ketone, dichloromethane, t-butyl methyl ether, and combinations thereof. In some embodiments, the organic solvent is acetonitrile or a mixture of chlorobenzene and dichloromethane.

[0278] As previously described herein, the compound of formula (IV) is already provided in step (a) in the organic solvent used in step (b), either because the same organic solvent is used in steps (a) and (b), or because of a solvent exchange in step (a). In some embodiments of compounds of formula (IV), (V), and (VI), Y 1 is t-butyl.

[0279] In some embodiments, the organic solvent used in step (b) is a mixture of acetonitrile and toluene, wherein the toluene is less than about 20% by weight, based on the total weight of the organic solvent.

[0280] In some embodiments, the conversion of the compound of Formula (IV) to the corresponding carbamate salt having Formula (V) in step (b) is carried out using excess ethyl chloroformate in acetonitrile containing less than about 20% by weight toluene, based on the total weight of the organic solvent, in the presence of pyridine at a temperature between 10°C and 20°C.

[0281] If step (b) is carried out in an organic solvent different from the organic solvent used in step (c), the organic solvent used in step (b) is exchanged for the organic solvent used in step (c) such that the compound of formula (V) remains in solution.

[0282] In some embodiments in which the organic solvents used in steps (b) and (c) are different, at least a portion of the organic solvent used in step (b) is evaporated, such as by distillation under reduced pressure, and the organic solvent in step (c) is added, such that the compound of formula (V) remains in solution during the exchange of the organic solvent. This process can be carried out by continuously evaporating the organic solvent used in step (b) and continuously adding the organic solvent in step (c), for example, until the amount of organic solvent used in step (b) falls below a certain threshold, based on the total amount of organic solvent. Alternatively, this process can be carried out in two or more batchwise steps by evaporating a portion of the organic solvent used in step (b) and then adding a portion of the organic solvent used in step (c), for example, until the amount of organic solvent used in step (b) falls below a certain threshold, based on the total amount of organic solvent.

[0283] The resulting mixture is preferably subjected to one or more treatments with aqueous sodium chloride and / or aqueous HCl, followed by separation of the aqueous phase, and then to one or more treatments with aqueous bicarbonate, followed by separation of the aqueous phase.

[0284] In some embodiments, the conversion of the compound of formula (IV) to the corresponding carbamate salt having formula (V) in step (b) is carried out in acetonitrile containing an excess of ethyl chloroformate in the presence of pyridine at a temperature between 10°C and 20°C, and this solvent is exchanged in step (b) for isopropyl acetate by distilling it off in two or more steps at a temperature below 60°C under reduced pressure, with intermediate addition of isopropyl acetate to a portion of the acetonitrile in an amount to obtain a solution of the compound of formula (V) in isopropyl acetate, and treating this solution one or more times with aqueous NaCl / HCl, followed by separation of the aqueous phase, and then one or more times with aqueous bicarbonate, followed by separation of the aqueous phase.

[0285] Next, the compound of formula (V) dissolved in an organic solvent is reacted with a compound of formula (VI) (wherein A n-is an anion and n is an integer from 1 to 3. The solid form of the salt according to formula (VI) is then isolated as a solid form.

[0286] In some embodiments, the salt of Formula (VI) is selected from sulfonate (e.g., besylate, tosylate, napsylate, camsylate, esylate, edisylate, or mesylate), sulfate (e.g., methylsulfate), halogen, acetate, aspartate, benzoate, bicarbonate, acid tartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate, or teoclate; and anion A n- The salt is selected from salts having the formula:

[0287] In some embodiments, the salt of Formula (VI) comprises an anion A selected from chloride, bromide, acid tartrate, sulfate, and sulfonate. n- The salt is selected from salts having the formula:

[0288] In some embodiments, the salt of Formula (VI) comprises an anion A selected from chloride, bromide, tartrate, and mesylate. n- The salt is selected from salts having the formula:

[0289] In some embodiments, the salt of Formula (VI) is a crystalline mesylate salt thereof, Compound 1D: [ka] It is a mesylate salt containing

[0290] In some embodiments of the salt of Formula (VI), n is 1.

[0291] The organic solvent used in the conversion of formula (V) to (VI) is not particularly limited, but in some embodiments is selected from cyclopentyl methyl ether, isopropyl ether, t-butyl methyl ether, ethyl acetate, isopropyl acetate, and combinations thereof. In some embodiments, isopropyl acetate or a mixture comprising dichloromethane, n-heptane, and isopropyl alcohol, such as a mixture of chlorobenzene, dichloromethane, n-heptane, and isopropyl alcohol, is used. It should be noted that the compound of formula (V) is already provided in an organic solvent by solvent exchange as previously described herein.

[0292] Thus, in some embodiments, the organic solvent used in converting the compound of Formula (V) to the corresponding salt of Formula (VI) is selected from cyclopentyl methyl ether, isopropyl ether, t-butyl methyl ether, ethyl acetate, isopropyl acetate, and combinations thereof, where the toluene is less than about 20% by weight and the acetonitrile is less than about 7% by weight, based on the total weight of the solvent. In some embodiments, the solvent is a mixture of isopropyl acetate, toluene, and acetonitrile, where the toluene is less than about 20% by weight and the acetonitrile is less than about 7% by weight, based on the total weight of the solvent.

[0293] In some embodiments, it is preferable to add an organic co-solvent that is different from the organic solvent already used in step (b). Exemplary organic co-solvents are selected from cyclopentyl methyl ether, isopropyl ether, t-butyl methyl ether, ethyl acetate, isopropyl acetate, and combinations thereof, such as methyl t-butyl ether. As will be understood by those skilled in the art, the necessity and advantages of using an organic co-solvent depend on the specific organic solvent already used in step (b). In some cases, the use of a co-solvent can be omitted.

[0294] In some embodiments, the organic solvent for converting the compound of Formula (V) to the corresponding salt of Formula (VI) comprises isopropyl acetate and methyl t-butyl ether as organic co-solvents.

[0295] An acid is then added to form the salt of formula (VI) as defined above. In some embodiments, the acid is selected from acidic tartaric acid, sulfuric acid, sulfonic acid, hydrogen bromide, and hydrogen chloride. In some embodiments, the acid is methanesulfonic acid. In embodiments where the salt of formula (VI) can be obtained in crystalline form, a portion of the acid required to form the salt of formula (VI) can be added before crystallization, and a portion can be added during crystallization.

[0296] The solid form of the salt of formula (VI) is isolated by crystallization (if the salt of formula (VI) is obtainable in crystalline form), filtration, optionally one or more washing steps of the filter residue, and drying.

[0297] In some embodiments, compound of formula (V) is converted to the corresponding mesylate salt according to formula (VI) using methanesulfonic acid in an organic solvent mixture of isopropyl acetate and methyl t-butyl ether, containing less than about 20% by weight toluene and less than 7% by weight acetonitrile, based on the total weight of the organic solvent, and the methylate salt according to compound 1D is crystallized from the organic solvent, followed by filtration, one or more optional washing steps of the filter residue, and drying.

[0298] In some embodiments where the salt according to formula (VI) may be obtained in crystalline form, crystallization is induced by adding seed crystals of the salt according to formula (VI).

[0299] In some embodiments in which the salt according to Formula (VI) may be obtained in crystalline form, the step of crystallizing the salt according to Formula (VI) to obtain the crystalline form of the salt according to Formula (VI) is carried out by adding an acid required to form the salt, stirring the resulting mixture at a temperature of 20°C to 25°C for at least 60 minutes, crystallizing under stirring at a temperature of 15°C to 25°C for more than 120 minutes, and then subjecting the resulting slurry to vacuum filtration, wherein the filter residue is washed one or more times with the same organic solvent used to crystallize the salt according to Formula (VI), and vacuum drying the crystalline form of the salt according to Formula (VI).

[0300] In one embodiment, the present invention relates to a salt according to formula (VI), wherein A n- is an anion, where n is an integer from 1 to 3. In some embodiments, the compound is a crystalline mesylate (MSA) salt of formula (VI) (e.g., compound 1D described herein).

[0301] In some embodiments, the step of crystallizing the mesylate salt of Formula (VI) from an organic solvent mixture of isopropyl acetate and methyl t-butyl ether to obtain a crystalline form of the mesylate salt according to Compound 1D is carried out by adding methanesulfonic acid required to form the salt, and allowing the resulting mixture to crystallize with stirring at a temperature of 15° C. to 25° C. (e.g., 20° C.) for more than 60 minutes, followed by allowing the mixture to crystallize with stirring at a temperature of 15° C. to 25° C. for more than 120 minutes. The resulting slurry is subjected to vacuum filtration, and the filter cake is washed one or more times with a mixture of isopropyl acetate and methyl t-butyl ether and dried under vacuum to obtain a crystalline form of the mesylate salt according to Compound 1D.

[0302] In some embodiments, the compound of Formula (VI) is obtained in at least 70% yield based on the number of moles of the compound of Formula (II). In some embodiments, the compound of Formula (VI) is obtained in a purity of 99% or greater, such as 99.1% or greater, 99.2% or greater, 99.3% or greater, 99.5% or greater, or greater.

[0303] Method for preparing obicetrapib - step (c) from aspects (a) to (d) In step (c) of the process according to the present disclosure, the isolated salt of formula (VI), or a desalted derivative thereof (e.g., a compound according to formula (V)), is alkylated with a compound of formula (VII) to produce a compound of formula (VIII): [ka] (In the formula, X 2 is a leaving group and Y 1 is a protecting group (e.g., as described herein) The present invention provides a compound of the formula:

[0304] In some embodiments of step (c), an isolated solid form of a salt according to Formula (VI), for example, a crystalline form of a salt according to Formula (VI) (e.g., a crystalline mesylate salt, Compound 1D), is reacted directly with a compound of Formula (VII) in an organic solvent to form a compound of Formula (VIII) (i.e., without a desalting step).

[0305] In some embodiments of step (c), an isolated solid form of a salt according to Formula (VI), such as a crystalline form of a salt according to Formula (VI) (e.g., a crystalline mesylate salt, Compound 1D), is desalted and reacted with a compound of Formula (VII) in an organic solvent to form a compound of Formula (VIII). Desalting of the compound of Formula (VI) provides a compound of Formula (V).

[0306] When the compound of formula (VI) is subjected to a desalting step, the desalting process and the subsequent reaction with the compound of formula (V) are carried out in the same organic solvent. In some embodiments, the organic solvent is selected from xylene, n-hexane, toluene, heptane (mixture of isomers), n-heptane, dichloromethane, chlorobenzene, and combinations thereof. In some embodiments, the organic solvent is toluene or n-heptane.

[0307] In some embodiments, step (c) is carried out in the presence of a base. In some embodiments, step (c) is carried out in the presence of a solid-liquid phase transfer catalyst.

[0308] In some embodiments, the base is selected from alkali metal hydrides, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates, and amines. In some embodiments, the base is selected from alkali metal alkoxides. In some embodiments, the base is sodium t-pentoxide or a mixture of sodium t-butoxide and potassium t-butoxide.

[0309] In some embodiments, the solid-liquid phase transfer catalyst is selected from t-butylammonium hydrogen sulfate, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, crown ethers, and combinations thereof. In some embodiments, the catalyst is t-butylammonium hydrogen sulfate.

[0310] In some embodiments, the reaction of a compound of Formula (V) or (VI) with a compound of Formula (VII) is carried out at a temperature between 0°C and 25°C (such as between 5°C and 20°C).

[0311] The coupling partner of formula (VII) in step (c) may include a leaving group X 2 Any convenient leaving group may be X 2 It will be appreciated that the compounds of formula (VII) can be useful in the present disclosure for: 2 is selected from halogen and a substituted sulfonyloxy group. In some embodiments, the leaving group X in the compound of formula (VII) 2 is a substituted sulfonyloxy group selected from methanesulfonyloxy, p-toluenesulfonyloxy, or trifluoromethanesulfonyloxy groups. In some embodiments, the leaving group X 2 is a halogen. In certain embodiments, the halogen is bromide. In some embodiments, the compound of formula (VII) has the following structure 1E [ka] It is of the type.

[0312] In some embodiments, the desalting of the compound of Formula (VI) and subsequent reaction with the compound of Formula (VII) in step (c) is carried out in toluene as an organic solvent in the presence of a base and a catalyst at a temperature of 5° C. to 25° C. In some embodiments, the desalting of the compound of Formula (VI) and subsequent reaction with the compound of Formula (VII) in step (c) is carried out in toluene as an organic solvent in the presence of sodium t-pentoxide as a base and t-butylammonium hydride as a catalyst with stirring at a temperature of 5° C. to 25° C. for about 1 hour to 8 hours. In some embodiments of the compound of Formula (VI), Y1 is t-butyl.

[0313] In some embodiments, in step (c), the alkylation of the compound of Formula (VI) with the compound of Formula (VII) (i.e., without an additional desalting step) is carried out in toluene as an organic solvent in the presence of a base and a catalyst at a temperature between 5° C. and 25° C. In some embodiments, in step (c), the alkylation of the compound of Formula (VI) with the compound of Formula (VII) is carried out in toluene as an organic solvent in the presence of t-sodium pentoxide as a base and t-butylammonium hydrogen sulfate as a catalyst with stirring at a temperature between 5° C. and 25° C. for about 1 hour to 8 hours.

[0314] In some embodiments, step (c) comprises providing crystalline 1D, desalting the compound, and converting the desalted compound to a compound of formula (VII) (X 2 is Br) in toluene as an organic solvent in the presence of sodium t-pentoxide as a base and t-butylammonium hydrogen sulfate as a catalyst, with stirring at a temperature of 5°C to 25°C for about 1 to 8 hours.

[0315] In some embodiments, step (c) comprises reacting crystalline 1D with a compound of formula (VII) (X 2is Br) in toluene as an organic solvent in the presence of sodium t-pentoxide as a base and t-butylammonium hydrogen sulfate as a catalyst, with stirring at a temperature of 5°C to 25°C for about 1 to 8 hours.

[0316] In some embodiments of step (c), the base is the last reagent added to the reaction mixture. Without being bound by theory, the inventors have discovered that adding the base as the last reagent can reduce the number of equivalents of both the base and the compound of formula (VII) used in the reaction mixture. Reducing the number of equivalents of the compound of formula (VII) can, in turn, reduce the risk of carryover of impurities related to formula (VII) into the final product.

[0317] Thus, step (c) results in the preparation of a compound of formula (VIII) in an organic solvent. In some embodiments of the compound of formula (VIII), Y 1 is t-butyl. In some embodiments, the reaction mixture in step (c) is subjected to one or more aqueous washing steps to remove impurities, followed by separation and removal of the aqueous phase and, optionally, one or more filtration steps to obtain a washed reaction mixture comprising the compound of Formula (VIII) in the organic solvent. In some embodiments, the reaction mixture comprising the compound of Formula (VIII) in the organic solvent is concentrated by distilling off a portion of the organic phase to obtain a concentrated reaction mixture comprising the compound of Formula (VIII) in the organic solvent. In some embodiments, the organic solvent comprises 30-40 wt % of the compound of Formula (VIII) based on the weight of the reaction mixture. In some embodiments, the organic solvent comprises 34-37 wt % of the compound of Formula (VIII) based on the weight of the reaction mixture.

[0318] The one or more aqueous washing steps, optionally one or more filtration steps, and concentration step are preferably combined to provide a washed and concentrated reaction mixture comprising a compound of Formula (VIII) in an organic solvent. In some embodiments, the organic solvent comprises 30-40 wt. % of the compound of Formula (VIII). In some embodiments, the organic solvent comprises 34-37 wt. % of the compound of Formula (VIII), based on the weight of the reaction mixture.

[0319] In some embodiments, the one or more aqueous washing steps include one or more washing steps with an aqueous solution of acetic acid.

[0320] In some embodiments, the reaction mixture comprising the compound of Formula (VIII) in toluene as an organic solvent is subjected in step (c) to one or more aqueous washing steps with aqueous acetic acid, followed by separation of the aqueous phase and then distillation of a portion of the toluene, typically under reduced pressure at a temperature of 75° C. to 90° C., to obtain a washed and concentrated reaction mixture comprising the compound of Formula (VIII) in toluene, with 30 to 40% by weight of the compound of Formula (VIII), based on the weight of the reaction mixture. In some embodiments, the concentrated mixture comprises 34 to 37% by weight of the compound of Formula (VIII), based on the weight of the reaction mixture.

[0321] If step (c) is carried out in an organic solvent different from the organic solvent used in step (d), the organic solvent used in step (c) is exchanged in step (c) with the organic solvent used in step (d) such that the compound of formula (VIII) remains in solution.

[0322] In some embodiments in which the organic solvents used in steps (c) and (d) are different, at least a portion of the organic solvent used in step (c) is evaporated, preferably using distillation under reduced pressure, before adding the organic solvent in step (d), such that the compound of Formula (VIII) remains in solution during the organic solvent exchange. This process can be carried out, for example, by continuously evaporating the organic solvent used in step (c) and continuously adding the organic solvent in step (d) until the amount of organic solvent used in step (c) is below a certain threshold, based on the total amount of organic solvent. Alternatively, this step can be carried out in two or more batchwise steps, for example, by evaporating a portion of the organic solvent used in step (c) and then adding a portion of the organic solvent used in step (d) until the amount of organic solvent used in step (c) is below a certain threshold, based on the total amount of organic solvent.

[0323] Method for preparing compounds of formula (I) - step (d) from aspects (a) to (d) In step (d) of the process according to the present disclosure, the compound of formula (VIII) is converted to obicetrapib (wherein Y 1 is a protecting group, e.g., as described herein). [ka]

[0324] The selection of the first organic solvent used in step (d) is not particularly limited. In some embodiments, the first organic solvent is not an ether or an ester. In some embodiments, the first organic solvent is toluene or a mixture of n-heptane and acetic acid. As explained earlier in this specification, the compound of formula (VIII) is already provided in step (c) in the first solvent used in step (d) either using the same organic solvent in steps (c) and (d) or due to solvent exchange in step (c).

[0325] Thus, in some embodiments, a first organic solvent as defined herein above is provided in step (d) comprising 30 to 40 wt. % of the compound of formula (VIII), for example, 34 to 37 wt. % of the compound of formula (VIII), based on the weight of the reaction mixture.

[0326] In some embodiments, toluene as the first organic solvent is provided in step (d), comprising 30 to 40 wt. %, for example 34 to 37 wt. %, of the compound of Formula (VIII), based on the weight of the reaction mixture.

[0327] Any convenient protecting group for a carboxylic acid, such as an ester moiety, can be used as Y in compounds of formula (VIII). 1 As disclosed herein, the selection of an appropriate protecting group for a carboxylic acid can be readily determined by one of ordinary skill in the art. In some embodiments of formula (VIII), the protecting group (Y 1 In some embodiments of formula (VIII), the protecting group (Y 1 ) is selected from t-butyl, methyl, ethyl, benzyl, allyl, substituted allyl, 2,2,2-trifluoroethyl, phenyl, 4-methoxybenzyl ester, 2,6-disubstituted phenol, and silyl groups. In some embodiments of the compound of Formula (VIII), the protecting group Y 1 is t-butyl. In some embodiments, the conversion of a compound of Formula (VIII) to obicetrapib is carried out by contacting a compound of Formula (VIII) with acetic acid (AcOH) and dry HCl in a first organic solvent, such as toluene or a mixture of n-heptane and acetic acid, with stirring. In some embodiments, the reaction mixture is heated to a temperature of 40° C. to 55° C., and the resulting mixture is maintained at this temperature with stirring for at least 3 hours.

[0328] Obicetrapib can be isolated from the resulting mixture using techniques known to those skilled in the art.

[0329] In some embodiments, the resulting mixture containing obicetrapib is subjected to one or more aqueous washing steps in step (d). In some embodiments, the one or more aqueous washing steps in step (d) are performed as follows: (AA) cooling the reaction mixture containing obicetrapib to a temperature of 15°C to 25°C, then adding a mixture of n-heptane, acetonitrile and water, and then stirring the resulting mixture at this temperature for 15 minutes or more; (BB) a step of separating the system obtained in step (AA) into an organic phase and an aqueous phase and separating the two phases; (CC) adding a mixture of n-heptane, acetonitrile, toluene and water to the aqueous phase obtained in step (BB), and then stirring the resulting system at a temperature of 15°C to 25°C for 15 minutes or more; (DD) A step of separating the system obtained in step (CC) into an organic phase and an aqueous phase and separating the two phases; (EE) combining the organic phase obtained in step (BB) with the organic phase obtained in step (DD), adding water, and stirring the resulting system at a temperature of 15°C to 25°C for 15 minutes or more; (FF) a step of separating the system obtained in step (EE) into an organic phase and an aqueous phase and separating the two phases; (GG) adding water to the organic phase obtained in step (FF) and stirring the resulting system at a temperature of 15°C to 25°C for 15 minutes or more; (HH) A step of separating the system obtained in step (GG) into an organic phase and an aqueous phase and separating the two phases; (II) adding an aqueous solution of trisodium citrate dihydrate to the organic phase obtained in step (HH), and then stirring the resulting mixture at a temperature of 15°C to 25°C for 15 minutes or more; (JJ) a step of separating the system obtained in step (II) into an organic phase and an aqueous phase and separating the two phases; (KK) adding water to the organic phase obtained in step (JJ) and stirring the resulting system at a temperature of 15°C to 25°C for 15 minutes or more; and (LL) A step of separating the system obtained in step (KK) into an organic phase and an aqueous phase and separating the two phases.

[0330] Steps (AA)-(LL) in this embodiment provide a washed compound of Formula (I) in an organic solvent mixture comprising n-heptane, acetonitrile, and a first organic solvent. In some embodiments, the first solvent is toluene.

[0331] In some embodiments, if the first organic solvent is not already based on cyclopentyl methyl ether, the organic solvent mixture is exchanged with CPME in a subsequent step (MM) such that obicetrapib remains in solution.

[0332] Thus, in some embodiments, step (LL) is followed by step (MM), in which at least a portion of the solvent in the organic solvent mixture obtained in step (LL) is evaporated, such as by distillation under reduced pressure, and cyclopentyl methyl ether is added during the solvent exchange so that obicetrapib remains in solution. In some embodiments, this process results in a cyclopentyl methyl ether solution of obicetrapib at a concentration of 30-40 wt% based on the weight of the solution. In some embodiments, the concentration of obicetrapib in cyclopentyl methyl ether is 33-37 wt% based on the weight of the solution, and the first organic solvent is less than 1 wt% and n-heptane is less than 1 wt% based on the weight of the solution.

[0333] This process can be carried out by continuously evaporating the solvent in the organic solvent mixture obtained in step (LL) and continuously adding cyclopentyl methyl ether until the amount of the specific solvent in the organic solvent mixture falls below a certain threshold, for example, based on the total amount of organic solvent. Alternatively, this process can be carried out in two or more batchwise steps by evaporating a portion of the solvent in the organic solvent mixture obtained in step (LL) and then adding cyclopentyl methyl ether until the amount of the specific solvent in the organic solvent mixture falls below a certain threshold, for example, based on the total amount of solvent.

[0334] In some embodiments, the first organic solvent is toluene, and step (LL) is followed by step (MM), in which at least a portion of the n-heptane, acetonitrile, and toluene in the organic solvent mixture obtained in step (LL) are evaporated, for example, by distillation at a temperature of 45°C or less and under reduced pressure (vacuum), with intermediate addition of cyclopentyl methyl ether, so that obicetrapib remains in solution during solvent exchange, thereby obtaining a cyclopentyl methyl ether solution of obicetrapib at a concentration of 30-40 wt%. In some embodiments, the concentration of obicetrapib in the cyclopentyl methyl ether is 33-37 wt%, based on the weight of the solution, with less than 0.5 wt% toluene, less than 0.5 wt% acetonitrile, and less than 2.7 wt% n-heptane.

[0335] Method for preparing crystalline ovicetrapi HCl - steps (e)-(f) added to aspects (a)-(d) In some embodiments of the subject method, step (d) is followed by steps (e)-(f), in which obicetrapib is treated with, for example, HCl in a suitable solvent. Such solvent may be either an aqueous solvent or an organic solvent. In some embodiments, the use of an organic solvent results in crystalline obicetrapib HCl.

[0336] In some embodiments, the organic solvent used in step (e) comprises a mixture of a solvent and an anti-solvent. In some embodiments, the solvent is selected from methanol, ethanol, isopropanol, acetic acid, acetonitrile, acetone, methyl isobutyl ketone, isopropyl acetate, tetrahydrofuran, methyl t-butyl ether, cyclopentyl methyl ether, N-methyl-2-pyrrolidone, dimethyl sulfoxide, dimethylformamide, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, 1,2-difluorobenzene, toluene, hexafluoroisopropanol, and water. In some embodiments, the anti-solvent is selected from n-heptane, n-hexane, n-pentane, and cyclohexane. In some embodiments, HCl has sufficient solubility in the anti-solvent so that it can be used as a suitable solvent. In some embodiments, the organic solvent used in step (e) comprises a mixture of cyclopentyl methyl ether and n-heptane. In some embodiments, the organic solvent used in step (e) further comprises toluene.

[0337] In some embodiments, step (e) comprises providing obicetrapib in a mixture of cyclopentyl methyl ether and n-heptane, raising the temperature to 35°C-40°C under stirring, adding dry HCl in cyclopentyl methyl ether, and then raising the temperature again to 50°C-55°C, followed by the addition of more n-heptane as an anti-solvent. At this point, a small portion of the reaction mixture can be extracted and cooled to a temperature of 10°C-15°C to obtain a slurry of crystals of crystalline obicetrapib HCl in a mixture of cyclopentyl methyl ether and n-heptane (referred to herein as a "seed slurry"). Optionally, all or a portion of the seed slurry of crystalline obicetrapib HCl can then be added back to the reaction mixture as seeds. Seeds aid in nucleation but are not required, and the processes described herein may be carried out without seeding. The resulting reaction mixture is then cooled to a temperature of 5°C to 15°C (e.g., 10°C to 15°C), and crystalline obicetrapib HCl is then crystallized from the system under stirring. In some embodiments, the crystalline obicetrapib HCl is crystallized for a period of 12 hours or more, followed by filtration (e.g., through a filter drier), one or more optional washing steps, such as with a mixture of cyclopentyl methyl ether and n-heptane, and drying. In some aspects, the wet filter cake of crystalline obicetrapib HCl is dried under vacuum using temperatures of 25°C to 30°C, 30°C to 40°C, 40°C to 50°C, and then 50°C to 55°C, e.g., 25°C, 35°C, 46°C, and 54°C.

[0338] Thus, in some embodiments, the method for preparing crystalline obicetrapib HCl includes adding seeds (e.g., as a seed slurry). Seed crystals of crystalline obicetrapib HCl can be formed as a slurry by carrying out step (i) as described above and adding dry HCl in cyclopentyl methyl ether and the anti-solvent n-heptane, followed by extracting a small portion of the reaction mixture and cooling to a temperature of 10°C to 15°C to obtain a slurry of crystals of crystalline obicetrapib HCl in cyclopentyl methyl ether and n-heptane.

[0339] In some embodiments, the organic solvent used in step (e) comprises a mixture of cyclopentyl methyl ether and n-heptane. Thus, in one embodiment, step (e) comprises providing obicetrapib in a mixture of cyclopentyl methyl ether and n-heptane, increasing the temperature to 35°C-45°C under stirring, adding dry HCl in cyclopentyl methyl ether, and again increasing the temperature to 50°C-55°C, adding more n-heptane as an anti-solvent, optionally adding seeds of crystalline obicetrapib HCl (e.g., as a seed slurry prepared as described herein), cooling to a temperature of 5°C-15°C (e.g., 10°C-15°C), and then crystallizing crystalline obicetrapib HCl from the system under stirring. In some embodiments, the crystalline obicetrapib HCl is allowed to crystallize for at least 12 hours, followed by filtration, one or more optional washing steps, such as with a mixture of cyclopentyl methyl ether and n-heptane, and drying. In some embodiments, the crystalline obicetrapib HCl is dried under vacuum. In some embodiments, the crystalline obicetrapib HCl is subjected to drying in a vacuum drying cabinet at a pressure of 25 mbar and a temperature of 55° C. for 10 hours or more. In some embodiments, after the drying procedure, the crystalline obicetrapib HCl contains less than 0.1% by weight of residual cyclopentyl methyl ether.

[0340] In some embodiments described hereinbefore, step (MM) of step (d) results in a cyclopentyl methyl ether solution of obicetrapib at a concentration of 30-40 wt %, e.g., 33-37 wt %, based on the weight of the solution, less than 1 wt % of the first organic solvent used in step (d), and less than 1 wt % of n-heptane. In some embodiments described hereinbefore, step (MM) of step (d) results in a cyclopentyl methyl ether solution of obicetrapib at a concentration of 30-40 wt %, e.g., 33-37 wt %, based on the weight of the solution, less than 1 wt % of toluene, and less than 1 wt % of n-heptane. These solutions can be advantageously used in step (e) after the addition of n-heptane. As will be understood by those skilled in the art, n-heptane can also be added in step (d).

[0341] Thus, in some embodiments, step (e) comprises providing a cyclopentyl methyl ether solution of obicetrapib at a concentration of 30-40 wt %, for example, 33-37 wt %, based on the weight of the solution, less than 1 wt % of the first organic solvent used in step (d), and less than 1 wt % of n-heptane; raising the temperature to 35-45°C under stirring; adding dry HCl in cyclopentyl methyl ether; raising the temperature again to 50-55°C; adding more n-heptane as an anti-solvent; optionally adding seed crystals of crystalline obicetrapib HCl (e.g., as a seed crystal slurry prepared as described herein); cooling to a temperature of 5-15°C (e.g., 10-15°C); and then allowing the crystalline obicetrapib HCl to crystallize from the system under stirring, for example, for at least 12 hours; followed by filtration, one or more optional washing steps, such as with a mixture of cyclopentyl methyl ether and n-heptane, and drying. Optionally, the wet filter cake of crystalline obicetrapib hydrochloride is vacuum dried in steps using temperatures of 25°C to 30°C, 30°C to 40°C, 40°C to 50°C, and then 50°C to 55°C, e.g., 25°C, 35°C, 46°C, 54°C.

[0342] In some embodiments, step (f) comprises: (aa) providing crystalline obicetrapib hydrochloride; (bb) dissolving crystalline obicetrapib HCl in ethanol under stirring (in some embodiments, at a temperature between 15°C and 25°C); (cc) adding aqueous NaOH to the solution obtained in step (bb) and stirring the resulting mixture, for example, at a temperature of 20°C to 25°C for at least 4 hours, to obtain a solution of sodium salt obicetrapib; (dd) optionally filtering the solution obtained in step (cc). (ee) preparing a CaCl2 solution by adding deionized water to CaCl2 under stirring, then adding ethyl acetate as a co-solvent, and stirring the resulting mixture for 10 to 30 minutes; (ff) cooling the CaCl2 solution obtained in step (ee) to a temperature of 8°C to 12°C and adding it through a filter to the solution obtained in step (dd) (or (cc)) while stirring at said temperature; (gg) stirring the slurry resulting from step (ff) for about 1 to about 10 hours (in some embodiments, the slurry is stirred at a temperature of 8°C to 12°C); (hh) isolating the solids from the slurry obtained in step (gg) by filtration (in some embodiments, the isolation is carried out at a temperature of 8°C to 12°C); (ii) washing the filter cake obtained in step (hh) with water in one or more washing steps (in some embodiments, the washing is carried out at a temperature of 8°C to 12°C); and (jj) drying the washed residue obtained in step (ii) in vacuum at a temperature of, for example, 40°C to 50°C for 16 hours or more (for example, 200 hours or more) to obtain amorphous obicetrapib hemi-calcium. Includes:

[0343] In some embodiments of the subject method, the crystalline obicetrapib HCl is isolated in step (f) with a purity of 98% or greater, eg, 98.5% or greater, 99% or greater, 99.5% or greater, or greater.

[0344] Another embodiment of the present disclosure relates to crystalline obicetrapib HCl obtained by or obtainable by the process defined herein.

[0345] Yet another embodiment of the present disclosure relates to crystalline obicetrapib HCl.

[0346] In some embodiments, crystalline obicetrapib HCl, including crystalline obicetrapib HCl, is hygroscopic and therefore, the crystalline obicetrapib HCl is stored at controlled room temperature and under a nitrogen atmosphere and protected from moisture to prevent the formation of amorphous solids.

[0347] Method for preparing amorphous obicetrapib hemi-calcium - steps (g) to (h) added to aspects (a) to (f) In some embodiments of the subject method, after step (f), steps (g)-(h) are performed, in which crystalline obicetrapib HCl is converted to amorphous obicetrapib hemi-calcium (Formula IB): [ka]

[0348] In some embodiments, step (g), i.e., preparation of amorphous obicetrapib hemi-calcium, comprises steps (g1) to (g3) as shown below: (g1) converting the crystalline obicetrapib hydrochloride of step (f) into obicetrapib in an organic solvent; (g2) treating obicetrapib in an organic solvent with aqueous sodium hydroxide to form a sodium salt of obicetrapib; and (g3) treating the sodium salt of obicetrapib with aqueous calcium chloride to form amorphous obicetrapib hemihydrate. wherein the compounds of steps (g1) and (g2) are not isolated.

[0349] Thus, in some embodiments, step (g1) comprises: (aa) providing crystalline obicetrapib hydrochloride as defined or obtained in step (f); (bb) dissolving crystalline obicetrapib HCl in a mixture of water and isopropyl acetate under stirring (in some embodiments, step (bb) is carried out at a temperature between 15°C and 25°C); (cc) subjecting the phases to separation and the resulting organic phase to one or more subsequent washing steps with water, separating the aqueous phase after each washing step to obtain a washed organic phase; and (dd) subjecting the washed organic phase obtained from step (cc) to two or more distillations with intermediate addition of ethanol at a temperature of 50° C. or less (e.g., 30° C. or less) to obtain an ethanol solution of the compound obicetrapib. In some embodiments, step (g2) comprises: (ee) adding aqueous NaOH to the solution obtained in step (dd) and stirring the resulting mixture, for example, at a temperature of 20°C to 25°C for at least 4 hours, to obtain a solution of the sodium salt of obicetrapib; and (ff) optionally filtering the solution obtained in step (ee). Includes:

[0350] In some embodiments, step (g3) comprises: (gg) preparing a CaCl2 solution by adding deionized water to CaCl2 under stirring, followed by adding ethyl acetate as a co-solvent, and stirring the resulting mixture for 10 to 30 minutes; (hh) cooling the CaCl2 solution obtained in step (gg) to a temperature of 8°C to 12°C and adding it through a filter to the solution obtained in step (ff) or (ee) at said temperature while stirring. (ii) stirring the slurry resulting from step (hh) for about 1 to 10 hours (in some embodiments of step (ii), the stirring is carried out at a temperature of 8°C to 12°C); (jj) isolating solids from the slurry obtained in step (ii) by filtration (in some embodiments of step (jj), the isolation is carried out at a temperature of 8°C to 12°C); (kk) washing the filter cake obtained in step (jj) with water in one or more washing steps (in some embodiments of step (kk), the washing is carried out at a temperature of 8°C to 12°C); and (ll) drying the washed residue obtained in step (kk) under vacuum at a temperature of 40°C to 50°C for 16 hours or more (50 hours, 100 hours, 150 hours, or 200 hours or more) to obtain amorphous obicetrapib hemi-calcium (also referred to herein as Compound 3). Includes.

[0351] In some embodiments, step (g) comprises: (aa) providing crystalline obicetrapib hydrochloride as defined or obtained in step (f); (bb) dissolving crystalline obicetrapib HCl in ethanol under stirring (in some embodiments, at a temperature between 15°C and 25°C); (cc) adding aqueous NaOH solution to the solution obtained in step (bb) and stirring the resulting mixture, for example, at a temperature of 20°C to 25°C for at least 4 hours, to obtain a solution of the sodium salt of obicetrapib; (dd) optionally filtering the solution obtained in step (cc); (ee) preparing a CaCl2 solution by adding deionized water to CaCl2 under stirring, followed by adding ethyl acetate as a co-solvent, and stirring the resulting mixture for 10 to 30 minutes; (ff) cooling the CaCl2 solution obtained in step (ee) to a temperature of 8°C to 12°C and adding it through a filter to the solution obtained in step (dd) or (cc) at said temperature while stirring; (gg) stirring the slurry resulting from step (ff) for about 1-10 hours (in some embodiments, the slurry is stirred at a temperature of 8°C-12°C); (hh) separating the solids from the slurry obtained in step (gg) by filtration (in some embodiments, the isolation is carried out at a temperature of 8°C to 12°C); (ii) washing the filter cake obtained in step (hh) with water in one or more washing steps (in some embodiments, the washing is carried out at a temperature between 8°C and 12°C); and (jj) drying the washed residue obtained in step (ii) under vacuum at a temperature of 40°C to 50°C for 16 hours or more (e.g., 50 hours, 100 hours, 150 hours, 200 hours, etc., or even more) to obtain the amorphous hemicalcium salt of formula (IB). Includes.

[0352] In some embodiments, amorphous obicetrapib hemi-calcium is stored sealed at a temperature below 30° C. and protected from light.

[0353] In some embodiments, the amorphous obicetrapib hemi-calcium is subjected to a subsequent reprocessing procedure. In some embodiments, the amorphous obicetrapib hemi-calcium is further reprocessed by dissolving it in ethanol (e.g., twice the weight of the amorphous obicetrapib hemi-calcium in ethanol at a temperature of 25°C to 50°C), cooling to 10°C to 15°C, filtering into a mixture of aqueous calcium chloride and ethyl acetate, again cooling to 10°C to 15°C, filtering, washing with water, and drying under vacuum at 45°C or below for 20 hours or more.

[0354] In many embodiments of the present disclosure, amorphous obicetrapib hemi-calcium is processed to achieve a particular particle size distribution. In many embodiments, such processing is by milling. Examples of milling include hammer milling, ball milling, and jet milling. In other embodiments, spray drying is used to achieve the particle size distribution. Thus, in some embodiments of the present disclosure, spray-dried amorphous obicetrapib hemi-calcium is provided. An example of jet-milled amorphous obicetrapib hemi-calcium is described in Example 11.14.

[0355] In many embodiments of the present disclosure, unmilled amorphous obicetrapib hemi-calcium is provided. In many embodiments of the present disclosure, milled amorphous obicetrapib hemi-calcium is provided.

[0356] In many embodiments, the particle size distribution of the amorphous obicetrapib hemi-calcium is such that 90% of the particles have a diameter of about 15 microns or less. In these and other embodiments, 90% of the particles have a diameter of about 14 microns or less, 13 microns or less, 12 microns or less, 11 microns or less, 10 microns or less, 9 microns or less, 8 microns or less, 7 microns or less, 6 microns or less, 5 microns or less, 4 microns or less, or 3 microns or less.

[0357] In some embodiments, 90% of the particles have a diameter between about 6 microns and 15 microns.

[0358] In these and other embodiments, the particle size distribution of the amorphous obicetrapib hemi-calcium is such that 50% of the particles have a diameter of about 5 microns or less, such as 4 microns or less or 3 microns or less.

[0359] In these and other embodiments, the particle size distribution of the amorphous obicetrapib hemi-calcium is such that 10% of the particles have a diameter of about 2 microns or less.

[0360] The amorphous obicetrapib hemi-calcium of the present disclosure can be produced with high chemical purity according to the process of the present disclosure. Such purity levels include purities of greater than 98.0%, such as 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% or greater. The highest levels of purity, such as greater than 99.8% or 99.9%, are more easily achieved in processes that use crystalline obicetrapib hydrochloride as an intermediate.

[0361] As summarized above, also provided herein are amorphous calcium salts of obicetrapib, including amorphous obicetrapib hemi-calcium. Novel intermediates for use in the synthesis of obicetrapib and its salts are also provided.

[0362] Thus, the subject method has been described with reference to the specific embodiments set forth above. It will be recognized that these embodiments are susceptible to various modifications and alternative forms known to those skilled in the art.

[0363] In certain preferred embodiments of the present invention, the obicetrapib contained in the pharmaceutical compositions of the present invention, used in the methods of the present invention, contained in unit dosage forms (including in pharmaceutical kits), etc., is a salt form of obicetrapib, more particularly, a salt as described by one or more of the following non-limiting clauses: Item 1. Amorphous calcium salt of obicetrapib. Section 2. Amorphous obiscetrapib hemi-calcium. Section 3. Stable amorphous obiscetrapib hemi-calcium. Section 4. Substantially pure amorphous obicetrapib hemi-calcium. Item 5. The amorphous obicetrapib hemicalcium salt according to items 2 to 4, which is substantially free of crystalline salts of obicetrapib hemicalcium. Item 6. Amorphous obicetrapib hemi-calcium according to items 2 to 5, having an X-ray powder diffraction pattern substantially identical to that of Figure 49. Item 7. Amorphous obicetrapib hemi-calcium according to items 2 to 5, having a powder X-ray diffraction pattern including one or more powder X-ray diffraction peaks at about 3.4°2θ, about 7.0°2θ, and about 9.2°2θ. Item 8. Amorphous obicetrapib hemi-calcium according to items 2 to 7, wherein the amorphous obicetrapib hemi-calcium is not birefringent. Item 9. Amorphous obicetrapib hemi-calcium according to items 2 to 8, having a glass transition temperature of about 107°C to about 112°C. Item 10. Amorphous obicetrapib hemi-calcium according to item 9, wherein the glass transition temperature is measured by modulated differential scanning calorimetry. Item 11. Amorphous obiscetrapib hemicaltrium according to item 10, wherein the measurement by modulated differential scanning calorimetry uses an open sample pan. Item 12. Amorphous obicetrapib hemi-calcium according to item 11, wherein the opening is a pinhole. Item 13. Amorphous obiscetrapib hemi-calcium according to items 8 to 12, having a glass transition temperature of about 110°C to about 112°C. Item 14. Amorphous obicetrapib hemi-calcium according to items 2 to 13, having a glass transition temperature of less than about 100°C as measured by differential scanning calorimetry using a closed sample pan. Item 15. Amorphous obicetrapib hemi-calcium according to item 14, having a glass transition temperature of about 70°C to about 92°C as measured by differential scanning calorimetry using a closed sample pan. Item 16. Amorphous obicetrapib hemi-calcium according to items 2 to 15, having a weight loss of less than about 1% when heated to about 200°C. Item 17. Amorphous obicetrapib hemi-calcium according to item 16, having a weight loss of about 0.8% to about 0.95%. Item 18. Amorphous obicetrapib hemi-calcium according to item 17, having a weight loss of about 0.84% ​​to about 0.92%. Item 19. Amorphous obicetrapib hemi-calcium according to items 2 to 18, having a water content of less than about 5%. Item 20. Amorphous obicetrapib hemi-calcium according to item 19, having a water content of less than about 4%. Item 21. Amorphous obicetrapib hemi-calcium according to item 20, having a water content of less than about 3%. Item 22. Amorphous obicetrapib hemi-calcium according to item 19, having a water content of about 0.5% to about 1.5%. Item 23. Amorphous obicetrapib hemi-calcium according to items 2 to 22, which is in bulk form or a formulated composition having a particle size distribution in which about 90% of the particles have a diameter of about 15 microns or less. Item 24. Amorphous obicetrapib hemi-calcium according to item 23, wherein about 90% of the particles have a diameter of about 6 microns to about 15 microns. Item 25. Amorphous obicetrapib hemi-calcium according to item 24, having a particle size distribution in which at least about 90% of the particles have a diameter of about 14 microns or less. Item 26. Amorphous obicetrapib hemi-calcium according to item 25, having a particle size distribution in which at least about 90% of the particles have a diameter of at most about 13 microns. Item 27. Amorphous obicetrapib hemi-calcium according to item 26, having a particle size distribution in which at least about 90% of the particles have a diameter of at most about 12 microns. Item 28. Amorphous obicetrapib hemi-calcium according to item 27, having a particle size distribution in which at least about 90% of the particles have a diameter of at most about 11 microns. Item 29. Amorphous obicetrapib hemi-calcium according to item 28, having a particle size distribution in which at least about 90% of the particles have a diameter of at most about 10 microns. Item 30. Amorphous obicetrapib hemi-calcium according to item 29, having a particle size distribution in which at least about 90% of the particles have a diameter of at most about 9 microns. Item 31. Amorphous obicetrapib hemi-calcium according to item 30, having a particle size distribution in which at least about 90% of the particles have a diameter of at most about 8 microns. Item 32. Amorphous obicetrapib hemi-calcium according to item 31, having a particle size distribution in which at least about 90% of the particles have a diameter of at most about 7 microns. Item 33. Amorphous obicetrapib hemi-calcium according to item 32, having a particle size distribution in which at least about 90% of the particles have a diameter of at most about 6 microns. Item 34. Amorphous obicetrapib hemi-calcium according to item 33, having a particle size distribution in which at least about 90% of the particles have a diameter of at most about 5 microns. Item 35. Amorphous obicetrapib hemi-calcium according to item 34, having a particle size distribution in which at least about 90% of the particles have a diameter of at most about 4 microns. Item 36. Amorphous obiscetrapib hemi-calcium according to item 35, having a particle size distribution in which at least about 90% of the particles have a diameter of about 3 microns or less. Item 37. Amorphous obicetrapib hemi-calcium according to items 2 to 36 in bulk form or in a formulated composition having a particle size distribution in which about 50% of the particles have a diameter of about 5 microns or less. Item 38. Amorphous obicetrapib hemi-calcium according to item 37, having a particle size distribution in which about 50% of the particles have a diameter of about 4 microns or less. Item 39. Amorphous obicetrapib hemi-calcium according to item 38, having a particle size distribution in which about 50% of the particles have a diameter of about 3 microns or less. Item 40. Amorphous obicetrapib hemi-calcium according to items 2 to 39 in bulk form or in a formulated composition having a particle size distribution in which about 10% of the particles have a diameter of about 2 microns or less. Item 41. Amorphous obicetrapib hemi-calcium according to items 2 to 40, having a chemical purity of at least 98.0%. Item 42. Amorphous obicetrapib hemi-calcium according to item 41, having a chemical purity of at least 99.0%. Item 43. Amorphous obicetrapib hemi-calcium according to item 42, having a chemical purity of at least 99.5%. Item 44. Amorphous obicetrapib hemi-calcium according to item 43, having a chemical purity of at least 99.6%. Item 45. Amorphous obicetrapib hemi-calcium according to item 44, having a chemical purity of at least 99.7%. Item 46. Amorphous obicetrapib hemi-calcium according to item 45, having a chemical purity of at least 99.8%. Item 47. Amorphous obicetrapib hemi-calcium according to item 46, having a chemical purity of at least 99.9%. Item 48. Solids substantially identical to the spectrum in Figure 65 13 Item 2 to 47, amorphous obicetrapib hemi-calcium, having a C-NMR spectrum. Item 49. Solids that do not have a peak at approximately 22.1 ppm 13Item 2 to 48, amorphous obicetrapib hemi-calcium, having a C-NMR spectrum. Item 50. Solids that do not have a peak at approximately 29.5 ppm 13 Amorphous obiscetrapib hemi-calcium of items 2 to 49 having a C-NMR spectrum. Item 51. Unground amorphous obiscetrapibhemicaltium. Item 52. Milled amorphous obiscetrapib hemi-calcium. Item 53. Amorphous obicetrapib hemi-calcium according to items 2 to 50, wherein the amorphous obicetrapib hemi-calcium is milled. Item 54. Amorphous obicetrapib hemi-calcium according to any one of items 2 to 50 or 53, wherein the amorphous obicetrapib hemi-calcium has been jet milled. Item 55. Amorphous obicetrapib hemi-calcium according to items 2 to 50 or 53 to 54, wherein the amorphous obicetrapib hemi-calcium is spray-dried. Item 56. Amorphous obicetrapib hemi-calcium prepared by a synthetic process, wherein an intermediate of said process comprises crystalline obicetrapib HCl. Item 57. Amorphous obicetrapib hemi-calcium according to items 2 to 56, wherein the amorphous obicetrapib hemi-calcium is prepared by a synthetic process, wherein an intermediate of said process comprises crystalline obicetrapib HCl. Item 58. Obicetrapib HCl. Item 59. Crystalline obicetrapib HCl. Item 60. Amorphous HCl obicetrapib compound. Item 61. A solvate of obicetrapib HCl according to items 58-60. Item 62. Obicetrapib HCl according to items 58-61, wherein the weight percent of HCl is about 0.01% to about 8%. Item 63. A composition comprising the crystalline obicetrapib HCl described in any one of items 58 to 62. Item 64. The crystalline obicetrapib HCl according to items 58-60 or 62-63, wherein the crystalline obicetrapib HCl is a solvate. Item 65. The crystalline obicetrapib hydrochloride according to item 64, wherein the solvate comprises obicetrapib and hydrochloric acid. Item 66. The crystalline obicetrapib hydrochloride according to item 65, wherein the solvate comprises an organic solvent. Item 67. The crystalline obicetrapib HCl of item 66, wherein the solvate comprises a solvent having sufficient solubility to dissolve sufficient HCl to provide sufficient HCl to form the crystalline obicetrapib HCl. Item 68. A solvate according to item 61 or any one of items 64 to 67, wherein the solvent of the solvate is selected from methanol, ethanol, isopropanol, acetic acid, acetonitrile, acetone, methyl isobutyl ketone, isopropyl acetate, tetrahydrofuran, methyl t-butyl ether, cyclopentyl methyl ether (CPME), N-methyl-2-pyrrolidone, dimethyl sulfoxide, dimethylformamide, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, 1,2-difluorobenzene, toluene, and hexafluoroisopropanol. Item 69. The crystalline obicetrapib HCl according to item 68, wherein the solvent is CPME. Item 70. Crystalline obicetrapib HCl according to any one of items 58-59 or 61-69, having an X-ray powder diffraction pattern substantially identical to that of Figure 67. Item 71. Crystalline obicetrapib HCl according to any one of items 58-59 or 61-69, having an X-ray powder diffraction pattern comprising a peak at about 9.8° 2θ. Item 72. The crystalline obicetrapib HCl of any one of items 58-59, 61-69, or 71, having an X-ray powder diffraction pattern comprising one or more peaks at about 8.1°2θ, about 9.8°2θ, about 13.8°2θ, about 16.7°2θ, and about 19.5°2θ. Paragraph 73. Formula (VI): [ka] (In the formula, Y 1 is a protecting group, An- is an anion; and n is an integer of 1 to 3. Salt. Item 74. A compound having the following structure (Compound 1D): [ka] 74. The salt according to item 73, which is the mesylate salt of Item 75. A crystalline mesylate salt of compound 1D described in item 74. Item 76. A crystalline mesylate salt of compound 1D described in item 75, having a powder diffraction pattern substantially the same as any of the four X-ray powder patterns shown in Figure 68. Item 77. A crystalline mesylate salt of compound 1D according to item 75, having an X-ray powder diffraction pattern comprising one or more peaks at about 5.2° 2θ and about 9.1° 2θ. Item 78. A crystalline mesylate salt of compound 1D described in items 75 to 77, having an X-ray powder diffraction pattern including one or more peaks at about 9.1°2θ, about 15.9°2θ, about 16.5°2θ, about 17.2°2θ, about 18.6°2θ, and about 19.2°2θ.

[0364] In certain preferred embodiments of the present invention, the obicetrapib contained in the pharmaceutical compositions of the present invention, used in the methods of the present invention, contained in unit dosage forms (included in pharmaceutical kits), etc., is a salt form of obicetrapib, more particularly, a salt that can be prepared using the methods described in one or more of the following non-limiting clauses: Item 79. A method for preparing obicetrapib, the method comprising: (a) preparing a compound of formula (IV) by coupling a compound of formula (II) or a salt thereof with a compound of formula (III): [ka] (In the formula, X 1 is a leaving group, and Y 1 is a protecting group); (b) preparing a carbamate salt of formula (V) from a compound of formula (IV) and isolating it as a solid salt form of formula (VI): [ka] (In the formula, Y 1 is a protecting group, and A n- is an anion, and n is an integer from 1 to 3; (c) optionally desalting the compound of formula (VI) and alkylating it with a compound of formula (VII) to provide a compound of formula (VIII): [ka] (In the formula, X 2 is a leaving group, and Y 1 is a protecting group); and (d) converting the compound of formula (VIII) to obicetrapib wherein the reaction steps (a) to (d) are carried out in an organic solvent, and compounds (IV), (V) and (VIII) are optionally not isolated from the organic solvent, and the process need not include chromatography. Item 80. The compound of formula (II) of step (a) is, prior to step (a), (Pre-a1) Formula (IIA) or (IIB): [ka] providing a compound of the formula: (Pre-a2) is obtained by carrying out a step of desalting a compound of formula (IIA) or (IIB) to obtain a compound of formula (II), 80. The method of claim 79, wherein the reaction of step (pre-a2) is carried out in an organic solvent, the compound of formula (II) is not isolated from the organic solvent, and the process does not include chromatography. Item 81. The method of item 80, wherein the salt of formula (IIA) or (IIB) is selected from sulfonate, halogen, acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate, and teoclate. Item 82. Anion A m- 82. The method of claim 81, wherein the salt having the formula: is selected from chloride, bromide, tartrate, sulfate, and sulfonate. Section 83. Anion A m- 83. The method of claim 82, wherein the salt having the formula: is selected from chloride, bromide, tartrate, and mesylate. Item 84. Y in the compounds of formulae (III) to (VI) and (VIII) 1 84. The method according to any one of items 79 to 83, wherein is selected from an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, an allyl group, a substituted allyl group and a silyl group. Item 85. Y in the compounds of formulae (III) to (VI) and (VIII) 1 85. The method of claim 84, wherein is selected from t-butyl, methyl, ethyl, benzyl, allyl, substituted allyl, 2,2,2-trifluoroethyl, phenyl, 4-methoxybenzyl ester, 2,6-disubstituted phenol, and silyl groups. Item 86. Y in the compounds of formulae (III) to (VI) and (VIII) 1 86. The method of claim 85, wherein is t-butyl. Item 87. The salt of formula (VI) is selected from sulfonate, sulfate, halogen, acetate, aspartate, benzoate, bicarbonate, acid tartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate, and teoclate, and an anion A is selected from the group consisting of hydroxypropyl methylcellulose, ... n- wherein the sulfonate is besylate, tosylate, napsylate, camsylate, esylate, edisylate, or mesylate; the sulfate is methylsulfate; and the halogen can be chloride, iodide, or bromide. Item 88. Anion A n- 88. The method of claim 87, wherein the salt having the formula: is selected from chloride, bromide, tartrate, sulfate, and sulfonate. Item 89. Anion A n- 88. The method of claim 87, wherein the salt having the formula: is selected from chloride, bromide, tartrate, and mesylate. Item 90. The salt form of formula (VI) is the mesylate, i.e., compound 1D: [ka] 88. The method of claim 87, wherein Item 91. The method of item 90, wherein the mesylate salt is crystalline. Item 92. X of the compound of formula (III) 1 92. The method of any one of paragraphs 79 to 91, wherein is selected from halogen, carbamate, and substituted sulfonyloxy group. Item 93. X of the compound of formula (III) 1 93. The method of claim 92, wherein is a halogen. Item 94. The method of item 93, wherein the halogen is chloride. Item 95. X of the compound of formula (VII) 2 Item 95. The method of any one of items 79 to 94, wherein is selected from halogen and substituted sulfonyloxy groups. Item 96. X of the compound of formula (VII) 2 96. The method of claim 95, wherein is a halogen. Item 97. The method of item 96, wherein the halogen is bromide. Item 98. A method for preparing an amorphous hemicalcium salt of obicetrapib, said method comprising: (i) treating obicetrapib with HCl to obtain a crystalline obicetrapib HCl compound; (ii) isolating the crystalline obicetrapib HCl compound; (iii) preparing an amorphous hemicalcium salt of obicetrapib from the crystalline obicetrapib HCl compound isolated in (ii); and (iv) isolating the amorphous hemicalcium salt of obicetrapib A method comprising: Item 99. The isolated crystalline obicetrapib HCl compound of step (ii) has the formula (IH): [ka] (wherein y is 0.002 to 1.5) 99. The method of claim 98, comprising the compound of formula (I). Item 100. The preparation of the amorphous hemicalcium salt of formula (I) in step (iii) comprises the steps of: (iii-1) converting the crystalline obicetrapib HCl of step (ii) to provide obicetrapib in an organic solvent; (iii-2) treating obicetrapib in an organic solvent with aqueous sodium hydroxide to form a sodium salt of obicetrapib; and (iii-3) treating the sodium salt of obicetrapib with aqueous calcium chloride to form amorphous obicetrapib hemi-calcium 99. The method of claim 98, wherein the compounds of steps (iii-1) and (iii-2) are not isolated. Item 101. The method according to any one of items 98 to 100, wherein the amorphous hemicalcium salt of obicetrapib is amorphous obicetrapib hemicalcium. Item 102. The method of any one of items 98 to 101, wherein the amorphous calcium salt of obicetrapib is isolated with a chemical purity of at least 99%. Item 103. The method of item 102, wherein the amorphous calcium salt of obicetrapib is isolated with a purity of at least 99.1%. Item 104. The method of item 102, wherein the amorphous calcium salt of obicetrapib is isolated with a purity of at least 99.2%. Item 105. The method of item 102, wherein the amorphous calcium salt of obicetrapib is isolated with a purity of at least 99.3%. Item 106. The method of item 102, wherein the amorphous calcium salt of obicetrapib is isolated with a purity of at least 99.4%. Item 107. The method of item 102, wherein the amorphous calcium salt of obicetrapib is isolated with a purity of at least 99.5%. Item 108. The method of item 102, wherein the amorphous calcium salt of obicetrapib is isolated with a purity of at least 99.6%. Item 109. The method of item 102, wherein the amorphous calcium salt of obicetrapib is isolated with a purity of at least 99.7%. Item 110. The method of item 102, wherein the amorphous calcium salt of obicetrapib is isolated with a purity of at least 99.8%. Item 111. The method of item 102, wherein the amorphous calcium salt of obicetrapib is isolated with a purity of at least 99.9%. Item 112. The method according to any one of items 102 to 111, wherein the amorphous calcium salt of obicetrapib is amorphous obicetrapib hemi-calcium. Item 113. A pharmaceutical composition comprising an amorphous salt of obicetrapib calcium according to any one of items 1 to 57 and one or more pharmaceutically acceptable carriers. Item 114. The pharmaceutical composition according to item 113, wherein the amorphous salt of obicetrapib calcium is amorphous obicetrapib hemi-calcium. Item 115. A method for treating a subject suffering from or at high risk of developing cardiovascular disease, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition described in item 113 or 114. Item 116. An amorphous calcium salt of obicetrapib prepared according to the process described in any one of items 79 to 112. Item 117. An amorphous calcium salt of item 116, which is amorphous obicetrapib hemi-calcium. Item 118. A method for producing amorphous obicetrapib calcium salt, comprising the steps of: treating obicetrapib with an acid to form a salt, a solvate composition, or a combination thereof; isolating the salt, solvate, composition, or combination thereof; and treating the salt, solvate, composition, or combination thereof with a calcium source to produce amorphous obicetrapib hemi-calcium salt. Item 119. The method of item 118, wherein the calcium source is calcium chloride. Item 120. A salt, solvate, composition, or combination thereof comprising obicetrapib and the free acid. Item 121. A salt as described in item 120. Item 122. A solvate according to item 120. Item 123. The composition described in Item 120. Item 124. The free acids are sulfonic, sulfuric, halogenated, acetic, aspartic, benzoic, bicarbonic, acid tartaric, carbonic, citric, decanoic, fumaric, gluceptic, gluconic, glutamic, glycolic, hexanoic, hydroxynaphthoic, isethionic, lactic, lactobionic, malic, maleic, mandelic, mucic, nitric, octanoic, oleic, pamoic, pantothenic, phosphoric, polygastric. Item 120. The salt, solvate, composition, or combination thereof according to item 120, wherein the sulfonic acid is selected from lacturonic acid, propionic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, and teoclic acid; wherein the sulfonic acid can be benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, ethanedisulfonic acid, or methanesulfonic acid; the sulfuric acid is methylsulfuric acid; and the halogenated acid can be HCl, HBr, or HI. Item 125. The method of item 118, wherein the calcium source is a calcium halide salt. Item 126. The method of item 118, wherein the calcium source is a soluble calcium salt. Item 127. The method of item 118, wherein the calcium source is a calcium salt.

[0365] The present disclosure may further be as described by one or more of the preceding non-limiting clauses. [Example]

[0366] Analytical and Physical Characterization Methods The methods used throughout the studies are summarized in Table A. The specific parameters and conditions for the analytical and physical evaluations used in each non-limiting example are described in the relevant section of that example.

[0367] [Table 5]

[0368] XRPD XRPD analyses were performed on an X'pert Pro / Empyrean X-ray diffractometer (PANalytical) equipped with an X'Celerator detector in transmission mode using standard XRPD Aptuit methods. Data were evaluated with Highscore Plus software. The instrument parameters used are listed in Table B below.

[0369] [Table 6]

[0370] Particle size distribution (PSD) PSD analysis was performed on a Sympatec Helos laser diffraction instrument equipped with a RODOS / M for dispersion and an ASPIROS or VIBRI for sample delivery. Powder dispersion is achieved using compressed air through a gun using the Venturi effect. Details of the PSD method are given in Table C.

[0371] [Table 7]

[0372] Identification dissolution method pH 6.8 (Obicetrapib)

[0373] [Table 8]

[0374] Identification dissolution method pH 4.5 (ezetimibe)

[0375] [Table 9]

[0376] QC elution method pH 6.8 (Obicetrapib)

[0377] [Table 10]

[0378] QC elution method pH 4.5 (ezetimibe)

[0379] [Table 11]

[0380] Assay and Impurities / Related Substances (Obicetrapib)

[0381] [Table 12]

[0382] Assay and Impurities / Related Substances (Ezetimibe)

[0383] [Table 13]

[0384] Example 1 Ezetimibe 10 mg, obicetrapib 5 mg fixed-dose combination tablets (small-scale batch approximately 500 g) High shear granulation and fluid bed drying Four prototype formulations were evaluated. Granules contained excipients: a plastic filler (Avicel PH101), a brittle filler (Pharmatose 200M), a binder (Kollidon 30), a disintegrant (Glycolys), and a surfactant (Kolliphor SLS fine). Four preliminary tests (granule batches A4459 / 05 / 01, A4459 / 05 / 02, A4459 / 05 / 03, and A4459 / 05 / 04) evaluated high and low levels of plastic and brittle fillers, and tested two high-shear granulation processing conditions. The final two tests (granule batches A4459 / 07 / 01 and A4459 / 08 / 01) were prepared with a high level of lactose and a low impeller speed (processing condition 2). The composition of excipients and the method of addition were modified as detailed in Table 1.

[0385] The materials were dispensed at target weight and ezetimibe, obicetrapib and intragranular excipients were manually sieved and transferred to a granulation bowl. The granulation solution was prepared by dissolving the required excipients in water.

[0386] Small-scale granules were dried using a STREA fluidized bed granulator, adjusting the air volume as needed to fluidize the material in the bowl until the LOD of the dried granules was equal to or below the initial LOD. The inlet air temperature, product temperature, exhaust temperature, and air flow rate were recorded throughout the drying process. After drying, the granules were tested for granule homogeneity, LOD, sieve analysis, TBD, and XRPD of the API.

[0387] Preparation of the final blend and tableting The final blend was prepared by accurately weighing the required amount of extragranular excipients. The excipients (except magnesium stearate (MgSt)) were then manually sieved and added to the appropriate volumetric bin along with the granules and blended using a Pharmatech mixer. MgSt was sieved separately and added to the bin. For compression, a single-punch compression machine (specifically, an EK0 tableting machine) was used to develop a compression profile and produce tablets with a target weight of 150.0 mg. Based on the information gathered for the compression profile, small-scale tablet production was conducted. These tablets were tested for appearance, assay and impurity content, differential dissolution, ezetimibe USP tablet dissolution method, content uniformity, and moisture content by KF and XRPD. All manufacturing intermediates and uncoated tablets were stored in double-layered LDPE bags closed with cable ties and transferred to sealed aluminum bags containing silica.

[0388] [Table 14]

[0389] result Small-scale study to produce 10mg ezetimibe tablets and 5mg obicetrapib tablets Granules for small-scale batches were successfully manufactured. Energy consumption during granulation increased with the addition of granulating solution, and the LOD of the dried granules was lower than the initial LOD (Table 2). Granules A4459 / 05 / 01 and A4459 / 05 / 02 exhibited coarser particles compared to granule batches A4459 / 05 / 03 and A4459 / 05 / 04. This was related to the higher level of lactose in the formulation rather than the granulation parameters (Process Condition 1 vs. Process Condition 2). By reducing the amount of binder and water for granulation and increasing the surfactant level, granule batches A4459 / 07 / 01 and A4459 / 08 / 01 (manufactured with higher levels of lactose) exhibited particles with a greater proportion of fines compared to batches A4459 / 05 / 01 and A4459 / 05 / 02 (Figures 1 and 2). Briefly, tablets containing a higher content of microcrystalline cellulose (batches A4459 / 05 / 07 and A4459 / 05 / 08) showed faster disintegration times, lower friability, and higher hardness values ​​than tablets containing a higher content of lactose (batches A4459 / 05 / 05 and A4459 / 05 / 06). Overall, these tablet batches exhibited favorable appearance. Tablet batches A4459 / 07 / 02 and A4459 / 08 / 02 (containing high levels of lactose) exhibited faster disintegration times and suitable dissolution profiles for both drug substances. However, tablet hardness and friability could not be improved to levels considered acceptable due to failure of capping and friability tests. Tablet hardness was lower than that obtained in previous studies (batches A4459 / 05 / 05 and A4459 / 05 / 06).

[0390] [Table 15]

[0391] Granule characterization Chemical characterization The granules were tested for homogeneity of both obicetrapib and ezetimibe and the results are reported in Table 3. The maximum RSD % value obtained for batch A4459 / 05 / 03 was within the typical acceptable range for granule homogeneity.

[0392] [Table 16]

[0393] Physical characterization Small amounts of ezetimibe (EZE) hydrate were found in all wet granule samples, as shown in Table 4. However, during the drying process, the formed EZE hydrate was converted to EZE anhydrate, except for Batch 05 / 01, where trace amounts of the hydrate polymorph appeared to remain.

[0394] [Table 17]

[0395] Tablet characterization Chemical characterization The characterization results of the small-scale batches are shown in Table 5. The assay and impurity results were as expected, and the impurity profile was consistent for both input APIs. The content uniformity results also showed that all prototypes were of uniform API content, with AV values ​​significantly lower than the pharmacopoeia requirements for AV. The moisture content results were found to be in the range of 4.5-5.0%, and no cosmetic defects were observed.

[0396] The dissolution profiles of obicetrapib showed similar trends for prototypes A4459 / 05 / 08, A4459 / 05 / 06, and A4459 / 05 / 07. Prototype A4459 / 05 / 08 (high Avicel content and slow impeller speed) rapidly dissolves in 5 to 15 minutes. Prototype A4459 / 05 / 05 (high lactose content and fast impeller speed) dissolves significantly slower. Dissolution results using the USP ezetimibe method (pH 4.5) were consistent with those observed at pH 6.8. Significant improvements in dissolution characteristics were observed for prototypes 3 and 4, batches A4459 / 07 / 02 (4% binder) and A4459 / 08 / 02 (1% binder), and prototype 4 showed a profile consistent with the commercially available reference ezetimibe tablets. The dissolution profiles are shown in Figures 3, 4, and 5. Assay, content uniformity and impurity profiles showed no significant differences among the four formulations of either obicetrapib or ezetimibe.

[0397] [Table 18]

[0398] [Table 19]

[0399] [Table 20]

[0400] Stress Stability The prototypes and 2 with different process conditions were evaluated in stress stability tests according to the following design.

[0401] [Table 21]

[0402] The results are shown in Tables 7, 8 and 9.

[0403] [Table 22]

[0404] [Table 23]

[0405] [Table 24]

[0406] [Table 25]

[0407] [Table 26]

[0408] [Table 27]

[0409] [Table 28]

[0410] [Table 29]

[0411] [Table 30]

[0412] Physical characterization For prototype tablet A4459 / 05 / 05, the presence of some EZE hydrate was observed in the early time point samples and all samples placed at steady state, while for the other tablet prototypes, small amounts of the EZE hydrate form were observed at 3WK and 4WK. The XRPD data are summarized in Table 10.

[0413] [Table 31]

[0414] Example 2 Fixed-dose combination for 10 mg ezetimibe and 10 mg obicetrapib tablets (small-scale batch approximately 500 g) Details of the prototype formulations prepared in this series of experiments are summarized in Tables 11 and 12. The primary modification to the formulation composition was an increase in the dose strength of obicetrapib (free acid) from 5.0 mg to 10.0 mg.

[0415] High shear granulation and fluid bed drying These trials were carried out as small scale batches (500 g batch size) according to process condition 2. However, batch A4459 / 16 / 02 (known as "Prototype C Scale-up") was carried out at a 2 Kg batch size scale.

[0416] The powder was manually sieved into a granulation bowl and mixed for 5 minutes. The granulation solution was sprayed at the required spray rate to perform wet granulation, after which the material was dried in a fluidized bed dryer. The inlet air temperature and air volume were adjusted as needed to fluidize the granules, which were then dried until the LOD was equal to or less than the initial LOD. The granules were characterized for API content homogeneity, LOD (immediately after milling), sieve analysis, TBD, and XRPD. Granule batch A4459 / 13 / 01 (prototype A) and batch A4459 / 16 / 02 (prototype C scale-up) were divided into two aliquots to produce the final blends required for the production of 150 mg and 200 mg tablets.

[0417] Preparation of the final blend, tableting and coating To produce tablets with the required composition, the final blend was prepared by accurately weighing the extragranular excipients. The excipients were manually sieved and mixed using a suitable volumetric bottle. The lubricant (MgSt) was sieved separately and added to a bowl for mixing. A single punch compression machine was used to generate a compression profile and produce small-scale batches of tablets. Tablet friability, disintegration time, hardness, appearance, and thickness were monitored throughout the process. Tablets were validated for the discriminant dissolution method, ezetimibe USP tablet dissolution method, and XRPD.

[0418] Three selected tablet batches (Prototype B, Prototype C Scale-Up, and Prototype C Scale-Up 200) were coated with 20% w / w Opadry AMB II white aqueous suspension. Coating process parameters and tablet weight gain were monitored during processing. The coated tablets were validated for XRPD, obicetrapib differential dissolution method, ezetimibe USP tablet dissolution method, and ezetimibe USP tablet dissolution method with a paddle speed of 75 rpm.

[0419] All manufacturing intermediates and final formulations were stored in double LDPE bags closed with cable ties and transferred to thermosealed aluminum bags containing silica.

[0420] [Table 32]

[0421] [Table 33]

[0422] result: These granulation tests were successful. Overall, the granules showed a similar PSD to batch A4459 / 08 / 01 (Prototype 4) and a relatively high amount of fines (Figure 18). Compared to batch A4459 / 08 / 02 (Prototype 4, Condition 2), for similar compression forces, the tablet batch showed similar disintegration times, higher hardness, and lower friability. No significant defects (e.g., capping, lamination) were observed in the tablets. The coated tablets presented a smooth, white surface and no visual defects were evident on close inspection.

[0423] Granule characterization Chemical characterization The granules were tested for homogeneity for both obicetrapib and ezetimibe and the results are shown in Table 13. The analysis was performed with n=6 except for the scale-up batch where n=10 was performed.

[0424] Physical characterization XRPD data for the development prototypes are summarized in Table 14. EZE hydrate can be observed in samples before or during the granulation process, however, the amount of EZE hydrate detected appears to be very limited at any one time.

[0425] Tablet characterization Chemical characterization The characterization results of the small-scale batches are shown in Table 15. The prototypes were validated for dissolution. The dissolution results for obicetrapib showed similar profiles for all prototypes tested, with minor differences attributed to analytical variability. For ezetimibe, prototypes D and C showed the most promising results, with prototype C meeting the USP specification of Q=80+5 at 30 minutes across three vessels. This most promising prototype was also characterized under the USP dissolution method conditions for ezetimibe, using a higher paddle speed of 75 rpm. This was appropriate, as it was emphasized that the USP method, developed for tablets lighter than the developed fixed-dose combination, appears to over-discriminate for tablets with target weights up to 200 mg. The results showed a profile consistent with the currently marketed formulation.

[0426] Physical characterization As reported in Table 16, all small scale prototype tablets produced showed small amounts of EZE hydrate, except for Prototype C and C scale-up 200 mg batches.

[0427] [Table 34]

[0428] [Table 35]

[0429] [Table 36]

[0430] [Table 37]

[0431] [Table 38]

[0432] Stress Stability To assess the feasibility of the coating process based on the process tableting parameters and dissolution data, the following: A4459 / 16 / 03 (150 mg / tablet, C scale-up prototype) A4459 / 18 / 03 (200mg / tablet, C scale-up prototype / 200mg) After tablet prototypes were selected, they were subjected to stress stability tests with the following design for stability. The results are reported in Tables 17 and 18.

[0433] [Table 39]

[0434] [Table 40]

[0435] [Table 41]

[0436] [Table 42]

[0437] [Table 43]

[0438] Physical characterization XRPD data for samples subjected to stress stability are summarized in Table 21. Both prototype tablets exhibit ezetimibe hydrate after 2 WK exposure at 40°C / 75% RH, but once packaged, no polymorphic conversion occurs up to 4 WK storage.

[0439] [Table 44]

[0440] Example 3 Co-granulated fixed dose combination (FDC1) of 10mg ezetimibe and 10mg obicetrapib (small scale batch approximately 500g) High shear granulation, drying, preparation of final blend and tableting Three compositions (Composition 1 batch A4459 / 20 / 02, Composition 2 batch A4459 / 20 / 03, and Composition 3 batch A4459 / 20 / 04) were prepared, as summarized in Table 22. The prototype formulation composition selected for these compositions was that of "Prototype C" (e.g., Granule Batch A4459 / 13 / 03). Granule preparation and characterization (LOD and XRPD) are described in the previous section (Small-Scale Manufacturing). Granules were tested for content uniformity, LOD, sieve analysis, TBD, and XRPD. Tableting blends and compression profiles, and small-batch tablet manufacturing at 150 mg tablet weight, were performed as described in the previous example. Tablets were verified for content uniformity, XRPD, dissolution, and moisture content by KF. All manufacturing intermediates and final drug product were stored as described in the previous section.

[0441] [Table 45]

[0442] result High shear granulation was successful. The drying process was carried out without issue, and after 15 minutes of drying, the LOD of the granules was lower than the initial LOD. In general, the granules exhibited a relatively large amount of fines, despite increasing the impeller speed (composition 1) (Figure 26), extending the wet granulation time (composition 2), or increasing the amount of granulating agent (composition 3). Tablet friability, disintegration time, thickness, and hardness were found to be similar between these tablet batches.

[0443] Chemical properties of the granules When the homogeneity of the granules was examined, it was found that obicetrapib and ezetimibe were uniformly dispersed.

[0444] Physical characterization XRPD data for blend / granule prototype FDC1 is summarized in Table 23. Eze hydrate appears only in the wet granule sample. All three prototypes exhibited similar flow properties.

[0445] Chemical properties of the tablets The results of the chemical characterization of FDC1 tablets are reported in Table 24. The analytical characterization results showed no significant differences between the three compositions.

[0446] Physical characterization XRPD data for tablets of the FDC1 composition are summarized in Table 25. No Eze hydrate was observed in any of the samples.

[0447] [Table 46]

[0448] [Table 47]

[0449] [Table 48]

[0450] [Table 49]

[0451] Example 4 Fixed-dose combination (FDC2) of 10 mg ezetimibe and 10 mg obicetrapib with granulation of ezetimibe and extragranular addition of obicetrapib High Shear Granulation and Drying Three compositions were prepared, as summarized in Table 26. The excipients contained in the granules were the same as those used to manufacture the granules for the FDC1 approach. The formulation composition of these granules represented that of FDC1 granule "Prototype C." The methods of high shear granulation, granule drying, and milling were described in the previous sections. The granules were verified for content uniformity (ezetimibe only), sieve analysis, TBD, and XRPD.

[0452] Preparation of the final blend, tableting and coating The ingredients of the extragranular formulation are listed below: -Ovicetrapib -Plastic filler (Avicel PH200) -Brittle filler (Pearlitol 200 SD) -Disintegrant (Glycolys) -Glydant (Aerosil 200) -Lubricant (Ligamed MF-2-V)

[0453] The final blend was prepared by accurately weighing and sieving the extragranular ingredients (excipients and API). The excipients and granules were filled into a jar of appropriate volume and mixed using a Pharmatech mixer. The lubricant (MgSt) was then added to the jar and mixed.

[0454] A single punch compression machine (EKO) equipped with a 9.0 mm round punch (R=11) was used to develop the compression profile and produce small batches of tablets. The target tablet weight was 230 mg, and tablet friability, disintegration time, hardness, appearance and thickness, as well as individual and 10 tablet weights, were monitored throughout the process.

[0455] Tablets were tested for content uniformity (stratified samples: beginning, middle and end of production), XRPD, dissolution and moisture content by KF.

[0456] Tablets were coated with a 20% w / w white aqueous suspension of Opadry AMB II to the required target weight gain (target weight gain 3% w / w, limit 2% w / w to 4% w / w). The coating suspension and coating method are described in the previous section. Coating parameters and tablet weight gain were monitored throughout the process. Coated tablets were examined for XRPD, dissolution, appearance, content uniformity, and moisture content by KF.

[0457] All manufacturing intermediates and final formulations were stored in double LDPE bags containing silica and transferred to thermally sealed aluminum bags.

[0458] [Table 50]

[0459] [Table 51]

[0460] result High shear granulation of the FDC2 composition was successful. The drying process was uneventful, and after approximately 16 minutes of drying, the LOD of the granules was lower than the initial LOD. The granules exhibited a relatively large amount of fines (Figure 29). Disintegration time and thickness values ​​were similar between FDC2 tablet batches.

[0461] Chemical characterization of granules The A4459 / 20 / 01 blend was tested for homogeneity of obicetrapib and ezetimibe and found to be homogeneously dispersed. Results for the other two granules were not collected.

[0462] Chemical characterization of tablets The results of the chemical characterization of FDC2 tablet prototype 1 are shown in Tables 27 and 28. The analytical characterization results showed no significant differences among the three prototypes of FDC2.

[0463] Physical characterization XRPD data for blends / granules from FDC2 composition are summarized in Table 29. XRPD data for tablets from the FDC2 approach are summarized in Table 30. A small amount of Eze hydrate was present in Prototype 1.

[0464] [Table 52]

[0465] [Table 53]

[0466] [Table 54]

[0467] [Table 55]

[0468] [Table 56]

[0469] [Table 57]

[0470] Stress Stability Prototype 2 coated tablets were selected for stress stability testing with the following design.

[0471] [Table 58]

[0472] The results are reported in Tables 66, 67 and 68.

[0473] [Table 59]

[0474] [Table 60]

[0475] [Table 61]

[0476] Example 5 Fixed-dose combination (FDC3) of 10 mg ezetimibe and 10 mg obicetrapib with granulation of obicetrapib and extragranular addition of ezetimibe Prototype compositions were prepared as summarized in Table 35. The granulation method followed Process Condition 2 described above. The methods for high shear granulation, granule drying, and milling were as described in the previous section. The granules were verified for content uniformity (obicetrapib only), sieve analysis, TBD, and XRPD.

[0477] Preparation of the final blend, tableting and coating The final blend was prepared by accurately weighing and sieving the extragranular ingredients (excipients and API). The excipients and granules were filled into a jar of appropriate volume and mixed using a Pharmatech mixer. The lubricant (MgSt) was then added to the jar and mixed.

[0478] A single punch compression machine was used to develop the compression profile and produce small batches of tablets. The target tablet weight was 230 mg, and throughout the process, tablets were monitored for friability, disintegration time, hardness, appearance, and thickness, as well as individual and 10-tablet weights. Tablets were verified for content uniformity (stratified samples: beginning, middle, and end of production), XRPD, dissolution, and moisture content by KF.

[0479] Tablets were coated with 20% w / w Opadry AMB II white aqueous suspension to the required target weight gain. The coating suspension and coating method are described in the previous section. Coating parameters and tablet weight gain were monitored throughout the process. Coated tablets were examined for XRPD, dissolution, appearance, content uniformity, and moisture content by KF.

[0480] All manufacturing intermediates and final formulations were stored in double LDPE bags containing silica and transferred to thermally sealed aluminum bags.

[0481] [Table 62]

[0482] Example 6 Fixed-dose combination (FDC4) of ezetimibe 10 mg and obicetrapib 10 mg as bilayer tablets by separate granulation of obicetrapib and ezetimibe followed by compression Prototype compositions were prepared as summarized in Table 36. The granulation method for ezetimibe was the same as that described for FDC1, and the granulation method for obicetrapib was the same as that described for FDC3. The high-shear granulation, granulation drying, and milling methods were the same as those described in the previous section for FDC1. The granules were then fed into a compactor via two hoppers. The first granules were filled into the die and then subjected to light compression. The second granules were then filled and compressed according to the method described in the previous example. Individual granules were verified for content uniformity (obicetrapib or ezetimibe), sieve analysis, TBD, and XRPD. The granules were compressed to form tablets according to the method described above. The tablets were verified for content uniformity (stratified samples: beginning, middle, and end of production), XRPD, dissolution, and moisture content by KF.

[0483] Tablets were coated with 20% w / w Opadry AMB II white aqueous suspension to the required target weight gain. The coating suspension and coating method are described in the previous section. Coating parameters and tablet weight gain were monitored throughout the process. Coated tablets were examined for XRPD, dissolution, appearance, content uniformity, and moisture content by KF.

[0484] All manufacturing intermediates and final formulations were stored in double LDPE bags containing silica and transferred to thermally sealed aluminum bags.

[0485] [Table 63]

[0486] Example 7 Scale-up of FDC1 and FDC2 compositions High shear granulation, drying, final blending, tableting and coating The API and excipients were precisely dispensed, sieved, and added to the granulation bowl according to the approaches detailed in the FDC1 and FDC2 formulation approaches above. Granulation parameters for both the FDC1 and FDC2 approaches were identical. Granulations were verified for content uniformity (FDC1 approach only), LOD, sieve analysis, TBD, and XRPD.

[0487] A final blend of the FDC1 and FDC2 compositions was prepared to manufacture tablets, the batch numbers and compositions of which are detailed in Table 37. The extragranular components were manually sieved and filled into bottles of appropriate volume. The granules were mixed with the extragranular material using a Pharmatech mixer. The FDC2 blend was then verified for content uniformity.

[0488] The use of a rotary press was evaluated for the development of compression profiles and tableting runs. Tablet friability, disintegration time, hardness, thickness and appearance, as well as individual and 10 tablet weights, were monitored during the tableting run. Tablets were examined for content uniformity (stratified samples: beginning, middle and end of run), moisture content by XRPD, dissolution and KF.

[0489] Tablets were coated with 20% w / w Opadry AMB II white aqueous suspension to the required target weight gain (target weight gain 3% w / w, limit 2% w / w to 4% w / w). The coating suspension and coating method are described in the previous section. Coating parameters and tablet weight gain were monitored throughout the process. Coated tablets were examined for XRPD, dissolution, appearance, assay, and moisture content by KF.

[0490] All manufacturing intermediates and final formulations were stored in double LDPE bags containing silica and transferred to thermally sealed aluminum bags.

[0491] [Table 64]

[0492] [Table 65]

[0493] result High-shear granulation of the scaled-up batches was successful. The granules showed similar PSDs by sieve analysis and a large amount of fines (Figure 37). These PSD values ​​were comparable to those observed in previous studies (e.g., batch A4459 / 16 / 02 as the reference for the FDC1 scaled-up batch and batch A4459 / 25 / 01 as the reference for the FDC2 scaled-up batch). Despite this similarity in the PSD data, the flowability of the scaled-up batches was improved compared to the reference batch, based on the Hauser ratio values. The disintegration time of these tablets was less than 5 minutes, and the friability was less than 0.2%. The coating process was carried out without significant issues, and the coated tablet surfaces were smooth, resulting in satisfactory appearance for both formulation approaches.

[0494] Chemical characterization of granules The granules and final blend were tested for homogeneity of both obicetrapib and ezetimibe and were found to be homogeneously dispersed. The dissolution of both obicetrapib and ezetimibe, as well as the impurity profile of ezetimibe, results are reported in Table 38, Figure 38, Figure 39 and Figure 40.

[0495] Chemical characterization of tablets The results of chemical characterization of the scaled-up batches of uncoated tablets are shown in Table 39. The dissolution results of the uncoated tablets at different compression forces are shown in Tables 40, 41, 42 and 43. The results of the coated tablets are reported in Table 42.

[0496] Physical characterization XRPD data for granules / tablets from scale-up batches are summarized in Table 43. No EZE hydrate was observed in all batches tested.

[0497] [Table 66]

[0498] [Table 67]

[0499] [Table 68]

[0500] [Table 69]

[0501] [Table 70]

[0502] [Table 71]

[0503] [Table 72]

[0504] [Table 73]

[0505] Example 8 Technical batches of FDC1 and FDC2 compositions The batch numbers and compositions of the technical manufacturing granules, tablets and coated tablets for FDC1 and FDC2 formulations are detailed in Table 49.

[0506] High Shear Granulation and Drying The ingredients for FDC1 granules (batch A4459 / 30 / 02) and FDC2 granules (batch A4459 / 30 / 01) were manually sieved and added to a granulation bowl. For both the FDC1 and FDC2 compositions, the granule batch size was 2 kg, and identical granulation processing conditions were used. The physical mixture was blended at 220 rpm for 5 minutes and LOD testing was performed. The granulating agent (purified water) was sprayed, and wet granulation was performed for 1 minute after spraying. Samples were taken for XRPD and LOD. The granules were then dried using a fluidized bed dryer. The drying process was terminated when the LOD of the granules was equal to or less than the initial LOD or less than 3% (w / w). The granules were verified for content uniformity (FDC1 only), PSD, LOD, sieve analysis, TBD, and XRPD.

[0507] Final Blend and Tableting The method for preparation of the final blend was described in the previous section (Scale-up Batch). The FDC2 blend was verified for content uniformity.

[0508] A rotary press was used to develop the compression profile and for the tableting campaign. 7.0 mm diameter punches were used to produce one FDC tablet (target tablet weight 150 mg), while 8.5 mm diameter punches were used to produce two FDC tablets (tablet weight 230.0 mg). Tablet friability, disintegration time, hardness, thickness, and appearance, as well as individual and 10-tablet tablet weights, were monitored during the tableting process. Tablets were verified for content uniformity (stratified samples: beginning, middle, and end of production), moisture content by XRPD, dissolution, and KF.

[0509] coating A 20% (w / w) solids coating suspension was prepared by adding the required amount of Opadry to water under stirring. The suspension was mixed for at least 45 minutes and visually inspected for homogeneity. The spray rate of the coating suspension was then measured. The coating suspension was maintained under constant stirring. Tablet weight gain was monitored throughout the manufacturing process, and spraying was stopped once the required target gain (3% w / w, 2% w / w to 4% w / w limits) was achieved. The coated tablets were visually inspected for XRPD, dissolution, appearance, content uniformity, and moisture content by KF.

[0510] All manufacturing intermediates and final formulations were stored in the stability laboratory using the following packaging: 60mL high-density polyethylene (HDPE) induction-sealed and closed with a child-resistant cap. 20 tablet capacity; 60mL high density polyethylene (HDPE) tablets, induction sealed with a 2g desiccant canister and closed with a child-resistant cap. Tablet capacity: 20 tablets.

[0511] [Table 74]

[0512] [Table 75]

[0513] result Technical batches of FDC1 and FDC2 compositions High-shear granulation of the technical batch was successful, with no issues encountered during the process. Powder consumption was comparable to that observed in the scale-up batch. Because the LOD of the granules was less than 3%, the drying step was completed within 45 minutes. The granules exhibited similar PSD values, with a relatively high amount of fines (e.g., approximately 70%-73% of particles less than 125 μm) (Figure 45). No relevant differences were observed compared to the scale-up batch. Compared to the FDC2 scale-up batch (batch A4459 / 29 / 06), the FDC2 technical batch yielded harder tablets at similar compression forces, but the disintegration times between these batches were very similar for a given tablet hardness.

[0514] Chemical characterization of granules The granules and final blend were tested for homogeneity of obicetrapib and ezetimibe and were found to be homogeneously dispersed.

[0515] Chemical characterization of tablets Chemical characterization of the technical batch coated tablets is shown in Table 50. The tablets exhibited satisfactory quality levels, with claims (%) within typical clinical acceptance criteria (i.e., 90.0-110.0%). Content uniformity test results met the pharmacopoeia requirement of AV<15.0. Dissolution met the recommended specification of Q=75% at 45 minutes (Figures 46 and 47).

[0516] Physical characterization The XRPD data for the granules / tablets from the technical batches are summarized in Table 51. All batches tested showed the absence of EZE hydrate, except for the granules from the FDC2 formulation. However, in the case of the coated tablets, the hydrate form disappeared. The granules from all batches exhibited similar flow properties. The PSD data for the granules are reported in Table 52 and Figure 48. The batches exhibited similar bimodal curves.

[0517] Stability testing A summary of the physicochemical analysis of technical batches of FDC2 composition after 3 months of storage is shown in Table 53 (without desiccant) and Table 54 (with desiccant), and a summary of FDC1 composition is shown in Table 55 (without desiccant) and Table 56 (with desiccant).

[0518] [Table 76]

[0519] [Table 77]

[0520] [Table 78]

[0521] [Table 79]

[0522] [Table 80]

[0523] [Table 81]

[0524] [Table 82]

[0525] [Table 83]

[0526] [Table 84]

[0527] Table 85

[0528] Table 86

[0529] Table 87

[0530] Table 88

[0531] Table 89

[0532] Table 90

[0533]

Table 91

[0534] Table 92

[0535]

Table 93

[0536] Table 94

[0537]

Table 95

[0538] Table 96

[0539] Table 97

[0540] Table 98

[0541]

Table 99

[0542]

Table 100

[0543] Table 101

[0544] Table 102

[0545] Table 103

[0546] Table 104

[0547] Table 105

[0548] [Table 106]

[0549] [Table 107]

[0550] Example 9 A comparative study to evaluate the bioavailability of two fixed-dose combinations of obicetrapib / ezetimibe 10mg / 10mg (FDC1 and FDC2) and obicetrapib 10mg co-administered with ezetimibe 10mg under fasting conditions in healthy adult subjects Study design This study was an open-label, single-dose, randomized, three-treatment, three-period, six-sequence crossover study comparing coadministration of two test formulations with a reference formulation under fasting conditions. During each study period, subjects received either Treatment T1 (1× obicetrapib 10 mg and ezetimibe 10 mg FDC tablet [Formulation #1]), Treatment T2 (1× obicetrapib 10 mg and ezetimibe 10 mg FDC tablet [Formulation #2]), or Treatment R (1× obicetrapib 10 mg tablet coadministered with 1× ZETIA® (ezetimibe) 10 mg tablet) after an overnight fast of at least 10 hours. The dosing sequence followed a six-sequence randomization schedule. Blood samples were collected pre-dose and at intervals of more than 336 hours post-dose during each study period. During each study period, subjects were confined to the clinical facility from at least 10 hours before dosing until 24 hours after dosing, and returned to the clinical facility for blood sampling at 48, 72, 96, 144, 192, 240, and 336 hours after dosing. The dosing interval was at least 49 days.

[0551] Plasma concentrations of obicetrapib, ezetimibe, and its metabolite ezetimibe glucuronide were measured using a fully validated analytical method.Statistical analysis using mean bioequivalence methodology was performed to evaluate the bioavailability of each test formulation compared to that of the co-administered reference formulation.

[0552] Selection of study population The subject population included 36 healthy, non-tobacco, non-nicotine-using adult male and female subjects.

[0553] Medication administration Subjects received Treatment T1, Treatment T2, or Treatment R under directly observed conditions after an overnight fast of at least 10 hours, according to a 3-treatment, 3-period, 6-sequence randomization schedule (Table 57). Treatment T1: 1 x obicetrapib 10 mg and ezetimibe 10 mg FDC tablet (Formulation #1) Treatment T2: 1 x obicetrapib 10 mg and ezetimibe 10 mg FDC tablet (formulation #2) Treatment T3: 1 x obicetrapib 10 mg, co-administered with 1 x ZETIA (ezetimibe) tablet 10 mg

[0554] [Table 108]

[0555] Each dose was administered with 240 mL of room temperature water, and subjects were instructed to swallow the tablet without chewing or biting.

[0556] Sample collection, handling and bioanalysis plan Sample size Collect 4 mL (K2EDTA vacutainer) for obicetrapib analysis Collect 4 mL (K2EDTA vacutainer) for analysis of ezetimibe and ezetimibe glucuronide

[0557] Collection time Pre-dose samples were taken within 60 minutes before dosing. All times are relative to the time of dosing.

[0558] For the analysis of obicetrapib: pre-dose (0 hours) and 0.50, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 9.0, 12.0, 16.0, 20.0, 24.0, 48.0*, 72.0*, 96.0*, 144.0*, 192.0*, 240.0* and 336.0* hours post-dose (*sample collection).

[0559] For the analysis of ezetimibe and ezetimibe glucuronide: Pre-dose (0 hours) and 0.25, 0.50, 0.75, 1.0, 1.333, 1.667, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 9.0, 12.0, 16.0, 20.0, 24.0, 48.0*, 72.0* and 96.0* hours post-dose (*sample collection)

[0560] Total number of samples per period / subject: 49

[0561] Total blood volume drawn per subject: The total volume of blood drawn for pharmacokinetic sampling was approximately 588 mL.

[0562] Sample processing for obicetrapib analysis: Blood samples were collected into 4 mL K2EDTA vacutainers at room temperature. After collection, the samples were gently mixed by inverting several times (i.e., 8–10 times) before being placed in an ice / water bath. The samples were then placed in a centrifuge and spun at 3000 rpm at 4°C for 10 minutes. The resulting plasma was divided into two aliquots (at least 1.0 mL in aliquot 1 and the remainder in aliquot 2), transferred to polypropylene sample storage tubes, and stored at -70°C (±10°C) until ready for shipment to the bioanalysis laboratory. Plasma aliquots were placed in a freezer within 30 minutes of sample collection. After collection, the blood / plasma samples were cooled in an ice / water bath until they were placed in the freezer.

[0563] Sample processing for ezetimibe and ezetimibe glucuronide analysis: Blood samples were collected in 4 mL K2EDT A vacutainers at room temperature. After collection, the samples were gently mixed by inverting several times (at least 8 times) before being placed in an ice / water bath. The samples were then placed in a centrifuge and spun at 3000 rpm at 4°C for 10 minutes. The resulting plasma was divided into two aliquots (at least 1.0 mL in aliquot 1 and the remainder in aliquot 2), transferred to polypropylene sample storage tubes (e.g., Sarstedt #60.546), and stored at -70°C (or colder) until ready for shipment to the bioanalysis laboratory. After collection, the blood / plasma samples were cooled in an ice / water bath until placed in the freezer.

[0564] Pharmacokinetic analysis For all treatments, the following pharmacokinetic parameters were calculated for obicetrapib, ezetimibe, and its metabolite ezetimibe glucuronide:

[0565] Key PK parameters Cmax: maximum measured plasma concentration AUC 0-t : Area under the plasma concentration versus time curve from time zero to the last measurable plasma concentration calculated by the linear trapezoidal method. AUC 0-∞ : Area under the plasma concentration versus time curve from time zero to infinity, AUCo-∞=AUCo-t+Ct / λz, where Ct is the final measurable concentration and λz is the terminal elimination rate constant.

[0566] Secondary PK parameters Tmax: Time of maximum measured plasma concentration. If a maximum value occurs at more than one time point, Tmax is defined as the time point at which this value first occurs.

[0567] λz: apparent first-order terminal elimination rate constant. This parameter was calculated from the negative of the slope of the data set by best-fit least-squares linear regression analysis of the terminal-phase in-linear concentration-time data. An estimable λz was calculated with a corrected R-squared (R) of 0.7 or greater.2 The number of data points (≥3) in the terminal phase (not including Cmax) was included in the final regression analysis because they were determined from data sets with (1) the last three points in the terminal phase were used to determine λz, and either the midpoint or the final point was higher than the immediately preceding point, or (2) the resulting adjusted R 2 If the value was less than 0.7, λz was considered unevaluable.

[0568] If the obtained apparent primary terminal half-life (t1 / 2,) value was longer than the time interval for which λz was estimated, the evaluable λz was considered unreliable and unreportable. If the obtained t1 / 2, value was longer than the time interval for which λz was determined, an interval longer than the estimated t1 / 2, was explored. 2 An interval with values ​​is selected and the corrected R 2 The decrease in values ​​was evaluated to determine whether a reliable estimate of λz was possible. If λz was determined to be unreliable, t1 / 2 and AUCo-∞ values ​​were not reported for that dataset.

[0569] t1 / 2: First-order terminal elimination half-life was calculated as ln(2) / λz.

[0570] Datasets and statistical methods for analysis Linear and semi-logarithmic graphs of concentration-time profiles for each subject were obtained using actual sample collection times. Actual sample collection times were used for calculation of pharmacokinetic parameters. Plasma concentration data obtained from all evaluable subjects without significant protocol deviations were used for estimation of Cmax and / or AUC from at least two study periods (one of which included treatment R).

[0571] PK parameters for all subjects who experienced vomiting within 2 times the median Tmax of obicetrapib or ezetimibe, respectively, calculated from the observed data for a particular treatment arm, were excluded from the statistical analysis for each analyte.

[0572] Analysis of variance was performed for in-transformed AUCo-t, AUCo-∞, and Cmax using an analysis of variance model (ANOVA). ANOVA was performed separately for treatment T1 vs. treatment R and treatment T2 vs. treatment R analyses using an incomplete block design. When comparing treatment T1 vs. treatment R, treatment T2 was omitted from the ANOVA, and when comparing treatment T2 vs. treatment R, treatment T1 was omitted from the ANOVA.

[0573] For comparison of each of the FDC formulations (T1 and T2) with treatment R, confidence intervals (90%) of the geometric mean ratios of AUCo-t, AUCo-∞, and Cmax (obtained from log-transformed data) were constructed to test two one-sided hypotheses at a significance level of a = 0.05.

[0574] result The 90% confidence intervals for the geometric mean ratios (from T1 and T2 of Formulation #1 and Formulation #2) of AUC0-t, AUC0-∞, and Cmax of obicetrapib, ezetimibe, and ezetimibe glucoronide were found to be within the ranges of 75% to 125%, preferably 80% to 125%, and more preferably 90% to 110% of AUC0-t, AUC0-∞, and Cmax of obicetrapib, ezetimibe, and ezetimibe glucoronide, respectively. Test Formulations #1 and #2 were found to be bioequivalent to the reference treatment arm (R). Adverse events observed in the T1 or T2 treatment arms were not statistically significantly different from the R arm.

[0575] Example 10 Phase 2B clinical trial (ROSE2; NCT05266586) 1. Introduction and Background Information Dyslipidemia is a disorder of lipoprotein metabolism involving lipoprotein overproduction or deficiency. It is manifested by elevated serum levels of total cholesterol, low-density lipoprotein (LDL) cholesterol (LDL-C), and triglycerides (TG), and decreased high-density lipoprotein (HDL) cholesterol (HDL-C). These disorders are generally diagnosed by measuring serum lipids and classified by the pattern of elevated or decreased lipid / lipoprotein fractions. While dyslipidemia itself generally does not cause any symptoms, it can lead to symptomatic vascular diseases such as coronary artery disease and peripheral artery disease. While many genetic and lifestyle factors contribute to the development of vascular disease, dyslipidemia is one of the most prominent risk factors, and normalizing lipid profiles is a major goal in cardiovascular (CV) protective strategies.

[0576] Statins are generally the first-line medications for treating dyslipidemia. Statins are considered the most potent, most effective, and best-tolerated agents for lowering LDL-C levels. Many patients do not achieve acceptable LDL-C levels with statins alone, despite treatment with high-intensity statin therapy.

[0577] There is a need for long-term therapy that can robustly lower high LDL-C levels in combination with high-intensity statin therapy.

[0578] 1.1 Cholesteryl ester transfer protein inhibitors Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein produced in the liver and adipose tissue. It circulates in the blood primarily bound to HDL-C and is involved in the transfer of cholesteryl esters and TGs between lipoproteins. In particular, it mediates the transfer of cholesteryl esters from HDL to apolipoprotein B (ApoB)-containing particles, such as very low-density lipoproteins (VDL) and LDL-C, in exchange for TGs. As a result, cholesteryl esters from HDL can be taken up by the liver via scavenger receptor class B type 1; this action leads to a decrease in HDL-C and ultimately an increase in LDL-C.

[0579] Inhibition of CETP activity reduces ApoB and LDL-C and increases HDL-C. CETP inhibitor therapy was initially developed based on the premise that increasing HDL-C levels could prevent CV disease. However, clinical trial results and Mendelian randomization data have revealed that these effects are driven by changes in the concentration of ApoB-containing particles (including LDL particles) rather than changes in HDL-C levels. Therefore, the LDL-C and ApoB-lowering effects of CETP inhibition, which occur through upregulation of the LDL receptor, may benefit patients with high LDL-C and increased CV risk.

[0580] Ference et al. recently invest...

Claims

1. a. obicetrapib or a pharmaceutically acceptable salt, solvate, or co-crystal thereof; b. ezetimibe or a pharmaceutically acceptable salt, solvate, or co-crystal thereof; c. one or more pharmaceutically acceptable excipients; A fixed dose pharmaceutical composition comprising or consisting of:

2. Upon oral administration of the composition to a subject, the area under the curve (AUC) of obicetrapib ０－∞ and / or AUC ０－ｔ ) and / or the 90% confidence interval of the geometric mean of Cmax is the area under the curve (AUC) of obicetrapib obtained upon oral administration of the reference pharmaceutical composition to similar subjects. ０－∞ and / or AUC ０－ｔ ) and / or Cmax within 75% to 125%, preferably 80% to 125%, more preferably 90% to 110%, respectively, wherein said reference composition comprises an equivalent dose of obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and said reference composition is administered alone or as simultaneous or sequential co-administration with another pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

3. Upon oral administration of the composition to a subject, the area under the curve (AUC) of ezetimibe and / or ezetimibe glucoronide is ０－∞ and / or AUC ０－ｔ ) and / or the 90% confidence interval of the geometric mean of Cmax is the area under the curve (AUC) of ezetimibe and / or ezetimibe glucoronide obtained upon oral administration of the reference pharmaceutical composition to similar subjects. ０－∞ and / or AUC ０－ｔ 3. The pharmaceutical composition of claim 1, wherein the Cmax and / or Cmax are within 75% to 125%, preferably 80% to 125%, more preferably 90% to 110%, of the Cmax and / or Cmax, respectively, wherein said reference comprises an equivalent dose of ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and said reference composition is administered alone or as simultaneous or sequential co-administration with another pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

4. 4. The pharmaceutical composition according to any one of claims 1 to 3 for use in treating a subject in need of a reduction in LDL cholesterol and / or an increase in HDL cholesterol, said pharmaceutical composition comprising: a. when the fixed dose pharmaceutical composition is orally administered to a subject; b. The concentration of obicetrapib in the subject's plasma is measured at one or more time points after administration to obtain a set of obicetrapib concentration / time data points to obtain the area under the curve (AUC); and c. Area under the curve (AUC) of obicetrapib ０－∞ and / or AUC ０－ｔ ) and / or the 90% confidence interval of the geometric mean of Cmax is the area under the curve (AUC) of obicetrapib obtained upon oral administration of the reference pharmaceutical composition to similar subjects. ０－∞ and / or AUC ０－ｔ ) and / or Cmax, respectively, is within 75% to 125%, preferably 80% to 125%, more preferably 90% to 110%, wherein said reference composition comprises an equivalent dose of obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and said reference composition is administered alone or as simultaneous or sequential co-administration with another pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

5. 5. The pharmaceutical composition according to any one of claims 1 to 4 for use in treating a subject in need of a reduction in LDL cholesterol and / or an increase in HDL cholesterol, said pharmaceutical composition comprising: a. when the fixed dose pharmaceutical composition is orally administered to a subject; b. Measuring the concentration of ezetimibe and / or ezetimibe glucoronide in the subject's plasma at one or more time points after administration to obtain a set of ezetimibe and / or ezetimibe glucoronide concentration / time data points, respectively, to obtain an area under the curve (AUC) for ezetimibe and / or ezetimibe glucoronide, respectively; and c. Area under the curve (AUC) of ezetimibe and / or ezetimibe glucoronide ０－∞ and / or AUC ０－ｔ ) and / or the 90% confidence interval of the geometric mean of Cmax is the area under the curve (AUC) of ezetimibe and / or ezetimibe glucoronide obtained upon oral administration of the reference pharmaceutical composition to similar subjects. ０－∞ and / or AUC ０－ｔ ) and / or Cmax, respectively, is within 75% to 125%, preferably 80% to 125%, more preferably 90% to 110%, wherein said reference composition comprises an equivalent dose of ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and said reference composition is administered alone or as simultaneous or sequential co-administration with another pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

6. 6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the use of the composition is for the purpose of lowering LDL cholesterol and / or increasing HDL cholesterol in a human suffering from heterozygous familial hypercholesterolemia (HeFH) and / or with a history of atherosclerotic cardiovascular disease (ASCVD).

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein t of AUC0-t is selected from 48 hours (AUC0-48), 72 hours (AUC0-72), 96 hours (AUC0-96), 144 hours (AUC0-144), 192 hours (AUC0-192), 240 hours (AUC0-240), 336 hours (AUC0-336) or AUC0-∞, preferably 48 hours (AUC0-48), more preferably AUC0-∞.

8. 8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the subject is a human, preferably a healthy human, more preferably a human in need of a reduction in LDL cholesterol and / or an increase in HDL cholesterol, suffering from heterozygous familial hypercholesterolemia (HeFH) and / or with a history of atherosclerotic cardiovascular disease (ASCVD).

9. The subject is a healthy, tobacco-free, nicotine-free adult male or female human between the ages of 18 and 65, and optionally the human has a blood cholesterol level between 18.5 and 29.9 Kg / m ２ 9. The pharmaceutical composition according to claim 1, wherein the body mass index is

10. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the human in need of LDL cholesterol reduction and / or the human suffering from heterozygous familial hypercholesterolemia (HeFH) and / or the human with a history of atherosclerotic cardiovascular disease (ASCVD) has an LDL-cholesterol level of ≥ 70 mg / dL, and optionally the human is not adequately controlled by current lipid-modifying therapy.

11. 11. The pharmaceutical composition according to any one of claims 1 to 10, wherein when the pharmaceutical composition is dissolved in 500 ml of a solution containing 0.45% SLS in 0.05 M sodium acetate buffer (pH 4.5) in a USP Type II apparatus at a rotation speed of about 75 rpm at 37±0.5°C, at least about 60%, preferably at least about 70%, more preferably at least about 80% of the ezetimibe is dissolved within about 30 minutes.

12. 12. The pharmaceutical composition according to any one of claims 1 to 11, wherein when the pharmaceutical composition is dissolved in 1000 ml of a solution containing pH 6.8 phosphate buffer plus 0.2% w / v polysorbate 80 in a USP Type II apparatus at a rotation speed of about 75 rpm at 37±0.5°C, at least about 70%, preferably at least about 80%, more preferably at least about 85% of the obicetrapib is dissolved within about 15 minutes.

13. 13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the composition comprises 1 to 20 mg of obicetrapib and 5 to 20 mg of ezetimibe, preferably 5 mg of obicetrapib and 10 mg of ezetimibe, or 10 mg of obicetrapib and 10 mg of ezetimibe.

14. 14. The pharmaceutical composition of any one of claims 1 to 13, wherein the composition is provided as a unit dosage form comprising 1 to 20 mg of obicetrapib and 5 to 20 mg of ezetimibe, preferably the unit dosage form comprising 5 mg of obicetrapib and 10 mg of ezetimibe, or 10 mg of obicetrapib and 10 mg of ezetimibe.

15. 15. The pharmaceutical composition of any one of claims 1 to 14, wherein the composition contains not more than about 2% (w / w), preferably not more than about 0.5% (w / w), more preferably not more than about 0.3% (w / w), and even more preferably not more than about 0.2% (w / w) of a tetrahydropyran analogue of ezetimibe as an impurity.

16. 16. The pharmaceutical composition of any one of claims 1 to 15, wherein either ezetimibe or obicetrapib or both are micronized.

17. The composition has a Dv of 10 μm or less, preferably in the range of 4 to 10 μm, and more preferably 8.5 μm or less. ９０ Dv of 4 μm or less, preferably in the range of about 1 to 4 μm, more preferably 3.8 μm or less ５０ , and Dv of 1 μm or less １０ 17. The pharmaceutical composition of any one of claims 1 to 16, comprising micronized ezetimibe having

18. The composition has a Dv of 14 μm or less, preferably in the range of about 5 to 14 μm. ９０ 5 μm or less, preferably in the range of about 3 to 5 μm; ５０ 18. The pharmaceutical composition of any one of claims 1 to 17, comprising micronized obicetrapib having a Dv10 of 3 μm or less.

19. 19. The pharmaceutical composition of any one of claims 1 to 18, wherein the composition comprises ezetimibe as anhydrous ezetimibe, ezetimibe monohydrate, or a mixture thereof.

20. 20. The pharmaceutical composition according to any one of claims 1 to 19, wherein the composition comprises obicetrapib as an alkali metal or alkaline earth metal salt of obicetrapib, preferably obicetrapib sodium, obicetrapib potassium or obicetrapib calcium, more preferably obicetrapib calcium salt.

21. 21. The pharmaceutical composition of any one of claims 1 to 20, wherein the composition is a two-component composition, one of the components comprising ezetimibe and the other component comprising obicetrapib.

22. 22. The pharmaceutical composition of any one of claims 1 to 21, wherein the composition is a two-component composition, one of the two components comprising both ezetimibe and obicetrapib.

23. 23. The pharmaceutical composition of claim 21 or 22, wherein the two-component composition is a bilayer tablet formulation, a capsule formulation containing or consisting of two types of granules, or a tablet formulation comprising an extragranular component and an intragranular component.

24. a. the intragranular component comprises ezetimibe and the extragranular component comprises obicetrapib; or 23. The pharmaceutical composition of claim 22, wherein the intragranular component comprises both ezetimibe and obicetrapib, and the extragranular component comprises only excipients.

25. a. the intragranular component comprises obicetrapib and the extragranular component comprises ezetimibe; or b) The pharmaceutical composition of claim 22, wherein the extragranular component comprises both ezetimibe and obicetrapib, and the intragranular component comprises only excipients.

26. 26. The pharmaceutical composition of any one of claims 1 to 25, wherein the composition further comprises one or more binders and surfactants, and preferably the ratio of binder to surfactant in the intragranular component is in the range of about 0.05:5.0 to about 5.0:0.05, preferably about 0.5:4.5 to about 4.5:0.5, more preferably about 1:4 to about 4:1, even more preferably about 1:2 to about 2:1, and most preferably about 1:

1.

27. 27. The pharmaceutical composition according to any one of claims 1 to 26, wherein the composition further comprises one or more binders selected from cellulose derivatives, preferably selected from methylcellulose and carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose and hydroxyethylcellulose; gelatin, glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone and its copolymers, starch paste, sucrose, sorbitol, pregelatinized starch, tragacanth gum, alginic acid and its salts, such as sodium alginate, magnesium aluminum silicate, polyethylene glycol, guar gum, bentonite; preferably, the binder is polyvinylpyrrolidone or a copolymer of polyvinylpyrrolidone, more preferably copovidone, and even more preferably, the binder is Kollidon 30.

28. The composition may further comprise one or more surfactants having an HLB value of at least 15, at least 20, at least 30, or at least 40; preferably, the one or more surfactants are selected from the following: lauric acid, palmitic acid, stearic acid, and oleic acid or salts thereof, polyethylene glycol glycerides, polyoxyethylene monoesters, polyoxyethylene monostearate, polyoxyethylene monolaurate, polyoxyethylene sorbitan monooleate, polyethoxylated castor oil, polyethylene glycols having a molecular weight in the range of about 2,000 to 10,000, propylene glycol caprylate, glycerol oleic acid and caprylate, esters of glycerol and fatty acids; more preferably, the one or more surfactants are selected from the following: dioctyl sodium sulfosuccinate, Capmul PG-8, Capryol 90, Capmul PG-10, Capmul PG-11, Capmul PG-12, Capmul PG-13, Capmul PG-14, Capmul PG-15, Capmul PG-16, Capmul PG-17, Capmul PG-18, Capmul PG-19 ...

28. The pharmaceutical composition according to any one of claims 1 to 27, wherein the surfactant is selected from MCM, polysorbate 20, polysorbate 40 or polysorbate 80, or sodium lauryl sulfate; more preferably, the surfactant is sodium lauryl sulfate.

29. The pharmaceutical composition according to any one of claims 1 to 28, wherein the composition further comprises one or more disintegrants selected from cross-linked polyvinylpyrrolidone, croscarmellose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropyl cellulose, alginic acid, sodium alginate, microcrystalline cellulose, sodium starch glycolate, and pregelatinized starch; preferably, the disintegrant is croscarmellose sodium or sodium starch glycolate; more preferably, the disintegrant is sodium starch glycolate.

30. 30. The pharmaceutical composition according to any one of claims 1 to 29, wherein the composition is stable at 40°C / 75% relative humidity for at least 1 month, preferably at least 3 months, more preferably at least 6 months, or at 25°C / 60% relative humidity for at least 3 months, preferably at least 6 months, more preferably at least 12 months.

31. The composition comprises: a. An intragranular component containing: i. obicetrapib calcium equivalent to 10 mg of obicetrapib free acid; ii. anhydrous ezetimibe or a mixture of anhydrous ezetimibe and ezetimibe monohydrate equivalent to 10 mg of ezetimibe; iii. a 1:1 ratio of binder and surfactant (preferably, the binder and surfactant each comprise about 1±0.5% w / w of the intragranular component granules; more preferably, the binder is 1±0.5% w / w of polyvidone or polyvinylpyrrolidone and the surfactant is 1±0.5% w / w of sodium lauryl sulfate); iv. a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate (preferably, said disintegrant is about 2-8% w / w, preferably 3-6% w / w, more preferably about 4.5±0.5% w / w of the intragranular component granules); v. One or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol, or mannitol. and; b. An extragranular component containing: i. a disintegrant selected from microcrystalline cellulose, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; ii. optionally, a lubricant, preferably magnesium stearate; iii. optionally, a lubricant, preferably colloidal silicon dioxide or talc, or both; iv. Optionally, one or more diluents selected from a disaccharide, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; a polysaccharide, preferably cellulose, more preferably microcrystalline cellulose; a sugar alcohol, preferably sorbitol, xylitol, or mannitol; more preferably mannitol and microcrystalline cellulose. A tablet formulation comprising or consisting of: c. The pharmaceutical composition of any one of claims 1 to 30, optionally comprising a film coating, preferably the film coating does not comprise a primary alcohol, more preferably the film coating does not comprise polyethylene glycol.

32. The composition comprises: a. An intragranular component containing: i. anhydrous ezetimibe or a mixture of anhydrous ezetimibe and ezetimibe hydrate equivalent to 10 mg of ezetimibe; ii. a 1:1 ratio of binder and surfactant (preferably, the binder and surfactant each comprise about 1±0.5% w / w of the intragranular component granules; more preferably, the binder is 1±0.5% w / w of polyvidone or polyvinylpyrrolidone and the surfactant is 1±0.5% w / w of sodium lauryl sulfate); iii. a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate (preferably, the disintegrant is about 2-8% w / w, preferably 3-6% w / w, more preferably about 4.5±0.5% w / w of the intragranular component granules); iv. One or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol, or mannitol. and; b. An extragranular component containing: i. obicetrapib calcium equivalent to 10 mg of obicetrapib free acid; ii. a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; iii. optionally, a lubricant, preferably magnesium stearate; iv. optionally, a lubricant, preferably colloidal silicon dioxide or talc, or both; v. Optionally, one or more diluents selected from a disaccharide, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; a polysaccharide, preferably cellulose, more preferably microcrystalline cellulose; a sugar alcohol, preferably sorbitol, xylitol, or mannitol; more preferably mannitol and microcrystalline cellulose. tablet formulations comprising or consisting of: c. The pharmaceutical composition of any one of claims 1 to 31, optionally comprising a film coating, preferably the film coating does not comprise a primary alcohol, more preferably the film coating does not comprise polyethylene glycol.

33. The composition comprises: a. An intragranular component containing: i. obicetrapib calcium equivalent to 10 mg of obicetrapib free acid; ii. a 1:1 ratio of binder and surfactant (preferably, the binder and surfactant each comprise about 1±0.5% w / w of the intragranular component granules; more preferably, the binder is 1±0.5% w / w of polyvidone or polyvinylpyrrolidone and the surfactant is 1±0.5% w / w of sodium lauryl sulfate); iii. a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate (preferably, the disintegrant is about 2-8% w / w, preferably 3-6% w / w, more preferably about 4.5±0.5% w / w of the intragranular component granules); iv. One or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol, or mannitol. and; b. An extragranular component containing: i. anhydrous ezetimibe or a mixture of anhydrous ezetimibe and ezetimibe hydrate equivalent to 10 mg of ezetimibe; ii. a disintegrant selected from microcrystalline cellulose, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; iii. optionally, a lubricant, preferably magnesium stearate; iv. optionally, a lubricant, preferably colloidal silicon dioxide or talc, or both; v. Optionally, one or more diluents selected from a disaccharide, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; a polysaccharide, preferably cellulose, more preferably microcrystalline cellulose; a sugar alcohol, preferably sorbitol, xylitol, or mannitol; more preferably mannitol and microcrystalline cellulose. tablet formulations comprising or consisting of: c. The pharmaceutical composition of any one of claims 1 to 32, optionally comprising a film coating, preferably the film coating does not comprise a primary alcohol, more preferably the film coating does not comprise polyethylene glycol.

34. 34. The pharmaceutical composition according to any one of claims 1 to 33 for use in treating a subject in need of lowering LDL cholesterol and / or increasing HDL cholesterol, preferably wherein the subject suffers from hyperlipidemia or mixed dyslipidemia.

35. 35. The pharmaceutical composition according to any one of claims 1 to 34, for use in lowering LDL cholesterol in patients in need thereof, i.e. in patients with heterozygous familial hypercholesterolemia (HeFH) and / or patients with a history of atherosclerotic cardiovascular disease (ASCVD).

36. Use of a pharmaceutical composition according to any one of claims 1 to 35 for the preparation of a medicament for the treatment of a subject suffering from hyperlipidemia or mixed dyslipidemia.

37. Use of a pharmaceutical composition according to any one of claims 1 to 36 for the preparation of a medicament for lowering LDL cholesterol in a subject in need thereof, i.e. in a subject with heterozygous familial hypercholesterolemia (HeFH) and / or a subject with a history of atherosclerotic cardiovascular disease (ASCVD).

38. Use of a pharmaceutical composition according to any one of claims 1 to 37 for the preparation of a medicament for reducing the risk of cardiovascular events.

39. The use according to any one of claims 1 to 38, wherein the subject suffers from mild dyslipidemia.

40. 40. A method for treating a subject in need of lowering LDL cholesterol and / or increasing HDL cholesterol, i.e. a subject with heterozygous familial hypercholesterolemia (HeFH) and / or a subject with a history of atherosclerotic cardiovascular disease (ASCVD), said method comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition according to any one of claims 1 to 39.

41. 41. A method of treating a subject suffering from hyperlipidemia or mixed dyslipidemia, said method comprising administering to a patient in need thereof the pharmaceutical composition of any one of claims 1 to 40.

42. 42. Use of a pharmaceutical composition for the preparation of a medicament or a method of treatment according to any one of claims 1 to 41, wherein the subject has an LDL-cholesterol level ≧50 mg / dL, preferably ≧70 mg / dL, and optionally the person is not adequately controlled on their current lipid-improving therapy.

43. 43. Use of the pharmaceutical composition or method of treatment according to any one of claims 1 to 42, wherein the composition is administered to the subject in need thereof to deliver a total daily oral dose of 5 mg obicetrapib and 10 mg ezetimibe, 10 mg obicetrapib and 10 mg ezetimibe, or 20 mg obicetrapib and 20 mg ezetimibe, preferably the composition is administered to the subject to deliver a daily oral dose of 10 mg obicetrapib and 10 mg ezetimibe.

44. 44. Use of the pharmaceutical composition or method of treatment according to any one of claims 1 to 43, wherein the subject in need thereof is a subject in need of further lowering of low-density lipoprotein cholesterol as an adjunct to dietary and / or maximally tolerated lipid-lowering therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or pre-existing atherosclerotic cardiovascular (CV) disease (ASCVD).

45. A pharmaceutical composition comprising obicetrapib and ezetimibe, or pharmaceutically acceptable salts, solvates or co-crystals thereof, and a pharmaceutically acceptable carrier for use in treating adults with heterozygous familial hypercholesterolemia (HeFH) or a history of atherosclerotic cardiovascular (CV) disease (ASCVD) in a subject in need of further lowering of low-density lipoprotein cholesterol as an adjunct to diet and / or maximally tolerated lipid-lowering therapy.

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