Amorphous obicetrapib solids including dispersions of obicetrapib and obicetrapib salts

Abstract

The disclosure is directed to solid forms of obicetrapib and amorphous solid dispersions comprising one or more of amorphous obicetrapib hemicalcium, amorphous obicetrapib free acid and / or obicetrapib alkali salts, one or more dispersion excipients, and optionally one or more surfactants. Further provided herein are methods of preparing such solid forms of obicetrapib and amorphous solid dispersions of obicetrapib and the solid forms and amorphous dispersions so prepared. The disclosure further provides pharmaceutical compositions comprising such solid forms of obicetrapib and / or amorphous solid dispersions of obicetrapib. Also included within the disclosure are methods of treating subjects in need thereof with such solid forms of obicetrapib and / or amorphous solid dispersions or pharmaceutical compositions of the disclosure.

Description

AMORPHOUS OBICETRAPIB SOLIDS INCLUDING DISPERSIONS OF OBICETRAPIB AND OBICETRAPIB SALTS1. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 741,340, filed January 02, 2025; U.S. Provisional Application No. 63 / 741,352, filed January 02, 2025; U.S. Provisional Application No. 63 / 846,867, filed July 18, 2025; U.S. Provisional Application No. 63 / 853,347, filed July 29, 2025; and U.S. Provisional Application No.63 / 902,412, filed October 20, 2025; which are hereby incorporated by reference in their entirety.2. BACKGROUND OF THE INVENTION

[0002] Prospective epidemiological studies have shown a strong association between low density lipoprotein-cholesterol (LDL-C) levels and cardiovascular disease (CVD) risk. The application of statin therapy to decrease these atherogenic LDL-C levels has resulted in a marked reduction of CVD-related morbidity and mortality: every 1 mmol / L decrease in LDL-C results in an estimated 22% reduction of CVD events and a 10% reduction of all-cause mortality.Notwithstanding these impressive benefits, a large residual disease burden persists that has a large impact on both individual patients as well as on global healthcare costs. Novel therapeutics are required to reduce further this residual CVD risk in patients.

[0003] One route which reduces LDL-C and elevates high-density lipoprotein cholesterol (HDL-C) levels is to inhibit Cholesterol Ester Transfer Protein (CETP). CETP is a plasma protein secreted primarily by liver and adipose tissue. CETP mediates the transfer of cholesteryl esters from HDL to apolipoprotein B (Apo B)-containing particles (mainly LDL and very low density lipoprotein VLDL) in exchange for triglycerides, thereby decreasing the cholesterol content in HDL in favor of that in VLDL. Hence, CETP inhibition has been hypothesized to retain cholesteryl esters in HDL-C and decrease the cholesterol content of the atherogenic Apo B fraction.

[0004] Clinical studies have shown that obicetrapib also known as ((27?,45)-4-{[3,5 bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-l -carboxylic acid ethyl ester), or a pharmaceuticallyacceptable salt thereof is a potent CETP- inhibitor. The structure of obicetrapib is set forth in Formula (I) below:

[0005] Compared to other known CETP -inhibitors, only a relatively low dose of obicetrapib is needed to reach near complete CETP inhibition. Typically, repeated daily dosages (once a day) as low as 2.5 mg of the compound of obicetrapib have proven to be already sufficient to reach near complete CETP inhibition. These are considerably lower dosages than had to be used for other CETP -inhibitors. Moreover, clinical studies have also shown that obicetrapib is well tolerated and that it does not lead to serious side effects. Obicetrapib free acid is the active moiety of obicetrapib hemicalcium.

[0006] The preparation of obicetrapib is disclosed, for example, in US Patent No. 7,872,126. Example 177 teaches the formation of obicetrapib, which, as seen in Formula (I), is a free acid but the resulting residue is not a solid. Likewise, obicetrapib free acid is taught in solution as a non-isolatable intermediate, also in U.S. Patent No. 12,006,305, which is incorporated herein by reference in its entirety. The ‘126 Patent also discloses the sodium salt of obicetrapib (also referred to herein as obicetrapib sodium) is described in Example 178, and the potassium salt (also referred to herein as obicetrapib potassium) in Example 180. These salts were generated through neutralization of the free acid of obicetrapib with a stoichiometric amount of the corresponding hydroxide (e.g., NaOH, KOH) followed by concentration to dryness. Such uncontrolled neutralization and concentration to dryness methods often yield materials of suboptimal pharmaceutical quality, with issues including residual organic solvent, residual water, incomplete reaction, and contamination with excess acid or base counter-ions.

[0007] While processes have been described for the manufacture of obicetrapib (see, e.g., WO 2005 / 095409A2 and U.S. Patent Nos. 7,872,126 and 8,158,640, Examples 1 and 177-180;WO 2007 / 116922 Al and US Patent No. 8,084,611; and WO 2016 / 024858 and U.S. Patent No.10,112,904) the prior art cited herein produces an unfavorable solid form. These references are incorporated herein by reference in their entirety.

[0008] The prior art teaches the formation of one developable solid form of obicetrapib, obicetrapib hemicalcium in U.S. Patent No. 12,006,305. The ‘305 patent describes amorphous obicetrapib hemicalcium.

[0009] Amorphous solid dispersions are often used to formulate active pharmaceutical ingredients. Herein are described amorphous solid dispersions of obicetrapib free acid, amorphous obicetrapib hemicalcium, or an alkali salt of obicetrapib such as obicetrapib sodium or obicetrapib potassium.3. SUMMARY OF THE INVENTION

[0010] In many aspects of the disclosure, amorphous solid dispersions comprising obicetrapib free acid, or amorphous obicetrapib hemicalcium, or obicetrapib alkali salts such as obicetrapib sodium or obicetrapib potassium, one or more dispersion excipients, and optionally a surfactant, are provided.

[0011] In some aspects of the disclosure, x-ray amorphous obicetrapib hemicalcium is provided.

[0012] In additional aspects of the disclosure, solid obicetrapib free acid, including amorphous obicetrapib free acid, is provided.

[0013] In further aspects of the disclosure, pharmaceutical compositions comprising amorphous solid dispersions comprising obicetrapib free acid, or amorphous obicetrapib hemicalcium, or obicetrapib alkali salts such as obicetrapib sodium or obicetrapib potassium, one or more dispersion excipients, and one or more surfactants, are provided.

[0014] In further aspects of the disclosure, pharmaceutical compositions comprising (1) amorphous solid dispersions comprising obicetrapib free acid, or amorphous obicetrapib hemicalcium, or obicetrapib alkali salts such as obicetrapib sodium or obicetrapib potassium, one or more dispersion excipients, and optionally a surfactant; and (2) one or more pharmaceutically acceptable excipients, are provided.

[0015] In still further aspects of the disclosure, methods of treatment using said amorphous solid dispersions comprising obicetrapib free acid, or amorphous obicetrapib hemicalcium, or obicetrapib alkali salts such as obicetrapib sodium or obicetrapib potassium, one or moredispersion excipients, and optionally one or more surfactants; or pharmaceutical compositions comprising said amorphous solid dispersions and one or more pharmaceutically acceptable excipients, are provided.

[0016] In additional aspects of the disclosure, methods of making amorphous solid dispersions comprising obicetrapib free acid, or amorphous obicetrapib hemicalcium, or obicetrapib alkali salts such as obicetrapib sodium or obicetrapib potassium, one or more dispersion excipients, and optionally one or more surfactants, are provided. Also included herein are the amorphous solid dispersions comprising obicetrapib free acid, or amorphous obicetrapib hemicalcium, or obicetrapib alkali salts such as obicetrapib sodium or obicetrapib potassium, one or more dispersion excipients, and optionally one or more surfactants, so made.

[0017] In still further aspect of the disclosure, methods of making alkali salts of obicetrapib, such as obicetrapib sodium and obicetrapib potassium, are provided.4. BRIEF DESCRIPTION OF FIGURES

[0018] FIG. l is a modulated differential scanning calorimetry (“mDSC”) thermogram corresponding to a spray-dried amorphous solid dispersion of amorphous obicetrapib hemicalcium and HPMC El 5 in a 1:2 (w / w) ratio.

[0019] FIG. 2 is an x-ray powder diffraction pattern of obicetrapib free acid.

[0020] FIG. 2A is an x-ray powder diffraction pattern of obicetrapib sodium.

[0021] FIG. 2B is an mDSC thermogram of obicetrapib sodium.

[0022] FIG. 2C is an x-ray powder diffraction pattern of obicetrapib potassium.

[0023] FIG. 2D is an mDSC thermogram of obicetrapib potassium.

[0024] FIG. 2E is an x-ray powder diffraction pattern of obicetrapib potassium.

[0025] FIG. 2F is an mDSC thermogram of obicetrapib potassium.

[0026] FIG. 3 is an mDSC thermogram corresponding to a spray-dried amorphous solid dispersion of amorphous obicetrapib hemicalcium and PVP K30 in a 1:2 (w / w) ratio.

[0027] FIG. 4 is an mDSC thermogram corresponding to a spray-dried amorphous solid dispersion of amorphous obicetrapib hemicalcium and Eudragit LI 00 in a 1:2 (w / w) ratio.

[0028] FIG. 5 is an mDSC thermogram corresponding to a spray-dried amorphous solid dispersion of amorphous obicetrapib hemicalcium and HPMC AS-HGin a 1:2 (w / w) ratio.

[0029] FIG. 6 is an mDSC thermogram corresponding to a spray-dried amorphous solid dispersion of amorphous obicetrapib hemicalcium and Methocel A4M in a 1:2 (w / w) ratio.

[0030] FIG. 7 is an mDSC thermogram corresponding to a spray-dried amorphous solid dispersion of amorphous obicetrapib hemicalcium and PVP VA64 in a 1:2 (w / w) ratio.

[0031] FIG. 8 is an mDSC thermogram corresponding to a spray-dried amorphous solid dispersion of amorphous obicetrapib hemicalcium and HPMC E5 in a 1:2 (w / w) ratio.

[0032] FIG. 9 is an x-ray powder diffraction pattern of spray-dried amorphous obicetrapib hemi calcium.

[0033] FIG. 9A is an x-ray powder diffraction pattern of spray-dried amorphous obicetrapib hemi calcium.

[0034] FIG. 10 is a mDSC thermogram of spray-dried amorphous obicetrapib hemi calcium.

[0035] FIG. 10A is a mDSC thermogram of spray-dried amorphous obicetrapib hemi calcium.

[0036] FIG. 11 is a scanning electron micrograph of spray-dried amorphous obicetrapib hemi calcium.

[0037] FIG. 12 is an x-ray powder diffraction pattern of amorphous obicetrapib hemicalcium and PVP-VA 64 in a 1 : 1 (w / w) ratio.

[0038] FIG. 13 is an mDSC thermogram of amorphous obicetrapib hemicalcium and PVP-VA 64 in a 1:1 (w / w) ratio.

[0039] FIG. 14 is an x-ray powder diffraction pattern of an amorphous solid dispersion of amorphous obicetrapib hemicalcium and PVP-VA 64 in a 1:3 (w / w) ratio.

[0040] FIG. 15 is an mDSC thermogram of an amorphous solid dispersion of amorphous obicetrapib hemicalcium and PVP-VA 64 in a 1:3 (w / w) ratio.

[0041] FIG. 16 is an x-ray powder diffraction pattern of an amorphous solid dispersion of amorphous obicetrapib hemicalcium, PVP-VA 64, and Tween 80 in a 25:73:2 (w / w / w) ratio.

[0042] FIG. 17 is an mDSC thermogram of an amorphous solid dispersion of amorphous obicetrapib hemicalcium, PVP-VA 64, and Tween 80 in a 25:73:2 (w / w / w) ratio.

[0043] FIG. 18 is an x-ray powder diffraction pattern of an amorphous solid dispersion of amorphous obicetrapib hemicalcium, PVP-VA 64, and VE-TPGS in a 25:70:5 (w / w / w) ratio.

[0044] FIG. 19 is an mDSC thermogram of an amorphous solid dispersion of amorphous obicetrapib hemicalcium, PVP-VA 64, and VE-TPGS in a 25:70:5 (w / w / w) ratio.

[0045] FIG. 20 is an x-ray powder diffraction pattern of a hot melt extrusion of amorphous obicetrapib hemicalcium and PVP-VA 64 in a 1:1 (w / w) ratio (first strand).

[0046] FIG. 21 is an x-ray powder diffraction pattern of a hot melt extrusion of amorphous obicetrapib hemicalcium and PVP-VA 64 in a 1:1 (w / w) ratio (second strand).

[0047] FIG. 22 is an mDSC thermogram of a hot melt extrusion of amorphous obicetrapib hemicalcium and PVP-VA 64 in a 1 : 1 (w / w) ratio (first strand).

[0048] FIG. 23 is an mDSC thermogram of a melt quench of amorphous obicetrapib hemicalcium and PVP-VA 64 in a 1 : 1 (w / w) ratio.

[0049] FIG. 24 is an x-ray powder diffraction pattern of an amorphous solid dispersion of amorphous obicetrapib hemicalcium and Soluplus® in a 1 : 1 (w / w) ratio.

[0050] FIG. 25 is an mDSC thermogram of an amorphous solid dispersion of amorphous obicetrapib hemicalcium and Soluplus® in a 1:1 (w / w) ratio.

[0051] FIG. 26 is an x-ray powder diffraction pattern of an amorphous solid dispersion of amorphous obicetrapib hemicalcium and Soluplus® HME in a 1:1 (w / w) ratio.

[0052] FIG. 27 is an mDSC thermogram of an amorphous solid dispersion of amorphous obicetrapib hemicalcium and Soluplus® HME in a 1 : 1 (w / w) ratio.

[0053] FIG. 28 is an x-ray powder diffraction pattern of an amorphous solid dispersion of amorphous obicetrapib hemicalcium and Eudragit L100-55 in a 1:1 (w / w) ratio.

[0054] FIG. 29 is an mDSC thermogram of an amorphous solid dispersion of amorphous obicetrapib hemicalcium and Eudragit L100-55 in a 1:1 (w / w) ratio.

[0055] FIG. 30 is an x-ray powder diffraction pattern of amorphous obicetrapib hemicalcium and PEG 6000 in a 3 : 1 (w / w) ratio.

[0056] FIG. 31 is an mDSC thermogram of amorphous obicetrapib hemicalcium and PEG 6000 in a 3 : 1 (w / w) ratio.

[0057] FIG. 32 is an x-ray powder diffraction pattern of amorphous obicetrapib hemicalcium and Poloxamer 407 NF in a 1:1 (w / w) ratio.

[0058] FIG. 33 is an mDSC thermogram of amorphous obicetrapib hemicalcium and Poloxamer 407 NF in a 1:1 (w / w) ratio.

[0059] FIG. 34 is an x-ray powder diffraction pattern of an amorphous spray-dried dispersion of amorphous obicetrapib hemicalcium and HPC-LF in a 3 : 1 (w / w) ratio.

[0060] FIG. 35 is an mDSC thermogram of an amorphous spray-dried dispersion of amorphous obicetrapib hemicalcium and HPC-LF in a 3 : 1 (w / w) ratio.

[0061] FIG. 36 is an x-ray powder diffraction pattern of an amorphous spray-dried dispersion of amorphous obicetrapib hemicalcium and PVP K30 in a 1:1 (w / w) ratio.

[0062] FIG. 37 is an mDSC thermogram of an amorphous spray-dried dispersion of amorphous obicetrapib hemicalcium and PVP K30 in a 1:1 (w / w) ratio.

[0063] FIG. 38 is an x-ray powder diffraction pattern of an amorphous spray-dried dispersion of amorphous obicetrapib hemicalcium and lactose in a 1:1 (w / w) ratio.

[0064] FIG. 39 is an mDSC thermogram of an amorphous spray-dried dispersion of amorphous obicetrapib hemicalcium and lactose in a 1:1 (w / w) ratio.

[0065] FIG. 40 is an x-ray powder diffraction pattern of the result of drying the obicetrapib hydrochloride of Example 32.

[0066] FIG. 41 is an x-ray powder diffraction pattern of the result of drying and grinding the obicetrapib hydrochloride of Example 32.

[0067] FIG. 42 is an x-ray powder diffraction pattern of the result of spray drying, grinding, and drying the obicetrapib hydrochloride of Example 32.

[0068] FIG. 43 is an mDSC thermogram of the result of spray drying, grinding, and drying the obicetrapib hydrochloride of Example 32.

[0069] FIG. 44 is an mDSC thermogram of the result of spray drying, grinding, and drying the obicetrapib hydrochloride of Example 32 after a heat-cool -heat cycle.

[0070] FIG. 45 is an x-ray powder diffraction pattern of the result of spray drying the obicetrapib hydrochloride of Example 33.

[0071] FIG. 46 is an x-ray powder diffraction pattern of the result of drying and grinding the obicetrapib hydrochloride of Example 34.

[0072] FIG. 47 is an mDSC thermogram of the result of spray drying and grinding the obicetrapib hydrochloride of Example 34.

[0073] FIG. 48 is a 'H-NMR spectrum of a solution of the obicetrapib hydrochloride of Example 34 after spray drying and grinding.

[0074] FIG. 49 is a DVS graph of the result of spray drying and grinding the obicetrapib hydrochloride of Example 34.

[0075] FIG. 50 is an overlay x-ray powder diffraction pattern of the result of spray drying and grinding obicetrapib the hydrochloride of Example 34 before and after a DVS experiment.

[0076] FIG. 51 is an x-ray powder diffraction pattern of the result of grinding and drying the obicetrapib hydrochloride for 45°C for two days and 55°C for one day of Example 35.

[0077] FIG. 52 is an x-ray powder diffraction pattern of the result of grinding and drying the obicetrapib hydrochloride for 45°C for two days and 55°C for 4 days of Example 35.

[0078] FIG. 53 is an x-ray powder diffraction overlay of obicetrapib hydrochloride Form A with a reference x-ray powder diffractogram of obicetrapib hydrochloride Form A.

[0079] FIG. 54 is an x-ray powder diffraction pattern of an amorphous solid dispersion of obicetrapib free acid / HPMCAS MF (1:1 by weight).

[0080] FIG. 55 is an mDSC thermogram of an amorphous solid dispersion of obicetrapib free acid / HPMCAS MF (1:1 by weight).

[0081] FIG. 56 is an x-ray powder diffraction pattern of an amorphous solid dispersion of obicetrapib free acid / HMPCAS MF (1:3 by weight).

[0082] FIG. 57 is an mDSC thermogram of an amorphous solid dispersion of obicetrapib free acid / HPMCAS MF NF (1 :3 by weight).

[0083] FIG. 58 is an x-ray powder diffraction pattern of an amorphous solid dispersion of obicetrapib free acid / HPC-LF (2:1 by weight).

[0084] FIG. 59 is an mDSC thermogram of an amorphous solid dispersion of obicetrapib free acid / HPC-LF (2:1 by weight).

[0085] FIG. 60 is an x-ray powder diffraction pattern of an amorphous solid dispersion of obicetrapib free acid and Soluplus® (1:3 by weight)

[0086] FIG. 61 is an mDSC thermogram of an amorphous solid dispersion of obicetrapib free acid and Soluplus® (1:3 by weight).5. DETAILED DESCRIPTION

[0087] Salt breaking of salts of active pharmaceutical ingredients is typically done by chemical neutralization. For example, to liberate the active moiety of an acid addition salt, one typically dissolves the salt in a solvent and applies a suitable base. It is atypical to perform a salt break, especially when the acid addition salt is that of a strong acid, such as hydrochloric acid, by physical, rather than chemical means, such as drying. In the instant case, it was surprising tofind that such physical means could be used to break obicetrapib HC1 such as by one or more of drying, grinding and spray drying as described herein. The resulting obicetrapib free acid is typically amorphous or x-ray amorphous as described herein.

[0088] Oils are notoriously difficult to handle and process and are thus generally unsuitable for pharmaceutical development. Oils also tend to be more difficult to purify than solids. It is therefore important in pharmaceutical development to use materials that are suitable for handling, development, and manufacture, and solids are capable of such development and especially in oral formulations.

[0089] Obicetrapib free acid has proved challenging to make as a solid. Chemical processes to make obicetrapib free acid have resulted typically in oils. Obicetrapib free acid is used in the solution phase as a non-isolated intermediate when making obicetrapib HC1. In contrast, by taking obicetrapib HC1 and physically removing the HC1, pharmaceutically developable solid obicetrapib free acid, such as amorphous or x-ray amorphous obicetrapib free acid, is prepared.

[0090] In many embodiments of the disclosure, solid obicetrapib free acid is provided. In many such embodiments the obicetrapib free acid is amorphous, and in many embodiments such amorphous obicetrapib free acid is x-ray amorphous. Substantially pure amorphous and / or x-ray amorphous obicetrapib free acid is further provided. Such purity may be physical purity, chemical purity, or both.

[0091] In many embodiments of the disclosure, there is no detectable chloride in the amorphous or x-ray amorphous obicetrapib free acid, negligible amounts of chloride, and / or chloride originating from an impurity or hydrochloric acid. The use of the term “amorphous” herein, in relation to amorphous obicetrapib free acid, does not mean that the material has no order whatsoever. As shown by the presence of peaks in several of the x-ray powder diffraction patterns of vacuum dried amorphous obicetrapib HC1, there is still order in such samples. Thus, as used herein, the term “amorphous” does not mean that the x-ray powder diffraction pattern must contain purely an amorphous halo, but instead may contain halo-like features as well as one or more peaks.

[0092] When a material has a substantially amorphous-like halo or halos, and does not exhibit discernible peaks (discrete Bragg diffraction peaks) then the term “x-ray amorphous” is used herein and is meant to generally be a subset of the term “amorphous”.

[0093] The obicetrapib hydrochloride used in the Examples is crystalline obicetrapib hydrochloride Form A, whose x-ray powder diffraction pattern is set forth in FIG. 53 and is overlaid with a reference x-ray powder diffraction pattern of obicetrapib hydrochloride Form A.

[0094] In many embodiments of the disclosure, crystalline obicetrapib HC1 is vacuum dried to reduce the HC1 present in the material. For example, in FIG. 40, obicetrapib HC1 was dried in a vacuum oven at 55°C for 48 hours. The diffraction pattern has an amorphous halo with some evidence of some peaks which are consistent with obicetrapib HC1 Form A. The disorder of the sample increased upon grinding and further drying, yielding FIG. 41. FIG. 42 represents the x-ray powder diffraction upon subsequent spray drying which is x-ray amorphous. Although chloride has not been measured on this sample, this material is believed to be x-ray amorphous obicetrapib free acid..

[0095] In some embodiments of the disclosure, x-ray amorphous obicetrapib hemicalcium is provided. Without being bound by theory, it has been found that by spray-drying amorphous obicetrapib hemicalcium containing one or more peaks, the disorder of the amorphous obicetrapib hemicalcium increases such that in the resulting x-ray powder diffraction pattern, there are no discernable peaks and instead the x-ray powder diffraction pattern comprises amorphous halos. For example, spray-dried amorphous obicetrapib hemicalcium can be made in accordance with Example 9 for which the x-ray powder diffraction pattern in FIG. 9 shows two amorphous halos, but no discernible peaks. In such embodiments of amorphous obicetrapib hemicalcium where there are no discernible peaks, but only one or more amorphous halos, the resulting amorphous obicetrapib hemicalcium is referred to as x-ray amorphous obicetrapib hemicalcium. In many embodiments, the majority of particles of x-ray amorphous obicetrapib hemicalcium is less than 10 microns in diameter. In some embodiments, more than 90% of the particles are less than 10 microns in diameter.

[0096] In some embodiments of the disclosure, improved processes for the preparation of alkali salts, such as sodium and potassium salts which improve the quality of the salts obtained and further enable the use of such salts in amorphous solid dispersions, are provided.

[0097] Amorphous solid dispersions are often used to formulate active pharmaceutical ingredients. While not necessary with amorphous obicetrapib hemicalcium, amorphous solid dispersions in general may provide the ability to stabilize amorphous active pharmaceutical ingredients which are otherwise unstable. Indeed, amorphous solid dispersions are oftendeployed, for example, when the stability or other physical properties of the amorphous active pharmaceutical ingredient present challenges for development and make direct formulation problematic (not an issue with amorphous obicetrapib hemicalcium).

[0098] Amorphous solid dispersions may be made by multiple different routes. Non-limiting methods include spray drying and hot-melt extrusion. For example, spray-dried amorphous solid dispersions of obicetrapib free acid, or amorphous obicetrapib hemicalcium, or obicetrapib alkali salts such as obicetrapib sodium or obicetrapib potassium, may be prepared by spray drying solutions comprising obicetrapib free acid, or amorphous obicetrapib hemi calcium, or obicetrapib alkali salts such as obicetrapib sodium or obicetrapib potassium, and one or more dispersion excipients and optionally, one or more surfactants. Amorphous solid dispersions, such as those made by spray drying or hot-melt extrusion, are solid forms and may be analyzed, for example, by x-ray powder diffraction to show the dispersion to be amorphous and mDSC to identify the glass transition temperature. Herein are described amorphous solid dispersions such as amorphous spray-dried dispersions or those made by holt-melt extrusion and the like of obicetrapib free acid, or amorphous obicetrapib hemicalcium, or obicetrapib alkali salts such as obicetrapib sodium or obicetrapib potassium and one or more dispersion excipients and optionally one or more surfactants.

[0099] In many embodiments, the weight percent of obicetrapib free acid, or amorphous obicetrapib hemicalcium or obicetrapib alkali salts such as obicetrapib sodium or obicetrapib potassium, is between about 5% and 80% in the amorphous solid dispersion, which further contains one or more dispersion excipients and optionally one or more surfactants. Other ranges include between about 5% and 50% (including the endpoints of the range). Additional ranges include (including the endpoints of the range) between about 10% and about 40%, between about 15% and about 35%, between about 18% and about 32 % and all amounts in between including about 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, and 32%. Other ranges include between about 18% and about 22% and between about 28% and about 32%. In many embodiments, the term “about” is meant to include normal variation in measurements including significant figures such that 19.6% may be viewed as “about” 20%.

[0100] As used herein, a “dispersion excipient” is an excipient used to make an amorphous solid dispersion of obicetrapib free acid, or amorphous obicetrapib hemicalcium, or obicetrapib alkalisalts such as obicetrapib sodium or obicetrapib potassium. Such dispersion excipients include polymers as set forth herein.

[0101] In many embodiments, the amorphous solid dispersions of the disclosure comprise obicetrapib free acid, or amorphous obicetrapib hemicalcium, or obicetrapib alkali salts such as obicetrapib sodium or obicetrapib potassium and one or more dispersion excipients such as one or more polymers. The weight ratios of the polymers may be used to adjust the properties of the dispersions, such as the glass transition temperature and the ability to form one phase (i.e., a homogenous solid dispersion). A higher glass transition temperature may signify a dispersion that is easier to process and less susceptible to chemical (degradation) and physical (recrystallization) stability than one that is lower, especially as the temperature approaches room temperature. In these and other embodiments the weight ratio of obicetrapib free acid, amorphous obicetrapib hemicalcium, or obicetrapib alkali salts such as obicetrapib sodium or obicetrapib potassium to polymer often ranges from about 4:1 to about 1:20 including all values in between such as about 3:1, about 3 :2, about 1:1, about 1:1.1, about 1:1.2, about 1:1.3, about 1:1.4, about 1:1.5, about 1:1.6, about 1:1.7, about 1:1.8, about 1:1.9, about 1:1.10, about 1:1.11, about 1:1.12, about 1:1.13, about 1:1.14, about 1:1.15; about 1:2; about 1:2.5; about 1:3; about 1:3.5; about 1:4; about 1:4:5, about 1:5, about 1:5.5, about 1:6, about 1:6.5, about 1:7, about 1:7.5, about 1:8, about 1:8.5, about 1:9, about 1:9.5, about 1:10, about 1:10.5, about 1:11, about 1:11.5, about 1:12, about 1:12.5, about 1:13, about 1:13.5, about 1:14, about 1:14.5, about 1:15, about 1:15.5, about 1:16, about 1:16.5, about 1.17:, about 1:17.5, about 1:18, about 1:18.5, and about 1:19.

[0102] In many embodiments, solid dosage formulations comprising an amorphous solid dispersion of obicetrapib free acid, obicetrapib hemicalcium, or an alkali salt of obicetrapib such as obicetrapib sodium or obicetrapib potassium, are provided. Solid dosage formulations may be in the form of a tablet or a capsule for oral administration, for example. The concentration of obicetrapib, based on obicetrapib free acid equivalent may range from 1% to 25% in many embodiments. Such solid dosage formulations may be administered to a patient daily.

[0103] In many embodiments, the dispersions comprise obicetrapib free acid, amorphous obicetrapib hemicalcium, or an alkali salt of obicetrapib such as obicetrapib sodium or obicetrapib potassium, and a dispersion excipient, wherein the dispersion excipient is a polymer, and optionally further comprising a surfactant.

[0104] In these and other embodiments, polymers of the disclosure include cellulose polymers such as cellulose ethers including hydroxypropyl methylcellulose (HPMC), methylcellulose (one brand being Methocel®), and hydroxypropyl cellulose (HPC). Further examples include modified cellulose polymers such as phthalic-half ester polymers such as hydroxypropyl methylcellulose phthalate (HPMCP). Other cellulose polymers include acetate succinate cellulose polymers such as hydroxypropyl methylcellulose acetate succinate. In some embodiments, the polymers may be Polyvinyl acetate phthalate (PVAP) or Poly(acrylic acid) (PAA), or (HPMCAS).

[0105] In these and other embodiments, the polymers of the disclosure include polyvinyllactam polymers such as Polyvinylpyrrolidone (PVP), Copovidone (PVP / VA), Hydroxypropyl methylcellulose phthalate (HPMCP), or Cellulose acetate phthalate (CAP). In some embodiments, the polymers may be acrylate and methacrylate (co)-polymers.In these and other embodiments, polymers of the disclosure include polyvinyl caprolactampolyvinyl acetate-polyethylene glycol graft copolymer (often sold under the tradename Soluplus®), HPMC E 15, PVP K30, Eudragit® L100, HPMCAS AS-HG, Methocel® AYM, PVP VA64, Eudragit L100-55, HPC-LF, Lactose, HPMCP-HP55, HPMCAS-M, Eudragit E100, HPMCAS-M, Eudragit® E PO, and Eudragit® SI 00.

[0106] In many embodiments, the amorphous solid dispersions of the disclosure comprise obicetrapib free acid, amorphous obicetrapib hemi calcium, or an alkali salt of obicetrapib such as obicetrapib sodium or obicetrapib potassium; a dispersion excipient selected from PVPVA 64, HPMCAS-M, HPMCP -HP55, Eudragit® E100, HPMCAS-MG, HPC-SSL, and Poloxamer; and optionally a surfactant.

[0107] In many embodiments, the amorphous solid dispersions of the disclosure comprise obicetrapib free acid, amorphous obicetrapib hemi calcium, or an alkali salt of obicetrapib such as obicetrapib sodium or obicetrapib potassium; a polyvinylpyrrrolidone such as PVP K30 or PVP VA64; and optionally a surfactant.

[0108] In many embodiments, the amorphous solid dispersions of the disclosure comprise obicetrapib free acid, amorphous obicetrapib hemi calcium, or an alkali salt of obicetrapib such as obicetrapib sodium or obicetrapib potassium; a polyvinyl caprolactam-polyvinyl acetatepolyethylene glycol graft copolymer such as Soluplus®; and optionally a surfactant.

[0109] In many embodiments, the amorphous solid dispersions of the disclosure comprise obicetrapib free acid, amorphous obicetrapib hemi calcium, or an alkali salt of obicetrapib such as obicetrapib sodium or obicetrapib potassium, and polymers which are esters of acrylic and methacrylic acid such as Eudragit® polymers such as Eudragit® LI 00 and LI 00-55; and optionally a surfactant.

[0110] In these and other embodiments, the amorphous solid dispersions of the disclosure further comprise a surfactant.[OHl] The term “surfactant” as used herein is a compound that contains a lipophilic segment and a hydrophilic segment, which when added to water or solvents, reduces the surface tension of the system. Surfactants may be anionic, cationic, neutral, or zwiterrionic or amphoteric.

[0112] Examples of anionic surfactants include carboxylates such as alkyl carboxylates-fatty acid salts; carboxylate fluoro surfactants; sulfates such as alkyl sulfates (e.g., sodium lauryl sulfate); alkyl ether sulfates (e.g., sodium laureth sulfate); branched alkyl sulphates; sulfonates such as docusates (e.g., dioctyl sodium sulfosuccinate); alkyl benzene sulfonates; and phosphate esters such as alkyl aryl ether phosphates and alkyl ether phosphates.

[0113] Examples of cationic surfactants include quaternary ammonium salts and pyridinium salts.

[0114] Examples of non-ionic surfactants include ethers of fatty alcohols, and polyol esters such as polyoxyethylene esters, pol oxamers, glycol and glycerol esters and sorbitan derivatives. Fatty acid esters of sorbitan (often referred to as Spans) and their ethoxylated derivatives (often referred to as Tweens) are also included. Specific examples include Span 8 (Sorbitan trioleate), Span 20 (Sorbitan monolaurate), Span 40 (Sorbitan monopalmitate), Span 60 (Sorbitan monostearate), Span 65 (Sorbitan tristearate) and Span 80 (Sorbitan mono-oleate), Tween 20 (Polyoxyethylene (20) sorbitan monolaurate), Tween 40 (Polyoxyethylene (20) sorbitan monopalmitate), Tween 60 (Polyoxyethylene (20) sorbitan monostearate), Tween 65 (Polyoxyethylene (20) sorbitan tristearate), Tween 80 (Polyoxyethylene (20) sorbitan monooleate), and Tween 85 (Polyoxyethylene (20) sorbitan tri -oleate). Polysorbate 20 and polysorbate 80 are also non-ionic surfactants. Further examples of non-ionic surfactants are poloxamers which are synthetic block copolymers of hydrophilic poly(oxy ethylene).

[0115] Examples of zwitterionic and / or amphoteric surfactants include lauryl betaine, lauroyl sarcosinate, lauryl sultaine, laurylamidopropyl betaine (also known as cocamidoproipylbetaine) and lauryldimethylamine oxide.

[0116] In many embodiments, the surfactant is a salt, an organosulfur compound, or both. In these and other embodiments, the surfactant contains an alkyl chain and may be monosubstituted such as with a sulfur moiety. That sulfur moiety in many embodiments is a sulphate ion.

[0117] In many embodiments, surfactants are selected from lauric, palmitic, stearic and oleic acid or salts thereof, polyethylene glycol glycerides, polyoxyethylene monoesters, polyoxyethylethylene monostearate, polyoxyethylene monolaurate, polyoxyethylene sorbitan monooleate, polyethoxylated castor oils, polyethylene glycol having molecular weight in the range of about 2000 to 10000, propylene glycol caprylates, glycerol oleates and caprylates, esters of glycerol and fatty acids. In many embodiments, one or more surfactants are selected from dioctyl sodium sulfosuccinate, Capmul PG-8, Capryol 90, Capmul MCM, polysorbate 20, polysorbate 40 or polysorbate 80 or sodium lauryl sulphate. In many embodiments, the surfactant is sodium lauryl sulphate such as Kolliphor SLS.

[0118] In particular, examples of surfactants of the disclosure include: sodium lauryl sulfate (SLS), polysorbate (Tween 80 etc.), tocopherol polyethylene glycol 1000 succinate (Vitamin E-TPGS also known as VE-TPGS), copolymer of polyoxyethylene-co-polyoxypropylene-co-poly oxy ethylene (Pol oxamer 188 and 407), polyoxyethylene (20) stearyl ether (Brij 20), polyoxylglycerides (Gelucire 44 / 14, Gelucire 50 / 13 etc.), macrogolglycerol ricinoleate (Kolliphor EL), polyethylene glycol 15-hydroxystearate (Kolliphor HS 15), glycerol polyethylene glycol oxy stearate (Kolliphor RH 40), Gelucire 44 / 14, or mixtures thereof. In some embodiments, the surfactant is selected from VE-TPGS, SLS, Tween 80, and Gelucire 44 / 14.

[0119] In many embodiments, the amount of surfactant ranges between about 0.5% and 20% by weight, including between about 1% and 10% by weight, including between about 1.5% and 8% by weight, including between about 2% and 7% by weight, including about 2%, 3%, 4%, 5%, 6%, 7%, and 8%.

[0120] In many of the embodiments of the disclosure, the amorphous solid dispersions prepared are x-ray amorphous in that there are no discernible peaks.

[0121] In these and other embodiments of the disclosure, pharmaceutical compositions comprising amorphous solid dispersions of the disclosure are provided and often further comprise one or more pharmaceutically acceptable excipients.

[0122] In many embodiments, solid dosage formulations comprising an amorphous solid dispersion of the disclosure are provided. Solid dosage formulations may be in the form of a tablet or a capsule for oral administration, for example. The concentration of obicetrapib, based on obicetrapib free acid equivalent may range from 1% to 25% in many embodiments. Such solid dosage formulations may be administered to a patient daily.

[0123] In these and other embodiments, the solid dosage formulations may further comprise one or more pharmaceutically acceptable excipients. As used herein, a “pharmaceutically acceptable excipient” is an excipient used to make a pharmaceutical composition such as a finished dosage form. Exemplary finished dosage forms include oral dosage forms such as tablets and capsules.

[0124] Such pharmaceutically acceptable excipients include but are not limited to one or more binders, fillers (also known as diluents), surfactants, disintegrants, coloring agents, glidant, opacifiers, lubricants, chelating agents, pH modifiers, or plasticizers. The following references which are all hereby incorporated by reference disclose techniques and excipients used to formulate 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).

[0125] The one or more binders used in the pharmaceutical compositions may be, for example, cellulose derivatives such as methylcellulose and carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, glucose, sucrose, lactose dextrose, xylitol, sorbitol, maltitol, polymethacrylates, polyvinylpyrrolidone and its copolymers, starch paste, pregelatinized starch, gum tragacanth, alginic acids and salts thereof such as sodium alginate, magnesium aluminum silicate, polyethylene glycol, guar gum, and bentonites.

[0126] The pharmaceutical composition may also comprise one or more disintegrants such as cross-linked polyvinylpyrrolidone, croscarmellose sodium, calcium carboxyl methylcellulose, low substituted hydroxypropyl cellulose, alginic acid, sodium alginate, microcrystalline cellulose, sodium starch glycolate or pregelatinized starch.

[0127] The one or more filler (also known as diluents) used in the pharmaceutical compositions may include inorganic phosphates like dibasic calcium phosphate, or sugars or sugar analogues and derivatives thereof, such as in particular lactose, such as lactose monohydrate or water-free lactose, dextrose, sorbitol, mannitol, saccharose, maltodextrin, isomaltose, or celluloses like microcrystalline cellulose or powdered celluloses, or the like.

[0128] The pharmaceutical compositions may optionally be film-coated using techniques well known in the art such as spray coating in a conventional coating pan or a fluidized bed processor or dip coating. Alternatively, coating may also be performed using a hot-melt technique. The film coat comprises film-forming polymers, one or more pharmaceutically acceptable excipients and pharmaceutically acceptable solvents. Examples of film-forming agents include, but are not limited to, cellulose derivatives such as methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyl ethylcellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, and ethyl cellulose; polyvinyl alcohol, waxes; fat substances; or mixtures thereof. Plasticizers may be present in the film coating and may be selected from, for example, polyethylene glycol and the like.

[0129] Glidants present in the pharmaceutical compositions may be selected from, for example, silicon dioxide, talc, magnesium stearate and the like.

[0130] Lubricants present in the pharmaceutical compositions may be, for example, fatty acids or fatty acid derivatives, such as alkali and earth alkali salts of stearic, lauric and / or palmitic acid and the like.

[0131] The pH modifiers which may be present in the pharmaceutical compositions may be selected from, for example, sodium carbonate, sodium hydrogen carbonate, calcium phosphate, calcium carbonate, and the like.Methods of Treatment for Cardiovascular Disease

[0132] The present disclosure further provides for methods of treating subjects suffering from or having an increased risk of developing a cardiovascular disease, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositionsthereof of the present disclosure to said subjects, optionally in combination with a therapeutically effective amount of ezetimibe or other lipid-modifying therapy.

[0133] In some embodiments, the method comprises administering a therapeutically effective amount of an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure to subjects with atherosclerotic cardiovascular disease (ASCVD) and / or heterozygous familial hypercholesterolemia (HeFH) who are not adequately controlled by maximally tolerated lipid-modifying therapies.

[0134] Obicetrapib and methods for treating subjects with ASCVD and / or HeFH are described in WO 2025 / 059594, the disclosure of which is incorporated herein by reference in its entirety.

[0135] In certain embodiments, the subject’s baseline fasting serum LDL-C on maximally tolerated lipid-modifying therapy is > 100 mg / dL.

[0136] In certain embodiments, the subject’s baseline fasting serum LDL-C on maximally tolerated lipid-modifying therapy is > 70 mg / dL to < 100 mg / dL with at least one of the following risk enhancers:• recent MI• type 2 diabetes mellitus• fasting triglycerides (TG) > 150 mg / dL• fasting Lp(a) > 30 mg / dL• fasting HDL-C < 40 mg / dL.

[0137] In certain embodiments, the subjects have not achieved adequate lipid lowering on a high-intensity statin (HIS) regimen. In specific embodiments, the HIS is 20 or 40 mg rosuvastatin per day. In specific embodiments, the HIS is 40 or 80 mg of atorvastatin per day.

[0138] In various embodiments, the therapeutically effective amount of obicetrapib in an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure with an obicetrapib free acid equivalent in the amount of 2.5 - 10 mg per day. In certain embodiments, thetherapeutically effective amount of obicetrapib free acid equivalent of the present disclosure is obicetrapib in the amount of 2.5, 5.0, 7.5, or 10 mg per day. In specific embodiments, the therapeutically effective amount of an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure is 10 mg obicetrapib free acid equivalent per day.

[0139] In various embodiments, amorphous solid dispersions comprising (i) obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof the obicetrapib of the present disclosure is administered in combination with maximally tolerated lipid-modifying therapy.

[0140] In some embodiments, the maximally tolerated lipid-modifying therapy comprises a statin. In certain embodiments, the subject is co-administered a HIS regimen.

[0141] In some embodiments, the maximally tolerated lipid-modifying therapy comprises ezetimibe. In certain embodiments, an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure is administered in combination with ezetimibe. In specific embodiments, an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure is administered with the free acid equivalent of 10 mg of obicetrapib in combination with 10 mg ezetimibe.

[0142] In specific embodiments, an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof is administered as a fixed dose combination with ezetimibe.

[0143] In specific embodiments of the method of the present disclosure, an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure in fixed dose combination with 10 mg ezetimibe, is administered on top of maximally tolerated lipid-modifying therapy to subjects with heterozygous familial hypercholesterolemia (HeFH) and / or Atherosclerotic Cardiovascular Disease (ASCVD) or Multiple ASCVD Risk Factors.

[0144] Obicetrapib and ezetimibe combination treatment and fixed dose pharmaceutical compositions thereof are described in WO 2024 / 042061, the disclosure of which is incorporated herein by reference in its entirety.

[0145] In various embodiments of the methods of the present disclosure, a therapeutically effective amount of an amorphous solid dispersion comprising: (i) obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure is administered to lower serum LDL-C as compared to baseline (level prior to first administration of obicetrapib), lower non-HDL-C as compared to baseline, lower ApoB as compared to baseline, raise HDL-C levels as compared to baseline, and / or lower Lp(a) as compared to baseline. In certain embodiments, an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure, is administered to lower serum LDL-C to < 100 mg / dL and in some embodiments, to lower serum LDL-C to 70 mg / dL or less.

[0146] In certain embodiments, an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure is administered in an amount and for a time sufficient to achieve one or more of the following: lower serum LDL-C as compared to baseline (level prior to first administrationof obicetrapib), lower non-HDL-C as compared to baseline, lower ApoB as compared to baseline, raise HDL-C levels as compared to baseline, and / or lower Lp(a) as compared to baseline.

[0147] In some embodiments, there is provided a method of reducing major adverse cardiovascular events (MACE) in subjects with atherosclerotic cardiovascular disease (ASCVD) and / or heterozygous familial hypercholesterolemia (HeFH) who are not adequately controlled by maximally tolerated lipid-modifying therapies.

[0148] In certain embodiments, the method reduces one or more of death, non-fatal myocardial infarction, non-fatal stroke, and coronary revascularization.

[0149] In specific embodiments, the method reduces death. In specific embodiments, the method reduces non-fatal myocardial infarction. In specific embodiments, the method reduces non-fatal stroke. In specific embodiments, the method reduces the need for coronary revascularization.

[0150] In some embodiments, an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure is administered to a subject on maximally tolerated lipid-modifying therapy who has atherosclerotic cardiovascular disease (ASCVD) as evidenced by having at least one feature in Group A and / or Group B below:A. Imaging evidence of vascular diseaseThis is defined as having one of the following on prior clinically indicated vascular imaging:1) Angiographic evidence of coronary artery disease (invasive or CCTA) with a visual diameter stenosis <50% in at least one major epicardial coronary artery 2) Angiographic evidence (invasive or CCTA derived) of coronary artery disease with a visual diameter stenosis >50% in at least one major epicardial coronary artery but fractional flow reserve 0.83) Carotid artery stenosis >50%B. Having established clinically manifest ASCVDThis is defined as having one of the following:1) History of myocardial infarction (MI)2) History of ischemic stroke3) Previous percutaneous coronary intervention (PCI)4) Previous carotid artery revascularization5) Documentation of a resting ankle-brachial index <0.856) Previous revascularization of an iliac, femoral, or popliteal artery or lower extremity amputation due to peripheral artery disease

[0151] In certain embodiments, administration of an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium , (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure, on top of prior maximally-tolerated lipid modifying therapy is sufficient, after 18 months of treatment, to show statistically significant improvement (reduction from baseline) as compared to placebo in one or more of (i) total non-calcified coronary atherosclerotic plaque volume (NCPV), (ii) NCPV in the most diseased coronary segment (NCPVMD), (iii) reduction in low attenuation plaque volume, (iv) reduction in calcified plaque volume, (v) reduction in perivascular fat attenuation index score measured in all of the left anterior descending artery (LAD), left circumflex artery (LCx), and right coronary artery (RCA) (collectively, the principal coronary arteries), (vi) reduction in FAI score age- and gender-matched population centile.

[0152] In specific embodiments, the equivalent of 10 mg obicetrapib free acid is administered per day. In certain embodiments, the equivalent of 10 mg obicetrapib free acid is administered per day in combination with 10 mg of ezetimibe. In specific embodiments, the equivalent of 10 mg obicetrapib is administered per day in fixed dose combination with 10 mg of ezetimibe. What is meant by the term “equivalent of 10 mg obicetrapib” is, for example, that if obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium were to be dosed, the corresponding amount of the obicetrapib free acid in that dosage form would be 10 mg.

[0153] In some embodiments, the subject is a hypo-responder to high-intensity statin (HIS) therapy, and is further receiving concomitant statin therapy.

[0154] In some embodiments, the cardiovascular disease is atherosclerotic cardiovascular disease (ASCVD).

[0155] In some embodiments, there is provided methods for treating subjects suffering from or having an increased risk of developing a cardiovascular disease comprising administering a pharmaceutically effective amount an amorphous solid dispersion comprising (i) obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure in combination with an HMG CoA reductase inhibitor (statin). In some embodiments, the HMG CoA reductase inhibitor is atorvastatin or rosuvastatin, or a pharmaceutically acceptable salt thereof.Method of Treatment for Neurodegenerative Disease

[0156] Also provided herein are methods for treating or slowing the progression of a neurodegenerative disease in a subject who has or is at risk of developing such a neurodegenerative disease. The method comprises administering a pharmaceutically effective amount of an amorphous solid dispersion comprising: (i) obicetrapib free acid, or alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure to said subject.

[0157] In some embodiments, the neurodegenerative disease is Alzheimer's Disease (AD), Lewy Body dementia, vascular or multi-infarct dementia, or frontotemporal dementia (FTD).

[0158] In some embodiments, there is provided a method of treating or slowing the progression of Alzheimer’s disease, comprising administering to the subject a therapeutically effective amount of an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure. In certain embodiments, the subject has at least one ApoE4 allele. In specific embodiments, the subject has one ApoE4 allele. In specific embodiments, the subject has two ApoE4 alleles. In some embodiments, the subject has no evidence of cognitive impairment prior to first administration ofobicetrapib. In some embodiments, the subject has mild cognitive impairment (MCI) prior to first administration of obicetrapib.

[0159] In various embodiments, methods are provided for attenuating increase in plasma phosphorylated Tau 217 (p-Tau217) in the plasma of a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of an amorphous solid dispersion having: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure, in an amount effective to attenuate increase in p-Tau217 in the plasma of the subject determined prior to the first administration of the obicetrapib.

[0160] In certain embodiments, methods are provided for attenuating increase in plasma phosphorylated Tau 217 (p-Tau217) in a subject in need thereof compared to the increase in plasma p-Tau217 of said subject observed at 12 months of non-obicetrapib therapy, the method comprising orally administering an amorphous solid dispersion having: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure, in an amount effective to attenuate increase in p-Tau217 in the plasma of the subject determined prior to the first administration of the obicetrapib.

[0161] In various embodiments of the method, the method comprises administering an amorphous solid dispersion having: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure, in a fixed dose combination with ezetimibe, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises 5 to 20 mg ezetimibe.

[0162] In various embodiments, methods are provided for reducing the rate of decrease in the AP42 / AP40 ratio in the plasma of a subject in need thereof, comprising administering to the subject an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkalisalts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure in an amount effective to reduce the rate of decrease in the AP42 / AP40 ratio in the plasma of the subject determined prior to the first administration of an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure. In certain embodiments, the subject has at least one ApoE4 allele. In specific embodiments, the subject has one ApoE4 allele. In specific embodiments, the subject has two ApoE4 alleles. In some embodiments, the subject has no evidence of cognitive impairment prior to first administration of an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure. In some embodiments, the subject has mild cognitive impairment (MCI) prior to first administration of an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure.

[0163] In some embodiments, there is provided a method of lowering ApoE4 concentration in the central nervous system (CNS) of a subject in need thereof, comprising administering to the patient an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants and / or pharmaceutical compositions thereof of the present disclosure in an amount effective to reduce ApoE4 concentration in the CNS. In certain embodiments, the subject has at least one ApoE4 allele. In specific embodiments, the subject has one ApoE4 allele. In specific embodiments, the subject has two ApoE4 alleles. In some embodiments, the subject has no evidence of cognitive impairment prior to first administration of obicetrapib. In someembodiments, the subject has mild cognitive impairment (MCI) prior to first administration of an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants and / or pharmaceutical compositions thereof of the present disclosure.Method of Treatment for Metabolic Disease

[0164] In some embodiments, there is provided a method for treating subjects suffering from or having an increased risk for hyperlipidemia or mixed dyslipidemia comprising administering a pharmaceutically effective amount of an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure and a pharmaceutically effective amount of ezetimibe, or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the subject is partially or completely intolerant to statins.

[0165] In some embodiments there is provided a method for treating subjects requiring additional lowering of low-density lipoprotein cholesterol as an adjunct to diet and / or as maximally tolerated lipid-lowering therapy for the treatment of heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular (CV) disease (ASCVD) comprising administering a therapeutically effective amount of an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure and a pharmaceutically effective amount of ezetimibe, or a pharmaceutically acceptable salt thereof.

[0166] Also provided herein are methods for treating or preventing a metabolic disorder in a subject who has or is at risk of developing a metabolic disorder comprising administering a therapeutically effective amount of an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and(iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure and a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0167] Pharmaceutical compositions comprising obicetrapib and at least one SGLT2 inhibitor are described in WO 2023 / 129595 and WO 2024 / 226537, the disclosures of which are incorporated herein by reference in their entireties.

[0168] In some embodiments there is provided a method for treating or preventing a disorder selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, obesity, metabolic syndrome, hypertension, hypercholesterolemia, cardiovascular disease, atherosclerotic cardiovascular disease, heart failure and chronic kidney disease in a subject who has or is at risk of said disorder, comprising administering a therapeutically effective amount of an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants and one or more dispersion excipients and / or pharmaceutical compositions thereof of the present disclosure and a therapeutically effective amount of an least one SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0169] Also provided herein, are methods of treating heterozygous familial hypercholesterolemia (HeFH) and / or atherosclerotic cardiovascular disease (ASCVD) in a subject in need thereof comprising administering an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure to such subjects.

[0170] In one embodiment, there is provided a method of treating heterozygous familial hypercholesterolemia (HeFH) in a subject in need thereof comprising administering a therapeutically effective amount of an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and(iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure to such subjects.

[0171] In some embodiments, there is provided a method of reducing or preventing vascular symptoms in a subject with a beta hemoglobinopathy, comprising orally administering an HDL-elevating amount of an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure to the subject. Optionally, an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof is coadministered with at least one liposoluble antioxidant.Method of Treatment for Atherosclerotic Plaque

[0172] In some embodiments, there is provided a method of improving atherosclerotic plaque characteristics in a subject with ASCVD comprising administering a therapeutically effective amount of an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure. Optionally, the obicetrapib is co-administered with a therapeutically effective amount of ezetimibe, or a pharmaceutically acceptable salt thereof.

[0173] In some embodiments, there is provided a method of reducing coronary artery inflammation in a subject with ASCVD comprising administering a therapeutically effective amount of an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure. Optionally, the obicetrapib is co-administered with a therapeutically effective amount of ezetimibe, or a pharmaceutically acceptable salt thereof.

[0174] In some embodiments of any of the methods described herein, the effective dosage amount of an amorphous solid dispersion comprising obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, is formulated in a pharmaceutical composition as disclosed herein.Dosing

[0175] In some embodiments, an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure is administered to the subject.

[0176] In various embodiments, an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure is administered orally. In some embodiments, an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure is administered in a solid dosage form. In some embodiments, the solid dosage form is a tablet. In some embodiments, the tablet further comprises a film coating. In typical embodiments, an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure is administered as a tablet for oral administration. In various embodiments, the dose of an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure is 2.5-40 mg obicetrapib free acid equivalent by mouth per day (2.5-40 mg poQD). In some embodiments, the dose of an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure is 0.1 to 3 mg obicetrapib free acid equivalent by mouth per day (0.1-3 mg po QD). In some embodiments, the dose of an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure is 5-40 mg of obicetrapib free acid equivalent by mouth per day (5-40 mg po QD). In some embodiments, the dose of an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure is 10-40 mg of obicetrapib free acid equivalent by mouth per day (10-40 mg po QD).

[0177] In some specific embodiments, the dose of an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure is obicetrapib free acid equivalent in the amount of 2.5 mg po QD, 3.0 mg po QD, 3.5 mg po QD, 4.0 mg po QD, 4.5 mg po QD, 5.0 mg po QD, 5.5 mg po QD, 6.0 mg po QD, 6.5 mg po QD, 7.0 mg po QD, 7.5 mg po QD, 8.0 mg po QD, 8.5 mg po QD, 9.0 mg po QD, 9.5 mg po QD, 10.0 mg po QD, 10.5 mg po QD, 11.0 mg po QD, 11.5 mg po QD, 12.0 mg po QD, 12.5 mg po QD, 13.0 mg po QD, 13.5 mg po QD, 14.0 mg po QD, 14.5 mg po QD, 15.0 mg po QD, 15.5 mg po QD, 16.0 mg po QD, 16.5 mg po QD, 17.0 mg po QD, 17.5 mg po QD, 18.0 mg po QD, 18.5 mg po QD, 19.0 mg po QD, 19.5 mg po QD, 20.0 mg po QD, 20.5 mg po QD, 21.0 mg po QD, 21.5 mg po QD, 22.0 mg po QD, 22.5 mg po QD, 23.0 mg po QD, 23.5 mg po QD, 24.0 mg po QD, 24.5 mg po QD, 25.0 mg po QD, 25.5 mg po QD, 26.0 mg po QD, 26.5 mg po QD, 27.0 mg po QD, 27.5 mg po QD, 28.0 mg po QD, 28.5 mg po QD, 29.0 mg po QD, 29.5 mg po QD, 30.0 mg po QD, 30.5 mg po QD, 31.0 mg po QD, 31.5 mg poQD, 32.0 mg po QD, 32.5 mg po QD, 33.0 mg po QD, 33.5 mg po QD, 34.0 mg po QD, 34.5 mg po QD, 35.0 mg po QD, 35.5 mg po QD, 36.0 mg po QD, 36.5 mg po QD, 37.0 mg po QD, 37.5 mg po QD, 38.0 mg po QD, 38.5 mg po QD, 39.0 mg po QD, 39.5 mg po QD, or 40.0 mg po QD.

[0178] In some specific embodiments, the dose of an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure is obicetrapib free acid equivalent in the amount of 2.5 mg po QD, 3.0 mg po QD, 3.5 mg po QD, 4.0 mg po QD, 4.5 mg po QD, 5.0 mg po QD, 5.5 mg po QD, 6.0 mg po QD, 6.5 mg po QD, 7.0 mg po QD, 7.5 mg po QD, 8.0 mg po QD, 8.5 mg po QD, 9.0 mg po QD, 9.5 mg po QD, 10.0 mg po QD, 10.5 mg po QD, 11.0 mg po QD, 11.5 mg po QD, 12.0 mg po QD, 12.5 mg po QD, 13.0 mg po QD, 13.5 mg po QD, 14.0 mg po QD, 14.5 mg po QD, 15.0 mg po QD, 15.5 mg po QD, 16.0 mg po QD, 16.5 mg po QD, 17.0 mg po QD, 17.5 mg po QD, 18.0 mg po QD, 18.5 mg po QD, 19.0 mg po QD, 19.5 mg po QD, 20.0 mg po QD, 20.5 mg po QD, 21.0 mg po QD, 21.5 mg po QD, 22.0 mg po QD, 22.5 mg po QD, 23.0 mg po QD, 23.5 mg po QD, 24.0 mg po QD, 24.5 mg po QD, 25.0 mg po QD, 25.5 mg po QD, 26.0 mg po QD, 26.5 mg po QD, 27.0 mg po QD, 27.5 mg po QD, 28.0 mg po QD, 28.5 mg po QD, 29.0 mg po QD, 29.5 mg po QD, 30.0 mg po QD, 30.5 mg po QD, 31.0 mg po QD, 31.5 mg po QD, 32.0 mg po QD, 32.5 mg po QD, 33.0 mg po QD, 33.5 mg po QD, 34.0 mg po QD, 34.5 mg po QD, 35.0 mg po QD, 35.5 mg po QD, 36.0 mg po QD, 36.5 mg po QD, 37.0 mg po QD, 37.5 mg po QD, 38.0 mg po QD, 38.5 mg po QD, 39.0 mg po QD, 39.5 mg po QD, or 40.0 mg po QD.

[0179] In some specific embodiments, the dose of an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure is obicetrapib free acid equivalent in the amount of 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15,1, 15.2,15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1, 18.2, 18.3, 18.4. 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9. 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30.0, 30.1, 30.2, 30.3, 30.4, 30.5, 30.6, 30.7, 30.8, 30.9, 31.0, 31.1, 31.2, 31.3, 31.4, 31.5, 31.6, 31.7, 31.8, 31.9, 32.0, 32.1, 32.2, 32.3, 32.4, 32.5, 32.6, 32.7, 32.8, 32.9, 33.0, 33.1, 33.2, 33.3, 33.4, 33.5, 33.6, 33.7, 33.8, 33.9, 34.0, 34.1, 34.2, 34.3, 34.4, 34.5, 34.6, 34.7, 34.8, 34.9, 35.0, 35.1, 35.2, 35.3, 35.4, 35.5, 35.6, 35.7, 35.8, 35.9, 36.0, 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36.9, 37.0, 37.1, 37.2, 37.3, 37.4, 37.5, 37.6, 37.7, 37.8, 37.9, 38.0, 38.1, 38.2, 38.3, 38.4, 38.5, 38.6, 38.7, 38.8, 38.9, 39.0, 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9, or 40.0 mg po QD.

[0180] In various embodiments, the dose is administered once per day. In some embodiments, the dose is divided and is administered as a plurality of divided doses.

[0181] In some specific embodiments, the daily dose of an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure is obicetrapib free acid equivalent in the amount of 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15,1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9. 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1,25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30.0, 30.1, 30.2, 30.3, 30.4, 30.5, 30.6, 30.7, 30.8, 30.9, 31.0, 31.1, 31.2, 31.3, 31.4, 31.5, 31.6, 31.7, 31.8, 31.9, 32.0, 32.1, 32.2, 32.3, 32.4, 32.5, 32.6, 32.7, 32.8, 32.9, 33.0, 33.1, 33.2, 33.3, 33.4, 33.5, 33.6, 33.7, 33.8, 33.9, 34.0, 34.1, 34.2, 34.3, 34.4, 34.5, 34.6, 34.7, 34.8, 34.9, 35.0, 35.1, 35.2, 35.3, 35.4, 35.5, 35.6, 35.7, 35.8, 35.9, 36.0, 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36.9, 37.0, 37.1, 37.2, 37.3, 37.4, 37.5, 37.6, 37.7, 37.8, 37.9, 38.0, 38.1, 38.2, 38.3, 38.4, 38.5, 38.6, 38.7, 38.8, 38.9, 39.0, 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9, or 40.0 mg per day. In some embodiments, the dose is provided in a plurality of doses.

[0182] In some embodiments, the tablet comprises an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof of the present disclosure is the equivalent of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg of obicetrapib free acid.

[0183] In various embodiments, an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof is administered once daily for at least 8 weeks, at least 6 months, at least 12 months, at least 24 months, or at least 36 months.

[0184] In some embodiments, the subject does not have cardiovascular disease. In some embodiments, the subject is not being treated for cardiovascular disease. In some embodiments, the subject is not concurrently undergoing treatment with one or more HMG Co A reductase inhibitors (statins). In some embodiments, the subject is not concurrently being treated with one or more statins selected from the group atorvastatin, pravastatin, fluvastatin, simvastatin, lovastatin, rosuvastatin and pitavastatin or their salts thereof.

[0185] In various embodiments, an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and(iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof is administered in an amount effective to increase levels of ApoAI in CSF.

[0186] In various embodiments, an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof is administered in an amount effective to decrease levels of ApoE4 in CSF.

[0187] In various embodiments, an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof is administered in an amount effective to decrease levels of ApoJ (clusterin) in CSF.

[0188] In various embodiments, an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof is administered in an amount effective to increase levels of lutein in CSF of the subject.

[0189] In various embodiments, an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof is administered in an amount effective to increase levels of a-tocopherol in CSF of the subject.

[0190] In various embodiments, an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof is administered in an amount effective to increase levels of zeaxanthin in CSF of the subject.

[0191] In various embodiments, an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof isadministered in an amount effective to increase levels of total ApoE-HDL in blood as compared to the level prior to commencement of treatment. In typical embodiments, blood levels of ApoE-HDL are measured in plasma. In preferred embodiments, an amorphous solid dispersion comprising: (i) one or more of obicetrapib free acid, alkali salts of obicetrapib such as obicetrapib sodium or obicetrapib potassium, or amorphous obicetrapib hemicalcium, (ii) one or more dispersion excipients and (iii) optionally one or more surfactants, and / or pharmaceutical compositions thereof is administered in an amount effective to increase plasma levels of ApoE-HDL in particles lacking ApoC3 and / or percentage of plasma HDL-ApoE in HDL particles lacking ApoC3.

[0192] The disclosure further includes the following non-limiting embodiments referred to below as clauses:

[0193] Clause 1. An amorphous solid dispersion comprising one or more of (i) obicetrapib free acid, amorphous obicetrapib hemicalcium, obicetrapib sodium, or obicetrapib potassium, (ii) one or more dispersion excipients, and (iii) optionally one or more surfactants.

[0194] Clause 2. The amorphous solid dispersion of Clause 1, wherein the one or more dispersion excipients is a polymer.

[0195] Clause 3. A pharmaceutical composition comprising an amorphous solid dispersion of Clause 1 or Clause 2, and one or more pharmaceutically acceptable excipients.

[0196] Clause 4. The pharmaceutical composition of any one of Clause 3 made by (a) direct compression or (b) dry granulation followed by encapsulation or tablet compression.

[0197] Clause 5. A method of treating a subject suffering from or having an increased risk of developing a cardiovascular disease, the method comprising:administering a therapeutically effective amount of an amorphous solid dispersion of Clause 1 or Clause 2 or a pharmaceutical composition of Clause 3 or Clause 4 to the subject.

[0198] Clause 6. A method of treating a subject suffering from or having an increased risk of developing a cardiovascular disease, the method comprising:administering a therapeutically effective amount of an amorphous solid dispersion of Clause 1 or Clause 2 or a pharmaceutical composition of Clause 3 or Clause 4 to the subject, further comprising administration of an HMG CoA reductase inhibitor.

[0199] Clause 7. A method of slowing the progression of a neurodegenerative disease in a subject who is at risk of developing a neurodegenerative disease, the method comprising:administering a therapeutically effective amount of an amorphous solid dispersion of Clause 1 or Clause 2 or a pharmaceutical composition of Clause 3 or Clause 4 to the subject.

[0200] Clause 8. The method of Clause 7, where the neurodegenerative disease is Alzheimer's Disease (AD), Lewy Body dementia, vascular or multi-infarct dementia, or frontotemporal dementia (FTD).

[0201] Clause 9. A method of treating a subject suffering from or having an increased risk for hyperlipidemia or mixed dyslipidemia, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of Clause 1 or Clause 2 or a pharmaceutical composition of Clause 3 or Clause 4, and a therapeutically effective amount of ezetimibe, or a pharmaceutically acceptable salt of ezetimibe to the subject.

[0202] Clause 10. A method of treating a subject requiring additional lowering of low-density lipoprotein cholesterol as an adjunct to diet and / or as maximally tolerated lipid-lowering therapy for the treatment of heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular (CV) disease (ASCVD), the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of Clause 1 or Clause 2 or a pharmaceutical composition of Clause 3 or Clause 4, and a therapeutically effective amount of ezetimibe, or a pharmaceutically acceptable salt of ezetimibe to the subject.

[0203] Clause 11. A method of treating or preventing a metabolic disorder in a subject who has or is at risk of developing a metabolic disorder, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of Clause 1 or Clause 2 or a pharmaceutical composition of Clause 3 or Clause 4, and a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt of an SGLT2 inhibitor to the subject.

[0204] Clause 12. A method of treating or preventing a disorder selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, obesity, metabolic syndrome, hypertension, hypercholesterolemia, cardiovascular disease, atherosclerotic cardiovascular disease, heart failure and chronic kidney disease in a subject who has or is at risk of said disorder, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of Clause 1 or Clause 2 or a pharmaceutical composition of Clause 3or Clause 4, and a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt of an SGLT2 inhibitor to the subject.

[0205] Clause 13. A method of treating heterozygous familial hypercholesterolemia (HeFH) and / or atherosclerotic cardiovascular disease (ASCVD) in a subject in need thereof, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of Clause 1 or Clause 2 or a pharmaceutical composition of Clause 3 or Clause 4 to the subject.

[0206] Clause 14. A method of reducing or preventing vascular symptoms in a subject with a beta hemoglobinopathy, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of Clause 1 or Clause 2 or a pharmaceutical composition of Clause 3 or Clause 4 to the subject.

[0207] Clause 15. The method of Clause 14, wherein an amorphous solid dispersion comprising one or more of (i) obicetrapib free acid, amorphous obicetrapib hemicalcium, obicetrapib sodium, or obicetrapib potassium, (ii) and one or more dispersion excipients and (iii) optionally one or more surfactants, or pharmaceutical composition thereof, is co-administered with at least one liposoluble antioxidant.

[0208] Clause 16. A method of improving atherosclerotic plaque characteristics in a patient with ASCVD, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of Clause 1 or Clause 2 or a pharmaceutical composition of Clause 3 or Clause 4 to the subject.

[0209] Clause 17. The method of Clause 16, wherein an amorphous solid dispersion of Clause 1 or Clause 2 or a pharmaceutical composition of Clause 3 or Clause 4, is co-administered with a therapeutically effective amount of ezetimibe, or a pharmaceutically acceptable salt thereof.

[0210] Clause 18. A method of reducing the rate of decrease in the AP42 / AP40 ratio in the plasma of a subject in need thereof, the method comprising administering to the subject an amorphous solid dispersion of Clause 1 or Clause 2 or a pharmaceutical composition of Clause 3 or Clause 4, in an amount effective to reduce the rate of decrease in the AP42 / AP40 ratio in the plasma of the subject determined prior to the first administration of an amorphous solid dispersion of amorphous obicetrapib hemicalcium, and one or more dispersion excipients and optionally one or more surfactants, or a pharmaceutical composition thereof.

[0211] Clause 19. A method of lowering ApoE4 concentration in the central nervous system (CNS) of a subject in need thereof, the method comprising administering to the subject anamorphous solid dispersion of Clause 1 or Clause 2 or a pharmaceutical composition of Clause 3 or Clause 4, in an amount effective to reduce ApoE4 concentration in the CNS.

[0212] Clause 20. A method of reducing major adverse cardiovascular events (MACE) in subjects with atherosclerotic cardiovascular disease (ASCVD) and / or heterozygous familial hypercholesterolemia (HeFH) who are not adequately controlled by maximally tolerated lipid-modifying therapies, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of Clause 1 or Clause 2 or a pharmaceutical composition of Clause 3 or Clause 4, to the subject.

[0213] Clause 21. The method of Clause 20, wherein the amorphous solid dispersion of Clause 1 or Clause 2 or a pharmaceutical composition of Clause 3 or Clause 4 is administered at an oral dose of 10 mg per day for at least six months.

[0214] Clause 22. The method of Clause 20 or 21, wherein the baseline fasting serum LDL-C on maximally tolerated lipid-modifying therapy is >100 mg / dL, and administration of an amorphous solid dispersion of Clause 1 or Clause 2 or a pharmaceutical composition of Clause 3 or Clause 4 lowers serum LDL-C to less than 100 mg / dL.

[0215] Clause 23. The method of any one of Clauses 20 to 22, wherein administration of an amorphous solid dispersion of Clause 1 or Clause 2 or a pharmaceutical composition of Clause 3 or Clause 4 on top of prior maximally-tolerated lipid modifying therapy is sufficient, after 18 months of treatment, to show reduction from baseline as compared to placebo in one or more of:(i) total non-calcified coronary atherosclerotic plaque volume (NCPV);(ii) NCPV in the most diseased coronary segment (NCPVMD);(iii) low attenuation plaque volume;(iv) calcified plaque volume;(iv) perivascular fat attenuation index score measured in all of the left anterior descending artery (LAD), left circumflex artery (LCx), and right coronary artery (RCA) (collectively, the principal coronary arteries); and(v) FAI score age- and gender-matched population centile.

[0216] Clause 24. The method of Clauses 5 to 23, wherein one or more dispersion excipients is a polymer.6. EXAMPLESExperimental Techniques for Examples 2,2A, 2B, 2C, 2D, 9A and 24 to 31 and 50 to 52 Table 1. Modulated Differential Scanning Calorimeter (mDSC) methodTable 1A. XRPD methodTable 2. Contact angle test methodExperimental Techniques for Examples 9 and 10 to 23 and 32 to 39Modulated Differential Scanning Calorimetry (mDSC)

[0217] The DSC analyses were carried out using a TA Instruments Q2000 Discovery Series instrument. The instrument temperature calibrations were performed using indium. The DSC cell was kept under a nitrogen purge of ~50 mL per minute during the analysis. Each sample was placed in a standard, crimped aluminum pan. For a modulated run, the sample was cooled to -50 or -30 °C and held at this temperature for 5 minutes. It was then modulated ±0.32 °C every 30 seconds while being heated to 250, 275, or 300 °C at a rate of 4 °C per minute. For a nonmodulated run, the sample was equilibrated to -30 °C and then heated to 300 °C at a rate of 10 °C per minute. For a heat-cool-heat run, samples were first equilibrated to -30 °C and then heated to 100 °C at 10 °C per minute. After this, the sample was cooled to -50 °C at 10 °C per minute, followed by a modulated sequence described above. mDSC may be used to measure glass transition temperatures.Powder X-ray Diffraction (PXRD)

[0218] A Rigaku SmartLab X-Ray Diffractometer was configured in Bragg-Brentano reflection geometry equipped with a beam stop and knife edge to reduce incident beam and air scatter. Data collection parameters are shown in Table 3.Table 3. PXRD Data Collection ParametersThermogravimetric Analysis (TGA)

[0219] TGA analysis was carried out using a TA Instruments Q5500 Discovery Series instrument. The instrument balance was calibrated using class M weights, and the temperature calibration was performed using alumel. The nitrogen purge was ~10 mL per minute at the balance and ~25 mL per minute at the furnace. The sample was placed into a pre-tared platinum pan and heated from approximately 25 °C to 300 °C at a rate of 10 °C per minute.Scanning Electron Microscopy (SEM)

[0220] Samples were sputter coated with gold to improve image quality and decrease sample damage. SEM images were collected using a Phenom XL Desktop SEM equipped with a CeB6 electron source. Phenom User Interface version 1.4 was used to acquire and save the images. Detailed image parameters are recorded in the footer of each image.Energy Dispersive X-Ray (EDX) Spectroscopy

[0221] EDX analysis was conducted using a Phenom XL Benchtop scanning electron microscope (SEM) equipped with a thermoelectrically cooled silicon drift detector for EDX analysis. An ultra-thin silicon nitride (Si3N4) X-ray window allowed detection of elements with atomic numbers ranging from 4 to 95. Solids were mounted to an aluminum SEM stub with double-sided carbon tape. The instrument was configured in backscatter electron detection (BSD) mode with a 6-7 mm working distance. The beam voltage was adjusted to optimize the signal intensity while avoiding charging at the sample surface. Phenom User Interface version 1.4 was used to acquire and save the images and spectral data. EDX data show both the atomic percent and the weight percent of the detected elements.Spray Dryer

[0222] Spray Drying was done with a Procept 4M8-TriX spray dryer.Example 1 - 1:2 Amorphous obicetrapib hemicalcium :HPMC El 5 (w / w)

[0223] Amorphous obicetrapib hemicalcium and HPMC El 5 in a 1:2 mass ratio was dissolved in an 80:20 by volume mixture of methanol to water and spray dried under a constant nitrogen flow. Samples were measured by mDSC in hermetically sealed pans without a pinhole indicating a glass transition of 156.9°C. The mDSC thermogram is provided in FIG. 1.Example 2- Obicetrapib free acid

[0224] A solution of 100g of amorphous obicetrapib hemicalcium (amorphous obicetrapib hemicalcium may be prepared as set forth in U. S. Patent No. 12,006,305) in dichloromethane (lOv, 1000 mL) was prepared at 20-25°C with stirring until fully dissolved. Aqueous HC1 (2 N, 30 equiv. relative to the calcium salt) was added in one portion with efficient agitation, and the biphasic mixture was stirred overnight at 20-25 °C. The layers were separated, and the organic phase was washed with water (3 x 5 vol) until the pH of the organic phase was > 5. The organic phase was then washed with saturated aqueous NaCl (1 x 5 vol), dried over anhydrous Mg2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford an oil, which was converted to a solid foam by applying repeated vacuum / vent cycles. Yield: 93.9 g. HPLC purity: 99.9%. FIG. 2 is an x-ray powder diffraction pattern of obicetrapib free acid.Example 2A - Obicetrapib sodium

[0225] Obicetrapib free acid prepared in general accordance with Example 2 (3 g, 1 equiv.) was dissolved in methyl t-butyl ether (MTBE) (2 vol.) with NaOH (182.7 mg, 1.1 equiv.) at 20-25°C to form a clear solution. This solution was added dropwise to heptane (30 vol.) at 0°C and the mixture was stirred at 0°C for 17 hours. A good suspension formed, which was filtered using a Buchner funnel under low humidity (<30% RH). The wet cake was washed with heptane (2 vol) and dried at 30°C for 18 hours. The final product was obtained as a white solid. Yield: 2.56 g. 1H-NMR (400 MHz, DMSO-d6) 5 ppm 0.62 - 0.90 (m, 3 H) 1.14 - 1.37 (m, 5 H) 1.38 - 1.53 (m, 1 H) 1.55 - 1.85 (m, 4 H) 1.89 - 2.05 (m, 2 H) 2.20 - 2.35 (m, 1 H) 3.89 - 4.04 (m, 2 H) 4.10 - 4.26 (m, 2 H) 4.44 (d, J=5.25 Hz, 1 H) 4.63 - 4.81 (m, 1 H) 5.24 - 5.38 (m, 1 H) 5.80 (s, 1 H) 6.83 - 6.92 (m, 1 H) 7.51 - 7.70 (m, 2 H) 7.92 - 8.10 (m, 3 H) 8.15 - 8.34 (m, 2 H).

[0226] FIG. 2A is an x-ray powder diffraction pattern of obicetrapib sodium. FIG. 2B is an mDSC thermogram of obicetrapib sodium.Example 2B - Obicetrapib Sodium

[0227] Amorphous obicetrapib hemicalcium(about 52.0 g) was charged to 2-MeTHF (10 vol., 520 mL) and stirred at ambient temperature until dissolution. An aqueous solution of sodium carbonate (11.2 g, 3.0 equiv.) in water (1.0 vol, 52 mL) was added, and the mixture was stirred overnight at ambient temperature. The resulting biphasic suspension was filtered to removeinorganic solids, with the cake washed using 10% w / w sodium chloride solution (5 vol). The phases were allowed to separate, and the organic phase was collected and concentrated under reduced pressure to about 2.5 vol (130 mL). With the solution maintained at about 20-30°C, n-heptane (20 vol, 1040 mL) was added dropwise to effect antisolvent precipitation, followed by stirring for approximately 1 h at the same temperature. The solids were collected by filtration, and the wet cake was dried under reduced pressure at 45-55 °C to constant weight, affording obicetrapib sodium salt as a white solid. Yield: 47.5 g. HPLC purity: 99.8%, assay of obicetrapib: 91.9%. Sodium content (by IC): 3.2%.Example 2C - Obicetrapib potassium

[0228] Obicetrapib potassium was prepared using the same procedure as for obicetrapib sodium of Example 2A, substituting KOH as the base. The reaction was conducted on a 3 g scale. The product was precipitated in MTBE / heptane and isolated as a white solid. 1H-NMR (400 MHz, DMSO-d6) 5 ppm 0.59 - 0.87 (m, 3 H) 1.24 (br t, J=7.00 Hz, 4 H) 1.37 - 1.53 (m, 1 H) 1.54 -1.85 (m, 4 H) 1.85 - 1.95 (m, 2 H) 2.21 - 2.35 (m, 1 H) 3.89 - 4.01 (m, 2 H) 4.06 - 4.26 (m, 2 H) 4.28 - 4.44 (m, 1 H) 4.73 (br d, J=17.13 Hz, 1 H) 5.26 - 5.38 (m, 1 H) 5.81 (s, 1 H) 6.83 -6.94 (m, 1 H) 7.55 - 7.69 (m, 2 H) 7.91 - 8.09 (m, 3 H) 8.14 - 8.36 (m, 2 H).

[0229] FIG. 2C is the x-ray powder diffraction pattern of obicetrapib potassium. FIG. 2D is an mDSC thermogram of obicetrapib potassium.Example 2D - Obicetrapib potassium

[0230] Amorphous obicetrapib hemicalcium salt (about 100 g) was charged to 2-MeTHF (10 vol., 1000 mL) and stirred at ambient temperature until dissolution. An aqueous solution of potassium carbonate (28.0 g, 3.0 equiv.) in water (1.0 vol, 100 mL) was added, and the mixture was stirred overnight at ambient temperature. The resulting biphasic suspension was filtered to remove inorganic solids, with the cake washed using water (500 mL). The phases were allowed to separate at -5° to 5°C, and the organic phase was collected and spray-dried to afford obicetrapib potassium salt as a white solid. Yield: 75.6 g. HPLC purity: 99.7%, assay of obicetrapib: 90.9%. Potassium content (by IC): 5.2%.

[0231] FIG. 2E is the x-ray powder diffraction pattern of obicetrapib potassium. Figure 2F is the mDSC thermogram of obicetrapib potassium.Example 3 - 1:2 Amorphous obicetrapib hemicalcium :PVP K30 (w / w)

[0232] Amorphous obicetrapib hemicalcium and PVP K30 in a 1:2 mass ratio was dissolved in an 80:20 by volume mixture of methanol to water and spray dried under a constant nitrogen flow. Samples were measured by mDSC in hermetically sealed pans without a pinhole indicating a glass transition of 85.5°C. The mDSC thermogram is provided in FIG. 3.Example 4 - 1:2 Amorphous obicetrapib hemical cium:Eudragit LI 00 (w / w)

[0233] Amorphous obicetrapib hemicalcium and Eudragit L100 in a 1:2 mass ratio was dissolved in methanol and spray dried under a constant nitrogen flow. Samples were measured by mDSC in hermetically sealed pans without a pinhole indicating a glass transition of 86-88.6°C. The mDSC thermogram is provided in FIG. 4.Example 5 - 1:2 Amorphous obicetrapib hemicalcium :HPMC AS-HG (w / w)

[0234] Amorphous obicetrapib hemicalcium and HPMC AS-HG in a 1 :2 mass ratio was dissolved in an 80:20 by volume mixture of methanol to water and spray dried under a constant nitrogen flow. Samples were measured by mDSC in hermetically sealed pans without a pinhole indicating a glass transition of 105-108.5°C. The mDSC thermogram is provided in FIG. 5.Example 6 - 1:2 Amorphous obicetrapib hemicalcium :Methocel A4M (w / w)

[0235] Amorphous obicetrapib hemicalcium and Methocel A4M in a 1:2 mass ratio was dissolved in an 80:20 by volume mixture of methanol to water and spray dried under a constant nitrogen flow. Samples were measured by mDSC in hermetically sealed pans without a pinhole indicating a glass transition of 106-109.8°C. The mDSC thermogram is provided in FIG. 6.Example 7 - 1:2 Amorphous obicetrapib hemicalcium :PVP VA64 (w / w)

[0236] Amorphous obicetrapib hemicalcium and PVP VA64 in a 1:2 mass ratio was dissolved in methanol and spray dried under a constant nitrogen flow. Samples were measured by mDSC in hermetically sealed pans without a pinhole indicating a glass transition of 99.6°C. The mDSC thermogram is provided in FIG. 7.Example 8 - 1:2 Amorphous obicetrapib hemicalcium :HPMC E5 (w / w)

[0237] Amorphous obicetrapib hemicalcium and HPMC E5 in a 1:2 mass ratio was dissolved in an 80:20 by volume mixture of methanol to water and spray dried under a constant nitrogen flow. Samples were measured by mDSC in hermetically sealed pans without a pinhole indicating a glass transition of 84.5°C. The mDSC thermogram is provided in FIG. 8.Example 9 - Spray-dried amorphous obicetrapib hemicalcium

[0238] ~5 g of amorphous obicetrapib hemicalcium was dissolved in 50 mL of methanol and filtered through a 0.22 pm PTFE syringe filter. The resulting clear orange solution was spray dried using a Procept 4M8-TriX spray dryer. The inlet temperature was 80 °C and the inlet gas flow rate was 0.5 m3 / min. The nozzle size was 0.6 mm, and the nozzle gas pressure was set at 0.4 bar. The sample injection pump speed was set to 200 rpm, and the cyclone gas pressure was maintained at 1 bar. The collected solids were dried in a vacuum desiccator for one day at room temperature, resulting in a 72.8% yield. An x-ray powder diffraction pattern of amorphous obicetrapib hemicalcium is found at FIG. 9. An mDSC thermogram is set forth in FIG. 10 using a standard, crimped aluminum pan and provides a glass transition temperature of about 113°C. An exemplary SEM image is set forth in FIG. 11 showing spherical morphology for the spray-dried particles.Example 9A - Spray-dried amorphous obicetrapib hemicalcium

[0239] Spray-dried amorphous obicetrapib hemicalcium was prepared in accordance with Example 28 and Table 6. An x-ray powder diffraction pattern is shown in FIG. 9A. FIG. 10A is an mDSC thermogram showing a glass transition temperature of about 109°C (in a pan with a manually punched pinhole) as set forth in Table 1.Example 10 - 1:1 Amorphous obicetrapib hemicalcium :PVP-VA 64 (w / w)

[0240] Amorphous obicetrapib hemicalcium (about 5 g) and PVP-VA 64 (about 5 g) in a 1 : 1 mass ratio was dissolved in 100 mL methanol, filtered through a 0.22 pm PTFE syringe filter, and spray dried under a constant nitrogen flow at an inlet temperature of 80 °C, a flow rate of 0.5 m3 / min, a nozzle gas pressure of 0.4 bar. A sample injection pump speed of 3.1 mL / min at 200 rpm, and a cyclone gas pressure of 1 bar. The sample was dried in a vacuum desiccator for oneday. The sample was analyzed by x-ray powder diffraction (FIG. 12). The mDSC thermogram is provided in FIG. 13. A glass transition temperature of 110°C is shown in FIG. 13.Example 11 - 1:3 Amorphous obicetrapib hemicalcium :PVP-VA 64 (w / w)

[0241] Amorphous obicetrapib hemicalcium (about 5 g) and PVP-VA 64 (about 15 g) in a 1:3 mass ratio was dissolved in 83.3 mL acetone and spray dried under a constant nitrogen flow at an inlet temperature of 80 °C, a flow rate of 0.5 m3 / min, a nozzle gas pressure of 0.4 bar, a sample injection pump speed of 150 rpm, and a cyclone gas pressure of 1 bar. The sample was dried in a vacuum desiccator for four days. The sample was analyzed by x-ray powder diffraction (FIG. 14). The mDSC thermogram is set forth in FIG. 15. A glass transition temperature of about 114°C is shown in FIG. 15.Example 12 - 25:73:2 Amorphous obicetrapib hemicalcium :PVP-VA 64:Tween 80 (w / w)

[0242] Amorphous obicetrapib hemicalcium (about 5 g), PVP-VA 64 (about 14.6 g), and Tween 80 (about 0.4 g) in a 25:73:2 mass ratio were dissolved in 83.3 mL acetone and spray dried under a constant nitrogen flow at an inlet temperature of 80 °C, a flow rate of 0.5 m3 / min, a nozzle gas pressure of 0.4 bar, a sample injection pump speed of 150 rpm, and a cyclone gas pressure of 1 bar. The sample was dried in a vacuum desiccator for four days. The sample was analyzed by x-ray powder diffraction (FIG. 16). The mDSC thermogram is set forth in FIG. 17. A glass transition temperature of about 107°C is shown on FIG. 17.Example 13 - 25:70:5 Amorphous obicetrapib hemicalcium :PVP-VA 64:VE-TPGS (w / w)

[0243] Amorphous obicetrapib hemicalcium (about 2.5 g), PVP-VA 64 (about 7.0 g), and VE-TPGS (about 0.5 g) in a 25:70:5 mass ratio were dissolved in 41.7 mL acetone and spray dried under a constant nitrogen flow at an inlet temperature of 80 °C, a flow rate of 0.5 m3 / min, a nozzle gas pressure of 0.4 bar, a sample injection pump speed of 150 rpm, and a cyclone gas pressure of 1 bar. The sample was dried in a vacuum desiccator for two days. The sample was analyzed by x-ray powder diffraction (FIG. 18). The mDSC thermogram is set forth in FIG. 19. A glass transition temperature of about 105°C is shown in FIG. 19.Example 14 - 1:1 Amorphous obicetrapib hemicalcium :PVP-VA 64 (w / w) (hot melt extrusion)

[0244] Amorphous obicetrapib hemicalcium (about 5 g) and PVP-VA 64 (about 5 g) in a 1 : 1 mass ratio were ground and hot-melt extruded at 180 °C between 50-100 rpm. The sample was analyzed by x-ray powder diffraction (FIG. 20 and FIG. 21 for two different extruded strands). The mDSC thermogram is set forth in FIG. 22 of the first strand. A glass transition temperature of about 133°C is shown in FIG. 22.Example 15 - 1:1 Amorphous obicetrapib hemicalcium :PVP-VA 64 (w / w) (melt quench)

[0245] Amorphous obicetrapib hemicalcium (about 100 mg) and PVP-VA 64 (about 100 mg) in a 1:1 mass ratio were ground and heated to approximately 170 °C to form a melt-quenched amorphous material. mDSC analysis showed a glass transition temperature of 114 °C. The mDSC thermogram is provided in FIG. 23.Example 16 - 1:1 Amorphous obicetrapib hemicalcium: Soluplus® (w / w)

[0246] Amorphous obicetrapib hemicalcium (about 5 g) and Soluplus® (about 5 g) in a 1 : 1 mass ratio were dissolved in 100 mL methanol and spray dried under a constant nitrogen flow at an inlet temperature of 80 °C, a flow rate of 0.5 m3 / min, a nozzle gas pressure of 0.4 bar, a sample injection pump speed of 3.1 mL / min at 200 rpm, and a cyclone gas pressure of 1 bar. The sample was analyzed by x-ray powder diffraction (FIG. 24). The mDSC thermogram is set forth in FIG. 25. A glass transition temperature of about 92°C is shown in FIG. 25.Example 17 - 1:1 Amorphous obicetrapib hemicalcium: Soluplus® (hot melt extrusion)

[0247] Amorphous obicetrapib hemicalcium (about 2.5 g) and Soluplus® (about 2.5 g) in a 1:1 mass ratio were ground and hot-melt extruded at 180 °C between 50-100 rpm. The sample was analyzed by x-ray powder diffraction (FIG. 26). The mDSC thermogram is set forth in FIG. 27. Two step changes are seen at about 120°C and 151°C.Example 18 - 1:1 Amorphous obicetrapib hemicalcium :Eudragit® L100-55 (w / w)

[0248] Amorphous obicetrapib hemicalcium (about 3g) and Eudragit® L100-55 (about 3 g) in a 1 : 1 mass ratio were dissolved in 160 mL methanol and spray dried under a constant nitrogen flow at an inlet temperature of 80 °C, a flow rate of 0.5 m3 / min, a nozzle gas pressure of 0.4 bar,a sample injection pump speed of 200 rpm, and a cyclone gas pressure of 1 bar. The sample was analyzed by x-ray powder diffraction (FIG. 28). The mDSC thermogram is set forth in FIG. 29. A glass transition temperature of about 92°C is shown in FIG. 29.Example 19- 3:1 Amorphous obicetrapib hemicalcium EG 6000 (w / w)

[0249] Amorphous obicetrapib hemicalcium (about 7.5 g) and PEG 6000 (about 2.5 g) in a 3:1 mass ratio were dissolved in 150 mL methanol and spray dried under a constant nitrogen flow at an inlet temperature of 95 °C, a flow rate of 0.5 m3 / min, a nozzle gas pressure of 0.4 bar, a sample injection pump speed of 200 rpm, and a cyclone gas pressure of 1 bar. The x-ray powder diffraction pattern (FIG. 30) shows peaks from PEG 6000. The mDSC thermogram shows no glass transition temperature but shows an endotherm at approximately 59-60 °C which is consistent with the melting point of PEG 6000 (FIG. 31).Example 20 - 1:1 Amorphous obicetrapib hemicalcium :Pol oxamer 407 NF (w / w)

[0250] Amorphous obicetrapib hemicalcium (about 5 g) and Poloxamer 407 NF (about 5 g) in a 1 : 1 mass ratio were dissolved in 100 mL methanol and spray dried under a constant nitrogen flow at an inlet temperature of 80°C, a flow rate of 0.5 m3 / min, a nozzle gas pressure of 0.4 bar, a sample injection pump speed of 200 rpm, and a cyclone gas pressure of 1 bar. The sample was dried for one day in a vacuum desiccator. The x-ray powder diffraction (FIG. 32) showed peaks due to Poloxamer 407 NF. The mDSC thermogram shows no glass transition temperature, but does show an endotherm at about 54°C which is consistent with the melting point of Poloxamer 407 NF (FIG. 33).Example 21 - 3:1 Amorphous obicetrapib hemicalcium :HPC-LF (w / w)

[0251] Amorphous obicetrapib hemicalcium (about 7.5 g) and HPC-LF (about 2.5 g) in a 3:1 mass ratio were dissolved in 150 mL methanol and spray dried under a constant nitrogen flow at an inlet temperature of 80 °C, a flow rate of 0.5 m3 / min, a nozzle gas pressure of 0.4 bar, a sample injection pump speed of 200 rpm, and a cyclone gas pressure of 1 bar. The sample was dried in a vacuum desiccator for one day. The sample was analyzed by x-ray powder diffraction (FIG. 34). The mDSC thermogram is set forth in FIG. 35. A glass transition temperature of about 112°C is shown in FIG. 35.Example 22 - 1:1 Amorphous obicetrapib hemicalcium :PVP K30 (w / w)

[0252] Amorphous obicetrapib hemicalcium (about 5 g) and PVP K-30 (about 5 g) in a 1:1 mass ratio were dissolved in 100 mL methanol and spray dried under a constant nitrogen flow at an inlet temperature of 80 °C, a flow rate of 0.5 m3 / min, a nozzle gas pressure of 0.4 bar, a sample injection pump speed of 200 rpm, and a cyclone gas pressure of 1 bar. The sample was dried in a vacuum desiccator for one day. The sample was analyzed by x-ray powder diffraction (FIG. 36). The mDSC thermogram is set forth in FIG. 37. A glass transition temperature of about 146°C is shown in FIG. 37.Example 23 - 1:1 Amorphous obicetrapib hemicalcium :Lactose (w / w)

[0253] Amorphous obicetrapib hemicalcium (about 2 g) and lactose (about 2 g) in a 1 : 1 mass ratio were dissolved in 400 mL of a 2: 1 mixture of methanol to water and spray dried under a constant nitrogen flow at an inlet temperature of 95 °C, a flow rate of 0.5 m3 / min, a nozzle gas pressure of 0.4 bar, a sample injection pump speed of 400 rpm, and a cyclone gas pressure of 1 bar. The sample was dried in a vacuum desiccator for one day. The sample was analyzed by x-ray powder diffraction (FIG. 38). The mDSC thermogram is set forth in FIG. 39. A glass transition temperature of about 61°C is shown in FIG. 39.Example 24 - Amorphous solid dispersion films

[0254] Amorphous solid dispersions were prepared as follows. Amorphous obicetrapib hemicalcium and corresponding polymer from Table 4 were weighed into 8-mL glass vials, and dissolved in DCM / MeOH (7 / 3, v / v) to prepare stock solution with the ratio indicated in Table 4. The resulting solutions were vacuum dried at 40°C for 2hrs to volatilize the solvent to prepare solid dispersions. Amorphous obicetrapib hemicalcium without a polymer was similarly prepared. The above procedures were performed in duplicate, one for the two-step dissolution test in Example 25 and the other for x-ray powder diffraction and mDSC. The resulting amorphous solid dispersions were in the form of films. All films were amorphous by x-ray powder diffraction.Example 25 - Dissolution of Example 24 films

[0255] Two-step dissolution tests of the amorphous solid dispersion films in Simulated Gastric Fluid (SGF) and Fasted State Simulated Intestinal Fluid (FaSSIF) were performed as follows. 3mL SGF (pH 1.8) was first added to the corresponding solid dispersion with a target obicetrapib concentration at 10 mg / mL to form suspensions. Then the suspensions were stirred magnetically at 37 °C (300 rpm). At 15 and 30 min, 300 pL of the suspensions were sampled and centrifuged at 14000 rpm for 5 mins. Then the supernatant liquor was analyzed by HPLC after 20-fold or 200-fold dilution. Subsequently, 2.4 mL 2xFaSSIF (pH 12) was added into the vials to make target obicetrapib concentrations at 5 mg / mL. Then the suspensions were continuously stirred at 37 °C (300 rpm). At 35, 60, 90 and 120 min, 300 pL of the suspensions were sampled and centrifuged at 14000 rpm for 5 mins. Then the supernatant liquor was analyzed by HPLC after 20-fold or 200-fold dilution. pH values of samples at 30 min and 120 min were measured. Table 4 shows various solid dispersions prepared and tested as set forth in Example 24 and Example 25.Table 4. Kinetic solubility and characterization results for solid dispersions prepared by fast evaporation<< < < << << < < < < < < < < << << < < < < < <Example 26 - Amorphous solid dispersion films

[0256] Amorphous obicetrapib hemicalcium and corresponding polymer and corresponding surfactant were weighed into 8-mL glass vials, and dissolved in of DCM / MeOH (7 / 3, v / v) to prepare stock solution with the ratio indicated in Table 5. Then the solutions were vacuum dried at 40°C for about 5 hours to volatilize the solvent to prepare solid dispersions. The above procedures were performed in duplicate, one for the two-step dissolution test and the other for the x-ray powder diffraction and mDSC. The resulting amorphous solid dispersions were in the form of films.Example 27 - Dissolution of Example 26 films

[0257] A two-step dissolution test of the amorphous solid dispersion film in SGF and FaSSIF was then performed. 3mL SGF (pH 1.8) was first added to the corresponding solid dispersion with target obicetrapib concentration at 10 mg / mL to form suspensions. Then the suspensions were stirring magnetically at 37 °C (300 rpm). At 15 and 30 min, 300 pL of the suspensions were sampled and centrifuged at 14000 rpm for 5 mins. Then the supernatant liquor was analyzed by HPLC after 20-fold or 200-fold dilution. Subsequently, 2.4 mL 2xFaSSIF (pH 12) was added into above vials to make target obicetrapib concentrations at 5 mg / mL. Then the suspensions were continuously stirred at 37 °C (300 rpm). At 35, 60, 90 and 120 min, 300 pL of suspensions were sampled and centrifuged at 14000 rpm for 5 mins. Then the supernatant liquor was analyzed by PLC after 20-fold or 200-fold dilution. pH values of samples at 30 min and 120 min were measured. Table 5 shows various solid dispersions prepared and tested as set forth in Example 26 and Example 27.Table 5. Kinetic solubility and characterization results for solid dispersions prepared by fast evaporation<< << < < << << << << << < < << << << << < < <<><< <<<< <

[0258] By “Ca Salt” in Table 5 above, what is meant is amorphous obicetrapib hemicalcium.Example 28 - Spray-dried amorphous dispersions

[0259] Acetone and corresponding polymer / surfactant were added into 1 L bottles, amorphous obicetrapib hemicalcium, obicetrapib sodium, or obicetrapib potassium as indicated were then added at obicetrapib concentration of 10 mg / mL, the samples were then stirred to obtain clear solutions, followed by spray drying to form solid dispersions. Spray drying was done in a B290 Buchi spray dryer using the parameters below in Table 6. The amorphous spray-dried dispersions so made are typically x-ray amorphous. Table 7 sets forth the results and tests associated with the spray-dried amorphous solid dispersions of this Example 28.Table 6. SDD preparation parameters of Obicetrapib Ca / K / Na SaltTable 7. Characterization results for spray-dried dispersions

[0260] By “Ca Salt” in Table 7 above, what is meant is amorphous obicetrapib hemicalcium.

[0261] “Spray-dried Ca Salt” means spray-dried amorphous obicetrapib hemicalcium. “Na Salt” means obicetrapib sodium prepared in accordance with as disclosed herein, and “K Salt” means obicetrapib potassium as prepared herein. The term “20% Ca Salt” means the solid dispersion was prepared with 20% by weight amorphous obicetrapib hemicalcium, for example.Example 29 - Two-step dissolution testing of the spray-dried amorphous solid dispersion of Example 28.

[0262] Spray-dried dispersions of Example 28 (100 mg for 30% loading and 150 mg for 20% loading) were weighed into 8 mL glass vial. 3 mL SGF (pH 1.8) was first added to the solid dispersion with a target obicetrapib concentration at 10 mg / mL. Then the suspensions were stirring magnetically at 37 °C (300 rpm). At 15 and 30 min, 300 pL of suspension was sampled and centrifuged at 14000 rpm for 5 mins. Then the supernatant liquor was analyzed by HPLC.After sampling at 30 min, 2.4 mL 2xFaSSIF (pH 12) was added into above vials to make target API concentration at 5 mg / mL. Then the suspensions were continuously stirred at 37 °C (300 rpm). At 35, 60, 90 and 120 min, 300 pL of suspension was sampled and centrifuged at 14000 rpm for 5 mins. The supernatant liquor was analyzed by HPLC. pH values of samples at 30 min and 120 min were measured. Table 8 sets out the results of the tests of Example 29.Table 8. Kinetic solubility and characterization results for amorphous spray-dried dispersions

[0263] By “Ca Salt” in Table 8 above, what is meant is amorphous obicetrapib hemicalcium.

[0264] “Spray-dried Ca Salt” means spray-dried amorphous obicetrapib hemicalcium. “Na Salt” means obicetrapib sodium prepared in accordance with as disclosed herein, and “K Salt” means obicetrapib potassium as prepared herein. The equilibrium solubility, however, is set forth in Table 12. The term “20% Ca Salt” means the solid dispersion was prepared with 20% by weight amorphous obicetrapib hemicalcium, for example.

[0265] The data in Tables 4, 5, 7, and 8 generally indicate the dissolution properties of various amorphous solid dispersions of the disclosure. These data show the concentration of obicetrapib over the dissolution time. As can be seen, the highest concentrations tend to come withcombinations of PVP VA 64 and surfactants such as sodium lauryl sulfate and VE-TPGS.Example 30 - Solid dispersions of amorphous obicetrapib hemicalcium made by hot meltextrusion

[0266] Amorphous obicetrapib hemicalcium, polymers and surfactants were weighed into 40 mL vial separately in the amounts set forth in Table 10 and mixed by vortex for 10 min, followed by hot melt extrusion to form solid dispersions. The obtained dispersions were ground into powders with an electric grinder. Table 9 shows the parameters used for the hot melt extrusion ofExample 30.Table 9. HME parameters for solid dispersion preparation of Ca salt

[0267] By “Ca Salt” in Table 9 above, what is meant is amorphous obicetrapib hemicalcium.

[0268] Table 10 sets forth the results and tests associated with the amorphous solid dispersions of Example 30.Table 10. Characterization results for Example 30

[0269] By “Ca Salt” in Table 10 above, what is meant is amorphous obicetrapib hemicalcium.Example 31 - Two step dissolution testing of the hot melt extrusion amorphous solid dispersions of Example 30

[0270] Amorphous solid dispersions of Example 30 were weighted into 8mL glass vial. 3mL SGF (pH 1.8) was first added to the solid dispersions with target obicetrapib concentrations at 10 mg / mL. Then the suspensions were stirred magnetically at 37 °C (300 rpm). At 15 and 30 min, 300 pL of the suspensions were sampled and centrifuged at 14000 rpm for 5 mins. Then the supernatant liquor was analyzed by HPLC after 20-fold or 200-fold dilution. Subsequently, 2.4 mL 2xFaSSIF (pH 12) was added into above vials to make target obicetrapib concentrations at 5 mg / mL. Then the suspensions were continuously stirring at 37 °C (300 rpm). At 35, 60, 90 and 120 min, 300 pL of the suspensions were sampled and centrifuged at 14000 rpm for 5 mins. Then the supernatant liquor was analyzed by HPLC after 200-fold dilution. pH values of samples at 30 min and 120 min were measured. Table 11 sets out the results of the tests of this Example 31.Table 11. Kinetic solubility and characterization results for Example 30 solid dispersions

[0271] By “Ca Salt” in Table 7 above, what is meant is amorphous obicetrapib hemicalcium.Example 32 - Spray Drying Obicetrapib HC1 (generating obicetrapib free acid)

[0272] Obicetrapib hydrochloride Form A may be prepared as disclosed in U.S. Patent No. 12,006,305.

[0273] 15 g of obicetrapib hydrochloride Form A was placed in a vacuum oven at 55°C for 48 hours. An x-ray powder diffraction of that material was set forth in FIG. 40. The material was hand ground and further dried in a vacuum oven at 55 °C for 2 days.

[0274] An x-ray powder diffraction pattern of that material is set forth in FIG. 41. 5 g of this material put in 50 mL of methyl alcohol and spray dried with a Procept 4M8-TriX spray dryer. The inlet temperature was 80°C and the flow rate was 0.5 m3 / min. the nozzle gas pressure was 0.4 bar and pump speed of 200 rpm was used. The cyclone gas pressure was 1 bar. The resulting yield was 86.4% obicetrapib free acid. An x-ray powder diffraction of this material is set forth in FIG. 42. 0.3% weight loss was seen between room temperature and 100°C by TGA. Glass transition temperatures of 53°C and 55°C were measured in two mDSC measurements (FIG. 43 and FIG. 44). In FIG. 44, the sample was exposed to a heat-cool-heat cycle. The initial heating was to 100°C, followed by cooling to -50°C followed by a modulated DSC measurement.Example 33 - Obicetrapib Free Acid

[0275] About 4 g of Obicetrapib HC1 Form A was dissolved in 20 mL acetone and spray dried on a Procept 4M8-TriX spray dryer. The inlet temperature was reduced from an initial 150 °C to 140 °C. The inlet gas flow rate was 0.3 m3 / min. The nozzle gas pressure was 1.0 bar. The sample injection pump speed was 100 rpm, and the cyclone gas pressure was raised from an initial 0.5 bar to 0.75 bar to an eventual 1.0 bar. The resulting material was dried in a vacuum desiccator for four days, and the yield was 73.1%. FIG. 45 is an x-ray powder diffraction pattern of the resulting material (obicetrapib free acid). Energy dispersive x-ray spectroscopy detected no chlorine.Example 34 - Obicetrapib Free Acid

[0276] 15 g of obicetrapib hydrochloride was placed in a vacuum oven at 55°C for 48 hours. A sample was then hand ground and dried in a vacuum oven for 55°C for 3 days. FIG. 46 is an x-ray powder diffraction pattern of the resulting material.

[0277] A glass transition temperature of 55°C was found by mDSC as seen in FIG. 47. A weight loss of 0.2% was seen by TGA between room temperature and 100°C. A 'H-NMR spectrum (FIG. 48) was consistent with the chemical structure of obicetrapib free acid, where peaks are shifted compared to obicetrapib HC1. A minor peak at 3.15 ppm was observed which may be due to residual CPME from the obicetrapib HC1 starting material. Energy dispersive x-ray spectroscopy showed a chloride presence of only 0.05% by weight, well below the chlorideamount in the HC1 salt and which is consistent with the material being predominantly obicetrapib free acid.

[0278] FIG. 49 is a DVS experiment on this material with FIG. 50 showing x-ray powder diffraction patterns prior to and after the DVS experiment.Example 35 - Obicetrapib Free Acid

[0279] A sample of obicetrapib hydrochloride was hand ground and dried in vacuum oven at 45°C for 2 days, and 1 day at 55°C when an x-ray powder diffraction pattern was taken (FIG. 51). The sample was further dried for another 3 days at 55°C and another x-ray powder diffraction pattern was taken (FIG. 52).Example 36 - Obicetrapib free acid dispersion with HPMCAS MF NF 1 : 1

[0280] ~2.5 g of Obicetrapib free acid and ~2.5 g of HPMCAS MF NF (AQOAT, Shin-Etsu) were added to 150 mL of acetone resulting in a slightly milky solution after stirring and sonication. The solution was spray dried on a Procept 4M8-TriX spray dryer. The inlet temperature was 70 °C and the inlet gas flow rate was 0.5 m3 / min. The nozzle gas pressure was set at 0.4 bar. Sample injection pump speed was 200 rpm and the cyclone gas pressure was set to 1 bar. The collected solids were dried in a vacuum desiccator for one day resulting in a 79.1% yield. FIG. 54 is an x-ray powder diffraction pattern of the dispersion and FIG. 55 is an mDSC thermogram.Example 37 - Obicetrapib free acid dispersion with HPMCAS MF NF 1 :3

[0281] ~1.5 g of Obicetrapib free acid and -4.5 g of HPMCAS-MF NF (AQOAT, Shin-Etsu) were added to 235 mL of 85:15 acetone: ethanol (vol / vol) resulting in a slightly hazy white solution after stirring and sonication. The solution was spray dried on a Procept 4M8-TriX spray dryer. The inlet temperature was 80 °C and the inlet gas flow rate was 0.5 m3 / min. The nozzle gas pressure was set at 0.4 bar. Sample injection pump speed was 400 rpm and the cyclone gas pressure was set to 1 bar. The collected solids were dried in a vacuum desiccator for one day resulting in a 78.1% yield. FIG. 56 is an x-ray powder diffraction pattern of the dispersion and FIG. 57 is an mDSC thermogram.Example 38 - Obicetrapib free acid dispersion with HPC-LF 2: 1

[0282] -4 g of Obicetrapib free acid and -2 g of HPC-LF (Klucel LF Pharm, Ashland) were added to 200 mL of acetone resulting in a clear orange solution after sonication. The solution was spray dried on a Procept 4M8-TriX spray dryer. The inlet temperature was 80 °C and the inlet gas flow rate was 0.5 m3 / min. The nozzle gas pressure was set at 0.4 bar. Sample injection pump speed was 400 rpm and the cyclone gas pressure was set to 1 bar. The collected solids were dried in a vacuum desiccator for three days resulting in an 80.6% yield. FIG. 58 is an x-ray powder diffraction pattern of the dispersion and FIG. 59 is an mDSC thermogram.Example 39 - Obicetrapib free acid dispersion with Soluplus® 1:3

[0283] ~1.5 g of Obicetrapib free acid and -4.5 g of Soluplus® (BASF) were added to 50 mL of 3:1 acetone: ethanol (vol / vol) resulting in a clear light-yellow solution. The solution was spray dried on a Procept 4M8-TriX spray dryer. The inlet temperature was 80 °C and the inlet gas flow rate was 0.5 m3 / min. The nozzle gas pressure was set at 0.4 bar. Sample injection pump speed was 200 rpm and the cyclone gas pressure was set to 1 bar. The collected solids were dried in a vacuum desiccator for one day resulting in a 91.2% yield. FIG. 60 is an x-ray powder diffraction pattern of the dispersion and FIG. 61 is an mDSC thermogram.Example 40 - Making an alkali salt of obicetrapib via ion exchange

[0284] A solution of obicetrapib hemicalcium is prepared by dissolving amorphous obicetrapib hemicalcium in a suitable solvent (e.g., MeOH, EtOH, mixed aqueous / organic). The solution is passed through a strong-acid ion-exchange resin preloaded with the target alkali cation (e.g., sodium or potassium cation). The pass-through is continued until Ca2+in the obicetrapib hemicalcium solution is fully consumed, indicating complete exchange of Ca2+with the target alkali cation. The eluted alkali salt solution can then be isolated by spray-drying, lyophilization, or anti-solvent precipitation.Example 41 - Making an alkali salt via metatheses with inorganic bases

[0285] Amorphous obicetrapib hemicalcium is dissolved in an organic solvent (with or without water) and is treated with a mild inorganic alkali base (e.g., Na2COs or K2CO3). The alkali salt forms in solution while insoluble byproducts (e.g., CaCCh) precipitate and are removed byfiltration. If biphasic, the aqueous phase is removed, then the organic phase is washed with water to remove any residual inorganic base or salts. A controlled precipitation with anti-solvent (e.g., heptane, hexane), leads to an alkali metal salt for isolation or the solution of the alkali metal salt may be spray-dried or lyophilized to give an alkali salt of obicetrapib.Example 42 - Making an alkali salt of obicetrapib from obicetrapib HC1 or obicetrapib free acid

[0286] Obicetrapib free acid or obicetrapib HC1 is dissolved in a solvent system with partial miscibility (e.g., MTBE, EtOAc, THF, mixed with a small amount of water). An alkali base such as NaHMDS, Na2CO3, NaHCOs, NaOH (for Na) or KHMDS, K2CO3, KHCO3, or KOH (for K) is added under controlled conditions (NMT 1.0 eq), optionally guided by in-process monitoring (e.g., pH, conductivity, titration). After salt formation, an optional solvent swap and / or partial concentration is performed, the solution is charged into an antisolvent (e.g., heptane, hexane) to precipitate the desired alkali salt of obicetrapib..Example 43 - Making an alkali salt of obicetrapib from obicetrapib HC1 or obicetrapib free acid

[0287] Obicetrapib free acid or obicetrapib HC1 salt is neutralized with an excess of alkali base in a suitable solvent. After reaction, the excess alkali base is removed via aqueous washes or ionexchange polishing. The organic phase containing the desired alkali salt is then processed by spray-drying, lyophilization, or anti-solvent precipitation to yield a solid alkali salt of obicetrapib.Example 44 - Alkali salt of obicetrapib solid amorphous dispersion

[0288] An alkali salt of obicetrapib, such as obicetrapib sodium or obicetrapib potassium, is prepared as described herein. The alkali salt of obicetrapib is dissolved in an organic solvent system (1 or more organic solvents or an organic / aqueous mixture) with a dispersion excipient and the solution is spray dried. After spray drying, a secondary drying in a vacuum oven is used. The resulting material is characterized by modulated differential scanning calorimetry to obtain a glass transition temperature. X-ray powder diffraction, solvent concentration including water concentration, purity assays are also performed.Example 45 - Alkali salt of obicetrapib solid amorphous dispersion

[0289] An alkali salt of obicetrapib, such as obicetrapib sodium or obicetrapib potassium, is prepared as described herein. The alkali salt of obicetrapib, such as obicetrapib sodium or obicetrapib potassium are combined with a dispersion excipient and surfactant for placement into a hot melt extruder. The combination is put in a hot melt extruder and extruded. The resulting material is characterized by modulated differential scanning calorimetry to obtain a glass transition temperature. X-ray powder diffraction, water content, purity and assays are also performed.Example 46 - Solid dosage formulations of amorphous dispersions of alkali salts of obicetrapib, including obicetrapib sodium or obicetrapib potassium

[0290] An amorphous dispersion of an alkali salt of obicetrapib, such as obicetrapib sodium or obicetrapib potassium is blended with one or more pharmaceutically acceptable excipients and compressed into tablets which are then optionally film coated.Example 47 - Solid dosage formulations of amorphous dispersions of alkali salts of obicetrapib, including obicetrapib sodium or obicetrapib potassium

[0291] An amorphous dispersion of an alkali salt of obicetrapib, such as obicetrapib sodium or obicetrapib potassium is dry granulated or roller compacted together with one or more pharmaceutically acceptable excipients. The resulting composition is then milled, blended, and compressed into tablets which are then optionally film coated.Example 48 - Equilibrium Solubility

[0292] Certain amounts of spray dried dispersion of Example 28 as well as non-dispersions of obicetrapib sodium, obicetrapib potassium, and obicetrapib free acid were weighed into 40mL glass vial with certain amount of FaSSIF. Then the samples were stirring magnetically at 37 °C (700 rpm). At 2, 24 and 48h, 500 pL suspensions were sampled in duplicate and one sample was centrifuged at 100000 rpm for 5 min (ultracentrifugation) and another was 14000 rpm for 5 min. Then the supernatant liquor was measured by HPLC after dilution. The results were shown in Table 12 below.Table 12. The equilibrium solubility test of SDDs / Ca / K / Na salt / free acid in FaSSIF*Note: samples were too sticky to be sampled.Example 49 - Contact angles of some amorphous dispersions

[0293] The contact angle results using simulated gastric fluid are set forth below in Table 13.The first material is amorphous obicetrapib hemicalcium and the second is spray-dried amorphous obicetrapib hemicalcium. The other samples are spray dried dispersions. Similarly, the contact angle results using FaSSIF is summarized in Table 14.Table 13. The contact angle result of Obicetrapib Ca SDD in SGFTable 14. The contact angle result of Obicetrapib Ca SDD in FaSSIF

[0294] Without being bound by theory, poor wettability may lead to slow in vitro dissolution with high variability which leads to low exposure and pharmacokinetic profiles with high interpatient variability. In general, sufficient wettability (contact angle not higher than 90 degrees, ideally lower than 45 degrees) is preferred. As can be seen from the presented data, many of the formulated amorphous obicetrapib hemicalcium solid dispersions meet these criteria whereas the API itself is super hydrophobic, has a much higher contact angles in both SGF and FaSSIFExample 50 - Obicetrapib free acid

[0295] A solution of amorphous obicetrapib hemicalcium (amorphous obicetrapib hemicalcium may be prepared as set forth in U. S. Patent No. 12,006,305) in dichloromethane (lOv, 1000 mL) was prepared at 20-25 °C with stirring until fully dissolved. Aqueous HC1 (2 N, 30 equiv relative to the calcium salt) was added in one portion with efficient agitation, and the biphasic mixture was stirred overnight at 20-25 °C. The layers were separated, and the organic phase was washed with water (3 ^ 5 vol) until the pH of the organic phase was > 5. The organic phase was then washed with saturated aqueous NaCl (1 x 5 vol), dried over anhydrous Mg2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford an oil, which was converted to a solid foam by applying repeated vacuum / vent cycles. Yield: 93.9 g. HPLC purity: 99.9%.Example 51 - Obicetrapib sodium

[0296] Obicetrapib free acid which may be prepared, for example, in accordance with Example 50, (3 g, 1 equiv.) was dissolved in MTBE (2 vol.) with NaOH (182.661 mg, 1.1 equiv.) at 20-25°C to form a clear solution. This solution was added dropwise to heptane (30 vol.) at 0 °C and the mixture was stirred at 0°C for 17 hours. A good suspension formed, which was filtered using a Buchner funnel under low humidity (<30% RH). The wet cake was washed with heptane (2 vol) and dried at 30 °C for 18 hours. The final product was obtained as a white solid. Yield: 2.56 g. 'H-NMR (400 MHz, DMSO-d6) 5 ppm 0.62 - 0.90 (m, 3 H) 1.14 - 1.37 (m, 5 H) 1.38 - 1.53 (m, 1 H) 1.55 - 1.85 (m, 4 H) 1.89 - 2.05 (m, 2 H) 2.20 - 2.35 (m, 1 H) 3.89 - 4.04 (m, 2 H) 4.10 - 4.26 (m, 2 H) 4.44 (d, J=5.25 Hz, 1 H) 4.63 - 4.81 (m, 1 H) 5.24 - 5.38 (m, 1 H) 5.80 (s, 1 H) 6.83 - 6.92 (m, 1 H) 7.51 - 7.70 (m, 2 H) 7.92 - 8.10 (m, 3 H) 8.15 - 8.34 (m, 2 H).Example 52 - Obicetrapib potassium

[0297] Obicetrapib potassium was prepared using the same procedure as for the sodium salt in Example 51 substituting KOH as the base. The reaction was conducted on a 3 g scale. The product was precipitated in MTBE / heptane and isolated as a white solid.1H-NMR (400 MHz, DMSO-d6) 5 ppm 0.59 - 0.87 (m, 3 H) 1.24 (br t, J=7.00 Hz, 4 H) 1.37 - 1.53 (m, 1 H) 1.54 -1.85 (m, 4 H) 1.85 - 1.95 (m, 2 H) 2.21 - 2.35 (m, 1 H) 3.89 - 4.01 (m, 2 H) 4.06 - 4.26 (m, 2 H) 4.28 - 4.44 (m, 1 H) 4.73 (br d, J=17.13 Hz, 1 H) 5.26 - 5.38 (m, 1 H) 5.81 (s, 1 H) 6.83 -6.94 (m, 1 H) 7.55 - 7.69 (m, 2 H) 7.91 - 8.09 (m, 3 H) 8.14 - 8.36 (m, 2 H).Example 53 - Free acid dispersions

[0298] Acetone and the corresponding polymer / surf actant were added into 1 L bottles, obicetrapib free acid was then added at a concentration of 10 mg / mL. The samples were then stirred to obtain clear solutions, followed by spray drying to form solid dispersions. The process parameters for solid dispersion preparations are in Table 15.Table 15. SDD preparation parameters of free acid

[0299] After secondary drying by vacuum drying, obtained spray-dried dispersions powders were characterized as set forth in Table 16.Table 16. Characterization results for free acid SDD7. EMBODIMENTS

[0300] The disclosure can further be described by the non-limiting embodiments as set forth below.

[0301] Embodiment 1. An amorphous solid dispersion comprising amorphous obicetrapib hemicalcium, and one or more dispersion excipients and optionally one or more surfactants.

[0302] Embodiment 2. The amorphous solid dispersion of Embodiment 1, wherein the one or more dispersion excipients is a polymer.

[0303] Embodiment 3. A pharmaceutical composition comprising amorphous obicetrapib hemicalcium, and one or more dispersion excipients and optionally one or more surfactants and one or more pharmaceutically acceptable excipients.

[0304] Embodiment 4. The pharmaceutical composition of any one of Embodiments 1 to 3 made by (a) direct compression or (b) dry granulation followed by encapsulation or tabletcompression.

[0305] Embodiment 5. A method of treating a subject suffering from or having an increased risk of developing a cardiovascular disease, the method comprising:administering a therapeutically effective amount of an amorphous solid dispersion of amorphous obicetrapib hemicalcium, and one or more dispersion excipients and optionally one or more surfactants, or a pharmaceutical composition thereof to the subject.

[0306] Embodiment 6. A method of treating a subject suffering from or having an increased risk of developing a cardiovascular disease, the method comprising:administering a therapeutically effective amount of an amorphous solid dispersion of amorphous obicetrapib hemicalcium, and one or more dispersion excipients and optionally one or more surfactants, or a pharmaceutical composition thereof to the subject, further comprising administration of an HMG CoA reductase inhibitor.

[0307] Embodiment 7. A method of slowing the progression of a neurodegenerative disease in a subject who is at risk of developing a neurodegenerative disease, the method comprising: administering a therapeutically effective amount of an amorphous solid dispersion of amorphous obicetrapib hemicalcium, and one or more dispersion excipients and optionally one or more surfactants, or a pharmaceutical composition thereof to the subject.

[0308] Embodiment 8. The method of Embodiment 7, where the neurodegenerative disease is Alzheimer's Disease (AD), Lewy Body dementia, vascular or multi-infarct dementia, or frontotemporal dementia (FTD).

[0309] Embodiment 9. A method of treating a subject suffering from or having an increased risk for hyperlipidemia or mixed dyslipidemia, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of amorphous obicetrapib hemicalcium, and one or more dispersion excipients and optionally one or more surfactants, or a pharmaceutical composition thereof, and a therapeutically effective amount of ezetimibe, or a pharmaceutically acceptable salt of ezetimibe to the subject.

[0310] Embodiment 10. A method of treating a subject requiring additional lowering of low-density lipoprotein cholesterol as an adjunct to diet and / or as maximally tolerated lipid-lowering therapy for the treatment of heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular (CV) disease (ASCVD), the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of amorphous obicetrapib hemicalcium, and one or more dispersion excipients and optionally one or more surfactants, or apharmaceutical composition thereof, and a therapeutically effective amount of ezetimibe, or a pharmaceutically acceptable salt of ezetimibe to the subject.

[0311] Embodiment 11. A method of treating or preventing a metabolic disorder in a subject who has or is at risk of developing a metabolic disorder, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of amorphous obicetrapib hemicalcium, and one or more dispersion excipients and optionally one or more surfactants, or a pharmaceutical composition thereof, and a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt of an SGLT2 inhibitor to the subject.

[0312] Embodiment 12. A method of treating or preventing a disorder selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, obesity, metabolic syndrome, hypertension, hypercholesterolemia, cardiovascular disease, atherosclerotic cardiovascular disease, heart failure and chronic kidney disease in a subject who has or is at risk of said disorder, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of amorphous obicetrapib hemicalcium, and one or more dispersion excipients and optionally one or more surfactants, or a pharmaceutical composition thereof, and a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt of an SGLT2 inhibitor to the subject.

[0313] Embodiment 13. A method of treating heterozygous familial hypercholesterolemia (HeFH) and / or atherosclerotic cardiovascular disease (ASCVD) in a subject in need thereof, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of amorphous obicetrapib hemicalcium, and one or more dispersion excipients and optionally one or more surfactants, or a pharmaceutical composition thereof to the subject.

[0314] Embodiment 14. A method of reducing or preventing vascular symptoms in a subject with a beta hemoglobinopathy, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of amorphous obicetrapib hemicalcium, and one or more dispersion excipients and optionally one or more surfactants, or a pharmaceutical composition thereof to the subject.

[0315] Embodiment 15. The method of Embodiment 45, wherein an amorphous solid dispersion of amorphous obicetrapib hemicalcium, and one or more dispersion excipients and optionallyone or more surfactants, or pharmaceutical composition thereof, is co-administered with at least one liposoluble antioxidant.

[0316] Embodiment 16. A method of improving atherosclerotic plaque characteristics in a patient with ASCVD, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of amorphous obicetrapib hemicalcium, and one or more dispersion excipients and optionally one or more surfactants, or a pharmaceutical composition thereof to the subject.

[0317] Embodiment 17. The method of Embodiment 16, wherein an amorphous solid dispersion of amorphous obicetrapib hemicalcium, and one or more dispersion excipients and optionally one or more surfactants, or pharmaceutical composition thereof, is co-administered with a therapeutically effective amount of ezetimibe, or a pharmaceutically acceptable salt thereof.

[0318] Embodiment 18. A method of reducing the rate of decrease in the AP42 / AP40 ratio in the plasma of a subject in need thereof, the method comprising administering to the subject an amorphous solid dispersion of amorphous obicetrapib hemicalcium, and one or more dispersion excipients and optionally one or more surfactants, or a pharmaceutical composition thereof, in an amount effective to reduce the rate of decrease in the AP42 / AP40 ratio in the plasma of the subject determined prior to the first administration of an amorphous solid dispersion of amorphous obicetrapib hemicalcium, and one or more dispersion excipients and optionally one or more surfactants, or a pharmaceutical composition thereof.

[0319] Embodiment 19. A method of lowering ApoE4 concentration in the central nervous system (CNS) of a subject in need thereof, the method comprising administering to the subject an amorphous solid dispersion of amorphous obicetrapib hemicalcium, and one or more dispersion excipients and optionally one or more surfactants, or a pharmaceutical composition thereof, in an amount effective to reduce ApoE4 concentration in the CNS.

[0320] Embodiment 20. A method of reducing major adverse cardiovascular events (MACE) in subjects with atherosclerotic cardiovascular disease (ASCVD) and / or heterozygous familial hypercholesterolemia (HeFH) who are not adequately controlled by maximally tolerated lipid-modifying therapies, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of amorphous obicetrapib hemicalcium, and one or more dispersion excipients and optionally one or more surfactants, or a pharmaceutical composition thereof to the subject.

[0321] Embodiment 21. The method of Embodiment 20, wherein the amorphous solid dispersion of amorphous obicetrapib hemicalcium, and one or more dispersion excipients and optionally one or more surfactants, or pharmaceutical composition thereof is administered at an oral dose of 10 mg per day for at least six months.

[0322] Embodiment 22. The method of Embodiment 20 or 21, wherein the baseline fasting serum LDL-C on maximally tolerated lipid-modifying therapy is >100 mg / dL, and administration of an amorphous solid dispersion of amorphous obicetrapib hemicalcium, and one or more dispersion excipients and optionally one or more surfactants, or pharmaceutical composition thereof lowers serum LDL-C to less than 100 mg / dL.

[0323] Embodiment 23. The method of any one of Embodiments 20 to 22, wherein administration of an amorphous solid dispersion of amorphous obicetrapib hemicalcium, and one or more dispersion excipients and optionally one or more surfactants, or pharmaceutical composition thereof on top of prior maximally-tolerated lipid modifying therapy is sufficient, after 18 months of treatment, to show reduction from baseline as compared to placebo in one or more of:(i) total non-calcified coronary atherosclerotic plaque volume (NCPV);(ii) NCPV in the most diseased coronary segment (NCPVMD);(iii) low attenuation plaque volume;(iv) calcified plaque volume;(v) perivascular fat attenuation index score measured in all of the left anterior descending artery (LAD), left circumflex artery (LCx), and right coronary artery (RCA) (collectively, the principal coronary arteries); and(vi) FAI score age- and gender-matched population centile.

[0324] Embodiment 24. The method of Embodiments 5 to 23, wherein one or more dispersion excipients is a polymer.

[0325] Embodiment 25. An amorphous solid dispersion comprising obicetrapib.

[0326] Embodiment 26. An amorphous solid dispersion comprising obicetrapib free acid and one or more dispersion excipients.

[0327] Embodiment 27. The amorphous solid dispersion of Embodiment 26 wherein the amorphous solid dispersion is spray dried.

[0328] Embodiment 28. The amorphous solid dispersion of Embodiments 26 or 27, wherein the one or more excipients is a polymer.

[0329] Embodiment 29. The amorphous solid dispersion of any one of Embodiments 1- 4 wherein the polymer is selected from Polyvinylpyrrolidone (PVP), Copovidone (PVP / VA), Polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), Hydroxypropyl cellulose (HPC), Hydroxypropyl methyl cellulose (HPMC), Hypromellose acetate succinate (HPMCAS), Hydroxypropyl methylcellulose phthalate (HPMCP), Cellulose acetate phthalate (CAP), Eudragit® E PO, Eudragit® LI 00, Eudragit® SI 00, Eudragit® L 1 GO-55, Polyvinyl acetate phthalate (PVAP), Poly(acrylic acid) (PAA), Polyethylene glycol / polyethylene oxide (PEG / PEO), PVPVA 64, HPMCAS-M, HPMCP -HP55, Eudragit® E100, HPMCAS-MG, HPC-SSL, or Poloxamer and where the optional surfactants are selected from VE-TPGS, SLS, Tween 80, Kolliphor HS15, Poloxamer 407, and Gelucire 44 / 14.

[0330] Embodiment 30. A pharmaceutical composition comprising the amorphous solid dispersion of any one of Embodiments 1, 2, or 25 to 29 and one or more pharmaceutically acceptable excipients.

[0331] Embodiment 31. The amorphous solid dispersions of any one of Embodiments 1, 2, or 25 to 30 made by the process of spray drying a solution or suspension comprising or made from obicetrapib free acid or comprising or made from obicetrapib hemicalcium and one or more spray-drying excipients.

[0332] Embodiment 32. The amorphous solid dispersion of Embodiment 31 wherein the spraydrying excipient is a polymer.

[0333] Embodiment 33. The amorphous solid dispersion of Embodiment 31 wherein the polymer is Polyvinylpyrrolidone (PVP), Copovidone (PVP / VA), Polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), Hydroxypropyl cellulose (HPC), Hydroxypropyl methyl cellulose (HPMC), Hypromellose acetate succinate (HPMCAS), Hydroxypropyl methylcellulose phthalate (HPMCP), Cellulose acetate phthalate (CAP), Eudragit® E PO, Eudragit® L100, Eudragit® S100, Eudragit® L 100-55, Polyvinyl acetate phthalate (PVAP), Poly(acrylic acid) (PAA), Polyethylene glycol / polyethylene oxide (PEG / PEO), PVPVA 64, HPMCAS-M, HPMCP-HP55, Eudragit® E100, HPMCAS-MG, HPC-SSL, or Poloxamer and where the optional surfactants are selected from VE-TPGS, SLS, Tween 80, Kolliphor HS 15, Poloxamer 407, and Gelucire 44 / 14.

[0334] Embodiment 34. An amorphous solid dispersion comprising obicetrapib free acid and a dispersion excipient wherein the amorphous solid dispersion is x-ray amorphous.

[0335] Embodiment 35. The amorphous solid dispersion of Embodiment 34, wherein the dispersion excipient is an HPMCAS polymer.

[0336] Embodiment 36. The amorphous solid dispersion of Embodiment 35, having an x-ray powder diffraction pattern substantially the same as FIG. 54 or FIG. 56.

[0337] Embodiment 37. The amorphous solid dispersion of Embodiment 35 or 36, wherein the HPMCAS polymer is HPMCAS-MF NF.

[0338] Embodiment 38. The amorphous solid dispersion of Embodiment 34, wherein the dispersion excipient is an HPC polymer.

[0339] Embodiment 39. The amorphous solid dispersion of Embodiment 38, having an x-ray powder diffraction pattern substantially the same as that of FIG. 58.

[0340] Embodiment 40. The amorphous solid dispersion of Embodiment 38 or 39, wherein the HPC polymer is HPC-LF.

[0341] Embodiment 41. The amorphous solid dispersion of Embodiment 34, wherein the dispersion excipient is Polyvinylcaprolactam-polyvinyl acetate-poly ethylene glycol graft copolymer.

[0342] Embodiment 42. The amorphous solid dispersion of Embodiment 41, having an x-ray powder diffraction pattern substantially the same as that of FIG. 60.

[0343] Embodiment 43. The amorphous solid dispersion of Embodiment 41 or 42, wherein the dispersion excipient is Soluplus®.

[0344] Embodiment 44. A method of treating a subject suffering from or having an increased risk of developing a cardiovascular disease, the method comprising:administering a therapeutically effective amount of an amorphous solid dispersion of obicetrapib free acid, or a pharmaceutical composition thereof to the subject.

[0345] Embodiment 45. A method of treating a subject suffering from or having an increased risk of developing a cardiovascular disease, the method comprising:administering a therapeutically effective amount of an amorphous solid dispersion of obicetrapib free acid, or a pharmaceutical composition thereof to the subject, further comprising administration of an HMG CoA reductase inhibitor.

[0346] Embodiment 46. A method of slowing the progression of a neurodegenerative disease in a subject who is at risk of developing a neurodegenerative disease, the method comprising: administering a therapeutically effective amount of an amorphous solid dispersion of obicetrapib free acid, or a pharmaceutical composition thereof to the subject.

[0347] Embodiment 47. The method of Embodiment 46, where the neurodegenerative disease is Alzheimer's Disease (AD), Lewy Body dementia, vascular or multi-infarct dementia, or frontotemporal dementia (FTD).

[0348] Embodiment 48. A method of treating a subject suffering from or having an increased risk for hyperlipidemia or mixed dyslipidemia, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of obicetrapib free acid, or a pharmaceutical composition thereof, and a therapeutically effective amount of ezetimibe, or a pharmaceutically acceptable salt of ezetimibe to the subject.

[0349] Embodiment 49. A method of treating a subject requiring additional lowering of low-density lipoprotein cholesterol as an adjunct to diet and / or as maximally tolerated lipid-lowering therapy for the treatment of heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular (CV) disease (ASCVD), the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of obicetrapib free acid, or a pharmaceutical composition thereof, and a therapeutically effective amount of ezetimibe, or a pharmaceutically acceptable salt of ezetimibe to the subject.

[0350] Embodiment 50. A method of treating or preventing a metabolic disorder in a subject who has or is at risk of developing a metabolic disorder, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of obicetrapib free acid, or a pharmaceutical composition thereof, and a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt of an SGLT2 inhibitor to the subject.

[0351] Embodiment 51. A method of treating or preventing a disorder selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, obesity, metabolic syndrome, hypertension, hypercholesterolemia, cardiovascular disease, atherosclerotic cardiovascular disease, heart failure and chronic kidney disease in a subject who has or is at risk of said disorder, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of obicetrapib free acid, or a pharmaceutical composition thereof,and a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt of an SGLT2 inhibitor to the subject.

[0352] Embodiment 52. A method of treating heterozygous familial hypercholesterolemia (HeFH) and / or atherosclerotic cardiovascular disease (ASCVD) in a subject in need thereof, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of obicetrapib free acid, or a pharmaceutical composition thereof to the subject.

[0353] Embodiment 53. A method of reducing or preventing vascular symptoms in a subject with a beta hemoglobinopathy, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of obicetrapib free acid, or a pharmaceutical composition thereof to the subject.

[0354] Embodiment 54. The method of Embodiment 53, wherein an amorphous solid dispersion of obicetrapib free acid, or pharmaceutical composition thereof, is co-administered with at least one liposoluble antioxidant.

[0355] Embodiment 55. A method of improving atherosclerotic plaque characteristics in a patient with ASCVD, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of obicetrapib free acid, or a pharmaceutical composition thereof to the subject.

[0356] Embodiment 56. The method of Embodiment 55, wherein an amorphous solid dispersion of obicetrapib free acid, or pharmaceutical composition thereof, is co-administered with a therapeutically effective amount of ezetimibe, or a pharmaceutically acceptable salt thereof.

[0357] Embodiment 57. A method of reducing the rate of decrease in the AP42 / AP40 ratio in the plasma of a subject in need thereof, the method comprising administering to the subject an amorphous solid dispersion of obicetrapib free acid, or a pharmaceutical composition thereof, in an amount effective to reduce the rate of decrease in the AP42 / AP40 ratio in the plasma of the subject determined prior to the first administration of the solid, amorphous, or x-ray amorphous obicetrapib free acid, or pharmaceutical composition.

[0358] Embodiment 58. A method of lowering ApoE4 concentration in the central nervous system (CNS) of a subject in need thereof, the method comprising administering to the subject an amorphous solid dispersion of obicetrapib free acid, or a pharmaceutical composition thereof, in an amount effective to reduce ApoE4 concentration in the CNS.

[0359] Embodiment 59. A method of reducing major adverse cardiovascular events (MACE) in subjects with atherosclerotic cardiovascular disease (ASCVD) and / or heterozygous familial hypercholesterolemia (HeFH) who are not adequately controlled by maximally tolerated lipid-modifying therapies, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of obicetrapib free acid, or a pharmaceutical composition thereof to the subject.

[0360] Embodiment 60. The method of Embodiment 59, wherein an amorphous solid dispersion of obicetrapib free acid, or pharmaceutical composition thereof is administered at an oral dose of 10 mg per day for at least six months.

[0361] Embodiment 61. The method of Embodiment 59 or 60, wherein the baseline fasting serum LDL-C on maximally tolerated lipid-modifying therapy is >100 mg / dL, and administration of an amorphous solid dispersion of obicetrapib free acid, or pharmaceutical composition thereof lowers serum LDL-C to less than 100 mg / dL.

[0362] Embodiment 62. The method of any one of Embodiments 59 to 61, wherein administration of an amorphous solid dispersion of obicetrapib free acid, or pharmaceutical composition thereof on top of prior maximally-tolerated lipid modifying therapy is sufficient, after 18 months of treatment, to show reduction from baseline as compared to placebo in one or more of:(i) total non-calcified coronary atherosclerotic plaque volume (NCPV);(ii) NCPV in the most diseased coronary segment (NCPVMD);(iii) low attenuation plaque volume;(iv) calcified plaque volume;(v) perivascular fat attenuation index score measured in all of the left anterior descending artery (LAD), left circumflex artery (LCx), and right coronary artery (RCA) (collectively, the principal coronary arteries); and(vi) FAI score age- and gender-matched population centile.

[0363] Embodiment 63. The methods of any one of Embodiments 44 to 62 wherein the amorphous solid dispersion of obicetrapib free acid or spray-dried amorphous solid dispersion of obicetrapib free acid comprises obicetrapib free acid and one or more spray-drying excipients.

[0364] Embodiment 64. The method of Embodiment 63, wherein the one or more spray-drying excipients is a polymer.

[0365] Embodiment 65. The method of Embodiment 64, wherein the polymer is selected from Polyvinylpyrrolidone (PVP), Copovidone (PVP / VA), Polyvinylcaprolactam-polyvinyl acetatepolyethylene glycol graft copolymer (Soluplus®), Hydroxypropyl cellulose (HPC), Hydroxypropyl methyl cellulose (HPMC), Hypromellose acetate succinate (HPMCAS), Hydroxypropyl methylcellulose phthalate (HPMCP), Cellulose acetate phthalate (CAP), Eudragit® E PO, Eudragit® L100, Eudragit® S100, Eudragit® L 100-55, Polyvinyl acetate phthalate (PVAP), Poly(acrylic acid) (PAA), Polyethylene glycol / polyethylene oxide (PEG / PEO), PVPVA 64, HPMCAS-M, HPMCP-HP55, Eudragit® E100, HPMCAS-MG, HPC-SSL, or Poloxamer and further comprising a surfactant wherein the surfactant is selected from VE-TPGS, SLS, Tween 80, Kolliphor HS15, Poloxamer 407, and Gelucire 44 / 14.

[0366] Embodiment 66. The method of any one of Embodiments 44 to 65 wherein the amorphous solid dispersion of obicetrapib free acid is made by spray drying.

[0367] Embodiment 67. A process for preparing an alkali salt of obicetrapib comprising contacting a solution comprising obicetrapib with an ion exchange resin loaded with an alkali cation to make an alkali solution and isolating an alkali salt of obicetrapib from the alkali solution.

[0368] Embodiment 68. The process of Embodiment 67, wherein the alkali salt of obicetrapib is obicetrapib sodium and the alkali cation is a sodium cation.

[0369] Embodiment 69. The process of Embodiment 67, wherein the alkali salt of obicetrapib is obicetrapib potassium and the alkali cation is a potassium cation.

[0370] Embodiment 70. The process of any one of Embodiments 67 to 69, wherein the solution comprising obicetrapib is prepared by dissolving amorphous obicetrapib hemicalcium or obicetrapib free acid in a suitable solvent or solvents.

[0371] Embodiment 71. A process for preparing an alkali salt of obicetrapib comprising contacting a solution comprising obicetrapib with an inorganic alkali base to form an alkali solution and isolating the alkali salt of obicetrapib from the alkali solution.

[0372] Embodiment 72. The process of Embodiment 71, wherein the alkali salt of obicetrapib is obicetrapib sodium and the inorganic alkali base is a sodium inorganic base.

[0373] Embodiment 73. The process of Embodiment 71, wherein the alkali salt of obicetrapib is obicetrapib potassium and the inorganic alkali base is a potassium inorganic base.

[0374] Embodiment 74. The process of any one of Embodiments 71 to 73, wherein the solution comprising obicetrapib is prepared by dissolving amorphous obicetrapib hemicalcium in a suitable solvent or solvents.

[0375] Embodiment 75. A process for preparing an alkali salt of obicetrapib comprising contacting a solution comprising obicetrapib with an inorganic alkali base wherein the solution comprising obicetrapib is prepared by dissolving one or more of obicetrapib free acid or obicetrapib HC1 in a suitable solvent or solvents.

[0376] Embodiment 76. The process of Embodiment 75, wherein the alkali salt of obicetrapib is obicetrapib sodium and the inorganic alkali base is an inorganic sodium base.

[0377] Embodiment 77. The process of Embodiment 75, wherein the alkali salt of obicetrapib is obicetrapib potassium and the inorganic alkali base is an inorganic potassium base.

[0378] Embodiment 78. The process of any one of Embodiments 75 to 77, wherein the alkali base is present not in stoichiometric excess with respect to obicetrapib.

[0379] Embodiment 79. The process of any one of Embodiments 75 to 77, wherein the alkali base is in stoichiometric excess with respect to obicetrapib.

[0380] Embodiment 80. An alkali salt of obicetrapib made by the process of any one of Embodiments 67-79.

[0381] Embodiment 81. An amorphous solid dispersion comprising an alkali salt of obicetrapib.

[0382] Embodiment 82. The amorphous solid dispersion of Embodiment 81, wherein the alkali salt is obicetrapib sodium.

[0383] Embodiment 83. The amorphous solid dispersion of Embodiment 81, wherein the alkali salt is obicetrapib potassium.

[0384] Embodiment 84. The amorphous solid dispersion of any one of Embodiments 81 to 83, wherein the amorphous solid dispersion further comprises one or more dispersion excipients and optionally a surfactant.

[0385] Embodiment 85. The amorphous solid dispersion of Embodiment 84, wherein the one or more dispersion excipients is a polymer.

[0386] Embodiment 86. The amorphous solid dispersion of Embodiment 85, wherein the polymer is selected from Polyvinylpyrrolidone (PVP), Copovidone (PVP / VA), Polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), Hydroxypropyl cellulose (HPC), Hydroxypropyl methyl cellulose (HPMC), Hypromelloseacetate succinate (HPMCAS), Hydroxypropyl methylcellulose phthalate (HPMCP), Cellulose acetate phthalate (CAP), Eudragit® E PO, Eudragit® LI 00, Eudragit® SI 00, Eudragit® L 1 GO-55, Polyvinyl acetate phthalate (PVAP), Poly(acrylic acid) (PAA), Polyethylene glycol / polyethylene oxide (PEG / PEO), PVPVA 64, HPMCAS-M, HPMCP -HP55, Eudragit® E100, HPMCAS-MG, HPC-SSL, or Poloxamer, and where the optional surfactants are selected from VE-TPGS, SLS, Tween 80, Kolliphor HS15, Poloxamer 407, and Gelucire 44 / 14

[0387] Embodiment 87. The amorphous solid dispersion of any one of Embodiments 81 to 83 further comprising a surfactant.

[0388] Embodiment 88. The amorphous solid dispersion of any one of Embodiments 81 to 87, wherein the amorphous solid dispersion is prepared by spray drying.

[0389] Embodiment 89. The amorphous solid dispersion of any one of Embodiments 81 to 87, wherein the amorphous solid dispersion is prepared by hot melt extrusion.

[0390] Embodiment 90. A process for preparing an amorphous dispersion of an alkali salt of obicetrapib or obicetrapib free acid or amorphous obicetrapib hemicalcium, comprising spray drying a solution comprising an alkali salt of obicetrapib, obicetrapib free acid, or amorphous obicetrapib hemicalcium with a dispersion excipient.

[0391] Embodiment 91. The process of Embodiment 90, wherein the alkali salt of obicetrapib is obicetrapib sodium or obicetrapib potassium.

[0392] Embodiment 92. A process for preparing an amorphous dispersion of an alkali salt of obicetrapib, obicetrapib free acid, or amorphous obicetrapib hemicalcium, comprising hot melt extruding a melt of an alkali salt of obicetrapib or obicetrapib free acid, or amorphous obicetrapib hemicalcium, and one or more dispersion excipients.

[0393] Embodiment 93. The process of Embodiment 92, wherein the alkali salt of obicetrapib is obicetrapib sodium or obicetrapib potassium.

[0394] Embodiment 94. A pharmaceutical composition comprising an alkali salt of obicetrapib and one or more pharmaceutically acceptable excipients.

[0395] Embodiment 95. The pharmaceutical composition of Embodiment 94, wherein the alkali salt of obicetrapib is obicetrapib sodium or obicetrapib potassium.

[0396] Embodiment 96. A pharmaceutical composition comprising an amorphous solid dispersion of an alkali salt of obicetrapib and one or more pharmaceutically acceptable excipients.

[0397] Embodiment 97. The pharmaceutical composition of Embodiment 96, wherein the alkali salt of obicetrapib is obicetrapib sodium or obicetrapib potassium.

[0398] Embodiment 98. A pharmaceutical composition comprising an amorphous solid dispersion of an alkali salt of obicetrapib of any one of Embodiments 80 to 89 and one or more pharmaceutically acceptable excipients.

[0399] Embodiment 99. The pharmaceutical composition of Embodiment 98, wherein the alkali salt of obicetrapib is obicetrapib sodium or obicetrapib potassium.

[0400] Embodiment 100. The pharmaceutical composition of any one of Embodiments 96 to 99 made by direct compression.

[0401] Embodiment 101. The pharmaceutical composition of Embodiments 96 to 99 made by dry granulation, followed by encapsulation or tablet compression.

[0402] Embodiment 102. A method of treating a subject suffering from or having an increased risk of developing a cardiovascular disease, the method comprising:administering a therapeutically effective amount of an amorphous solid dispersion of an alkali salt of obicetrapib, or a pharmaceutical composition thereof to the subject.

[0403] Embodiment 103. A method of treating a subject suffering from or having an increased risk of developing a cardiovascular disease, the method comprising:administering a therapeutically effective amount of an amorphous solid dispersion of an alkali salt of obicetrapib, or a pharmaceutical composition thereof to the subject, further comprising administration of an HMG CoA reductase inhibitor.

[0404] Embodiment 104. A method of slowing the progression of a neurodegenerative disease in a subject who is at risk of developing a neurodegenerative disease, the method comprising: administering a therapeutically effective amount of an amorphous solid dispersion of an alkali salt of obicetrapib, or a pharmaceutical composition thereof to the subject.

[0405] Embodiment 105. The method of Embodiment 104, where the neurodegenerative disease is Alzheimer's Disease (AD), Lewy Body dementia, vascular or multi-infarct dementia, or frontotemporal dementia (FTD).

[0406] Embodiment 106. A method of treating a subject suffering from or having an increased risk for hyperlipidemia or mixed dyslipidemia, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of an alkali salt of obicetrapib,or a pharmaceutical composition thereof, and a therapeutically effective amount of ezetimibe, or a pharmaceutically acceptable salt of ezetimibe to the subject.

[0407] Embodiment 107. A method of treating a subject requiring additional lowering of low-density lipoprotein cholesterol as an adjunct to diet and / or as maximally tolerated lipid-lowering therapy for the treatment of heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular (CV) disease (ASCVD), the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of an alkali salt of obicetrapib, or a pharmaceutical composition thereof, and a therapeutically effective amount of ezetimibe, or a pharmaceutically acceptable salt of ezetimibe to the subject.

[0408] Embodiment 108. A method of treating or preventing a metabolic disorder in a subject who has or is at risk of developing a metabolic disorder, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of an alkali salt of obicetrapib, or a pharmaceutical composition thereof, and a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt of an SGLT2 inhibitor to the subject.

[0409] Embodiment 109. A method of treating or preventing a disorder selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, obesity, metabolic syndrome, hypertension, hypercholesterolemia, cardiovascular disease, atherosclerotic cardiovascular disease, heart failure and chronic kidney disease in a subject who has or is at risk of said disorder, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of an alkali salt of obicetrapib, or a pharmaceutical composition thereof, and a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt of an SGLT2 inhibitor to the subject.

[0410] Embodiment 110. A method of treating heterozygous familial hypercholesterolemia (HeFH) and / or atherosclerotic cardiovascular disease (ASCVD) in a subject in need thereof, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of an alkali salt of obicetrapib, or a pharmaceutical composition thereof to the subject.

[0411] Embodiment 111. A method of reducing or preventing vascular symptoms in a subject with a beta hemoglobinopathy, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of an alkali salt of obicetrapib, or a pharmaceutical composition thereof to the subject.

[0412] Embodiment 112. The method of Embodiment 111, wherein an amorphous solid dispersion of an alkali salt of obicetrapib, or pharmaceutical composition thereof, is coadministered with at least one liposoluble antioxidant.

[0413] Embodiment 113. A method of improving atherosclerotic plaque characteristics in a patient with ASCVD, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of an alkali salt of obicetrapib, or a pharmaceutical composition thereof to the subject.

[0414] Embodiment 114. The method of Embodiment 113, wherein an amorphous solid dispersion of an alkali salt of obicetrapib, or pharmaceutical composition thereof, is coadministered with a therapeutically effective amount of ezetimibe, or a pharmaceutically acceptable salt thereof.

[0415] Embodiment 115. A method of reducing the rate of decrease in the AP42 / AP40 ratio in the plasma of a subject in need thereof, the method comprising administering to the subject an amorphous solid dispersion of an alkali salt of obicetrapib, or a pharmaceutical composition thereof, in an amount effective to reduce the rate of decrease in the AP42 / AP40 ratio in the plasma of the subject determined prior to the first administration of the amorphous solid dispersion of an alkali salt of obicetrapib, or a pharmaceutical composition thereof.

[0416] Embodiment 116. A method of lowering ApoE4 concentration in the central nervous system (CNS) of a subject in need thereof, the method comprising administering to the subject an amorphous solid dispersion of an alkali salt of obicetrapib, or a pharmaceutical composition thereof, in an amount effective to reduce ApoE4 concentration in the CNS.

[0417] Embodiment 117. A method of reducing major adverse cardiovascular events (MACE) in subjects with atherosclerotic cardiovascular disease (ASCVD) and / or heterozygous familial hypercholesterolemia (HeFH) who are not adequately controlled by maximally tolerated lipid-modifying therapies, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of an alkali salt of obicetrapib, or a pharmaceutical composition thereof to the subject.

[0418] Embodiment 118. The method of Embodiment 117, wherein an amorphous solid dispersion of an alkali salt of obicetrapib, or pharmaceutical composition thereof is administered at an oral dose of 10 mg per day for at least six months.

[0419] Embodiment 119. The method of Embodiment 117 or 118, wherein the baseline fasting serum LDL-C on maximally tolerated lipid-modifying therapy is >100 mg / dL, and administration of an amorphous solid dispersion of an alkali salt of obicetrapib, or pharmaceutical composition thereof lowers serum LDL-C to less than 100 mg / dL.

[0420] Embodiment 120. The method of any one of Embodiments 117 to 119, wherein administration of an amorphous solid dispersion of an alkali salt of obicetrapib, or pharmaceutical composition thereof on top of prior maximally-tolerated lipid modifying therapy is sufficient, after 18 months of treatment, to show reduction from baseline as compared to placebo in one or more of:(i) total non-calcified coronary atherosclerotic plaque volume (NCPV);(ii) NCPV in the most diseased coronary segment (NCPVMD);(iii) low attenuation plaque volume;(iv) calcified plaque volume;(v) perivascular fat attenuation index score measured in all of the left anterior descending artery (LAD), left circumflex artery (LCx), and right coronary artery (RCA) (collectively, the principal coronary arteries); and(vi) FAI score age- and gender-matched population centile.

[0421] Embodiment 121. The methods of any one of Embodiments 102 to 120, wherein the amorphous solid dispersion of an alkali salt of obicetrapib comprises an alkali salt of obicetrapib and one or more dispersion excipients.

[0422] Embodiment 122. The method of Embodiment 121, wherein one or more dispersion excipients is a polymer.

[0423] Embodiment 123. The method of Embodiment 122, wherein the polymer is selected from Polyvinylpyrrolidone (PVP), Copovidone (PVP / VA), Polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), Hydroxypropyl cellulose (HPC), Hydroxypropyl methyl cellulose (HPMC), Hypromellose acetate succinate (HPMCAS), Hydroxypropyl methylcellulose phthalate (HPMCP), Cellulose acetate phthalate (CAP), Eudragit® E PO, Eudragit® L100, Eudragit® S100, Eudragit® L 100-55, Polyvinyl acetate phthalate (PVAP), Poly(acrylic acid) (PAA), Polyethylene glycol / polyethylene oxide (PEG / PEO), PVPVA 64, HPMCAS-M, HPMCP-HP55, Eudragit® E100, HPMCAS-MG, HPC-SSL, orPoloxamer.

[0424] Embodiment 124. The method of any one of Embodiments 102 to 123, wherein the alkali salt of obicetrapib is obicetrapib sodium.

[0425] Embodiment 125. The method of any one of Embodiments 102 to 123, wherein the alkali salt of obicetrapib is obicetrapib potassium.

[0426] Embodiment 126. An amorphous solid dispersion comprising one or more of obicetrapib free acid, amorphous obicetrapib hemicalcium, obicetrapib sodium or obicetrapib potassium, and one or more dispersion excipients, and a surfactant.

[0427] Embodiment 127. The amorphous solid dispersion of Embodiment 126 wherein the percent by weight of the obicetrapib free acid, amorphous obicetrapib hemicalcium, obicetrapib sodium or obicetrapib potassium is between 10% and 60%.

[0428] Embodiment 128. The amorphous solid dispersion of Embodiment 127 wherein the percent by weight of the obicetrapib free acid, amorphous obicetrapib hemicalcium, obicetrapib sodium or obicetrapib potassium is between 15% and 35%.

[0429] Embodiment 129. The amorphous solid dispersion of Embodiment 128 wherein the percent by weight of the obicetrapib free acid, amorphous obicetrapib hemicalcium, obicetrapib sodium or obicetrapib potassium is between 18% and 22%.

[0430] Embodiment 130. The amorphous solid dispersion of Embodiment 128 wherein the percent by weight of the obicetrapib free acid, amorphous obicetrapib hemicalcium, obicetrapib sodium or obicetrapib potassium is between 28% and 32%.

[0431] Embodiment 131. The amorphous solid dispersion of Embodiment 129 wherein the percent by weight of the obicetrapib free acid, amorphous obicetrapib hemicalcium, obicetrapib sodium or obicetrapib potassium is about 20 %.

[0432] Embodiment 132. The amorphous solid dispersion of Embodiment 129 wherein the percent by weight of the obicetrapib free acid, amorphous obicetrapib hemicalcium, obicetrapib sodium or obicetrapib potassium is about 30 %.

[0433] Embodiment 133. The amorphous solid dispersion of any one of Embodiments 126 to 132, wherein the one or more dispersion excipients is a polymer.

[0434] Embodiment 134. The amorphous solid dispersion of Embodiment 133, wherein the polymer is selected from Polyvinylpyrrolidone (PVP), Copovidone (PVP / VA), Polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), Hydroxypropyl cellulose (HPC), Hydroxypropyl methyl cellulose (HPMC), Hypromelloseacetate succinate (HPMCAS), Hydroxypropyl methylcellulose phthalate (HPMCP), Cellulose acetate phthalate (CAP), Eudragit® E PO, Eudragit® LI 00, Eudragit® SI 00, Eudragit® L 1 GO-55, Polyvinyl acetate phthalate (PVAP), Poly(acrylic acid) (PAA), Polyethylene glycol / polyethylene oxide (PEG / PEO), PVPVA 64, HPMCAS-M, HPMCP -HP55, Eudragit® E100, HPMCAS-MG, HPC-SSL, orPoloxamer.

[0435] Embodiment 135. The amorphous solid dispersion of Embodiment 134, wherein the polymer is selected from PVPVA 64, HPMCAS-M, HPMCP-HP55, Eudragit® E100, HPMCAS-MG, HPC-SSL, orPoloxamer.

[0436] Embodiment 136. The amorphous solid dispersion of any one of Embodiments 126 to 135, wherein the surfactant is selected from VE-TPGS, SLS, Tween 80, Kolliphor HS15, Poloxamer 407, and Gelucire 44 / 14.

[0437] Embodiment 137. The amorphous solid dispersion of any one of Embodiments 126 to 136, wherein the polymer is selected from PVPA 64, HPMCAS-M, HMPCP-HP55, Eudragit E100, HPMCAS-MG, and HPC-SSL.

[0438] Embodiment 138. The amorphous solid dispersion of any one of Embodiments 126 to 137, wherein the surfactant is selected from VE-TPGS, SLS, Tween 80, Kolliphor HS15, Poloxamer 407, and Gelucire 44 / 14.

[0439] Embodiment 139. The amorphous solid dispersion of Embodiment 137, wherein the polymer is PVPVA 64.

[0440] Embodiment 140. The amorphous solid dispersion of Embodiment 139, wherein the surfactant is selected from VE-TPGS, SLS, Tween 80, Kolliphor HS15, Poloxamer 407, and Gelucire 44 / 14,

[0441] Embodiment 141. A pharmaceutical composition comprising an amorphous solid dispersion of any one of Embodiments 126 to 140.

[0442] Embodiment 142. The pharmaceutical composition of Embodiment 141, further comprising a pharmaceutically acceptable excipient.

[0443] Embodiment 143. A process for preparing an amorphous solid dispersion of any one of Embodiments 126 to 140 comprising the steps of spray drying a solution comprising obicetrapib, wherein the obicetrapib is formed from the dissolution of obicetrapib free acid, obicetrapib hemicalcium or obicetrapib sodium, a polymer and a surfactant.

[0444] Embodiment 144. A spray-dried amorphous solid dispersion of obicetrapib made from the process of Embodiment 143.

[0445] Embodiment 145. The spray-dried amorphous solid dispersion of Embodiment 144, comprising amorphous obicetrapib hemicalcium.

[0446] Embodiment 146. The spray dried amorphous solid dispersion of Embodiment 145, comprising amorphous obicetrapib sodium.

[0447] Embodiment 147. The spray-dried amorphous solid dispersion of Embodiment 146, comprising amorphous obicetrapib potassium.

[0448] Embodiment 148. The spray-dried amorphous dispersion of Embodiment 147, comprising obicetrapib free acid.

[0449] Embodiment 149. A process for preparing an amorphous solid dispersion of amorphous obicetrapib hemicalcium of any one of Embodiments 126 to 140 comprising holt-melt extruding a mixture of amorphous obicetrapib, a polymer, and a surfactant.

[0450] Embodiment 150. An amorphous solid dispersion made by the process of Embodiment 149.

[0451] Embodiment 151. A pharmaceutical composition comprising an amorphous solid dispersion of any one of Embodiments 144 tol48, or 150 and optionally a pharmaceutical acceptable excipient.

[0452] Embodiment 152. A method of treating a subject for the diseases or conditions of any one of Embodiments 5 to 23, 44 to 66, or 102 to 125 comprising the steps of administering to the subject an amorphous solid dispersion of any one of Embodiments 126 to 140 or 144 tol48, or 150, or the pharmaceutical composition of any one of Embodiments 141, 142, or 151.

Claims

WHAT IS CLAIMED IS:

1. An amorphous solid dispersion comprising one or more of (i) obicetrapib free acid, amorphous obicetrapib hemicalcium, obicetrapib sodium, or obicetrapib potassium, (ii) one or more dispersion excipients, and (iii) optionally one or more surfactants.

2. The amorphous solid dispersion of claim 1, wherein the one or more dispersion excipients is a polymer.

3. A pharmaceutical composition comprising an amorphous solid dispersion of claim 1 or claim 2, and one or more pharmaceutically acceptable excipients.

4. The pharmaceutical composition of any one of claim 3 made by (a) direct compression or (b) dry granulation followed by encapsulation or tablet compression.

5. A method of treating a subject suffering from or having an increased risk of developing a cardiovascular disease, the method comprising:administering a therapeutically effective amount of an amorphous solid dispersion of claim 1 or claim 2 or a pharmaceutical composition of claim 3 or claim 4 to the subject.

6. A method of treating a subject suffering from or having an increased risk of developing a cardiovascular disease, the method comprising:administering a therapeutically effective amount of an amorphous solid dispersion of claim 1 or claim 2 or a pharmaceutical composition of claim 3 or claim 4 to the subject, further comprising administration of an HMG CoA reductase inhibitor.

7. A method of slowing the progression of a neurodegenerative disease in a subject who is at risk of developing a neurodegenerative disease, the method comprising: administering a therapeutically effective amount of an amorphous solid dispersion of claim 1 or claim 2 or a pharmaceutical composition of claim 3 or claim 4 to the subject.

8. The method of claim 7, where the neurodegenerative disease is Alzheimer's Disease (AD), Lewy Body dementia, vascular or multi-infarct dementia, or frontotemporal dementia (FTD).

9. A method of treating a subject suffering from or having an increased risk for hyperlipidemia or mixed dyslipidemia, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of claim 1 or claim 2 or a pharmaceutical composition of claim 3 or claim 4, and a therapeutically effective amount of ezetimibe, or a pharmaceutically acceptable salt of ezetimibe to the subject.8810. A method of treating a subject requiring additional lowering of low-density lipoprotein cholesterol as an adjunct to diet and / or as maximally tolerated lipid-lowering therapy for the treatment of heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular (CV) disease (ASCVD), the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of claim 1 or claim 2 or a pharmaceutical composition of claim 3 or claim 4, and a therapeutically effective amount of ezetimibe, or a pharmaceutically acceptable salt of ezetimibe to the subject.

11. A method of treating or preventing a metabolic disorder in a subject who has or is at risk of developing a metabolic disorder, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of claim 1 or claim 2 or a pharmaceutical composition of claim 3 or claim 4, and a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt of an SGLT2 inhibitor to the subject.

12. A method of treating or preventing a disorder selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, obesity, metabolic syndrome, hypertension, hypercholesterolemia, cardiovascular disease, atherosclerotic cardiovascular disease, heart failure and chronic kidney disease in a subject who has or is at risk of said disorder, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of claim 1 or claim 2 or a pharmaceutical composition of claim 3 or claim 4, and a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt of an SGLT2 inhibitor to the subject.

13. A method of treating heterozygous familial hypercholesterolemia (HeFH) and / or atherosclerotic cardiovascular disease (ASCVD) in a subject in need thereof, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of claim 1 or claim 2 or a pharmaceutical composition of claim 3 or claim 4 to the subject.

14. A method of reducing or preventing vascular symptoms in a subject with a beta hemoglobinopathy, the method comprising administering a therapeutically effective89amount of an amorphous solid dispersion of claim 1 or claim 2 or a pharmaceutical composition of claim 3 or claim 4 to the subject.

15. The method of claim 14, wherein an amorphous solid dispersion comprising one or more of (i) obicetrapib free acid, amorphous obicetrapib hemicalcium, obicetrapib sodium, or obicetrapib potassium, (ii) and one or more dispersion excipients and (iii) optionally one or more surfactants, or pharmaceutical composition thereof, is co-administered with at least one liposoluble antioxidant.

16. A method of improving atherosclerotic plaque characteristics in a patient with ASCVD, the method comprising administering a therapeutically effective amount of an amorphous solid dispersion of claim 1 or claim 2 or a pharmaceutical composition of claim 3 or claim 4 to the subject.

17. The method of claim 16, wherein an amorphous solid dispersion of claim 1 or claim 2 or a pharmaceutical composition of claim 3 or claim 4, is co-administered with a therapeutically effective amount of ezetimibe, or a pharmaceutically acceptable salt thereof.

18. A method of reducing the rate of decrease in the AP42 / AP40 ratio in the plasma of a subject in need thereof, the method comprising administering to the subject an amorphous solid dispersion of claim 1 or claim 2 or a pharmaceutical composition of claim 3 or claim 4, in an amount effective to reduce the rate of decrease in the AP42 / AP40 ratio in the plasma of the subject determined prior to the first administration of an amorphous solid dispersion of amorphous obicetrapib hemicalcium, and one or more dispersion excipients and optionally one or more surfactants, or a pharmaceutical composition thereof.

19. A method of lowering ApoE4 concentration in the central nervous system (CNS) of a subject in need thereof, the method comprising administering to the subject an amorphous solid dispersion of claim 1 or claim 2 or a pharmaceutical composition of claim 3 or claim 4, in an amount effective to reduce ApoE4 concentration in the CNS.

20. A method of reducing major adverse cardiovascular events (MACE) in subjects with atherosclerotic cardiovascular disease (ASCVD) and / or heterozygous familial hypercholesterolemia (HeFH) who are not adequately controlled by maximally tolerated lipid-modifying therapies, the method comprising administering a therapeutically90effective amount of an amorphous solid dispersion of claim 1 or claim 2 or a pharmaceutical composition of claim 3 or claim 4, to the subject.

21. The method of claim 20, wherein the amorphous solid dispersion of claim 1 or claim 2 or a pharmaceutical composition of claim 3 or claim 4 is administered at an oral dose of 10 mg per day for at least six months.

22. The method of claim 20 or 21, wherein the baseline fasting serum LDL-C on maximally tolerated lipid-modifying therapy is >100 mg / dL, and administration of an amorphous solid dispersion of claim 1 or claim 2 or a pharmaceutical composition of claim 3 or claim 4 lowers serum LDL-C to less than 100 mg / dL.

23. The method of any one of claims 20 to 22, wherein administration of an amorphous solid dispersion of claim 1 or claim 2 or a pharmaceutical composition of claim 3 or claim 4 on top of prior maximally-tolerated lipid modifying therapy is sufficient, after 18 months of treatment, to show reduction from baseline as compared to placebo in one or more of: (i) total non-calcified coronary atherosclerotic plaque volume (NCPV);(ii) NCPV in the most diseased coronary segment (NCPVMD);(iii) low attenuation plaque volume;(iv) calcified plaque volume;(v) perivascular fat attenuation index score measured in all of the left anterior descending artery (LAD), left circumflex artery (LCx), and right coronary artery (RCA) (collectively, the principal coronary arteries); and(vi) FAI score age- and gender-matched population centile.

24. The method of claims 5 to 23, wherein one or more dispersion excipients is a polymer.91

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