Crystalline forms of deuterium-enriched pioglitazone

Abstract

Provided herein are crystalline forms of deuterium-enriched (R)-pioglitazone and compositions thereof. Also provided herein are methods of using the crystalline forms of deuterium-enriched (R)-pioglitazone and compositions thereof.

Description

[0001] Related applications

[0002] This application claims priority to U.S. Patent Application Serial No. 17 / 314,538, filed May 7, 2021; U.S. Provisional Patent Application Serial No. 63 / 046,304, filed June 30, 2020; and U.S. Provisional Patent Application Serial No. 63 / 046,309, filed June 30, 2020, the contents of which are incorporated herein by reference in their entirety. Background Technology

[0003] Thiazolidinediones (TZDs) are antidiabetic drugs that sensitize the body to insulin. These compounds have been empirically identified as agonists of peroxisome proliferator-activated receptors (PPARs) (including PPAR-γ (PPARγ)), ligand-activated nuclear receptors that drive a broad transcriptional program associated with adipogenesis, lipid metabolism, innate immune function, and metabolic homeostasis (see, for example, J. Clin. Invest. 2000, 106, 1305-1307, Trends Endocrinol. Metab. 2012, 23, 205-215). Therefore, the antidiabetic mechanism of action of TZDs has to date been attributed to binding to and activation of PPARγ (see, for example, J Biol Chem 1995, 270, 12953-12956, Nat Med 2013, 19, 557-566).

[0004] Therapeutic agents that regulate PPAR have been commercialized for the treatment of medical conditions such as metabolic disorders. One such example is pioglitazone hydrochloride (TZD), which has been approved by the U.S. Food and Drug Administration as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes in a variety of clinical settings. Pioglitazone hydrochloride is a registered trademark. Available for sale. The prescribing information indicates that pioglitazone is an agonist of PPARγ. It has been reported that... PPARγ-related side effects include, for example, weight gain, edema, and an increased incidence of fractures.

[0005] However, emerging genetic and pharmacological evidence suggests that TZDs exert many beneficial effects independently of PPARy activation (see Biochem. Pharmacol. 2005, 70, 177-188). For example, liver and skeletal muscle remain responsive to TZDs despite tissue-specific deletion of PPARy (see J Clin Invest 2003, 112, 608-618, J Biol Chem 2012, 287, 23537-23548), and systemic insulin sensitization by rosiglitazone persists when PPARy is deleted in mature adipocytes (see Mol Cell Biol 2018, 38, e00677-17). Pharmacological evidence also suggests that TZDs have PPARy-independent effects. They can acutely alter metabolic homeostasis on a time scale that can be too fast to be driven by broad changes in gene expression (see Am. J. Physiol. Endocrinol. Metab. 2006, 291, E175-81), and some in vitro and in vivo experiments suggest that ordering affinity for PPARy does not always correlate with efficacy (see Biochem. Pharmacol. 2005, 70, 177-188). Pioglitazone and other TZDs have also been shown to have anti-inflammatory activity, which appears to be mediated at least in part by mechanisms that do not involve PPARs (Curr. Drug Targets Inflamm. Allergy 2002, 1, 243-248).

[0006] Recent studies have shown that most of the PPARy-independent effects of TZDs can be attributed to the inhibition of the mitochondrial pyruvate carrier (MPC), an inner mitochondrial membrane transporter responsible for the uptake of cytoplasmic glucose-derived pyruvate into the mitochondrial matrix (see Biochim. Biophys. Acta-Mol Cell Res, 2016, 1863, 2436-2442). TZDs are acute and specific inhibitors of MPC activity at clinically relevant concentrations (see Biochim. Biophys. Acta-Mol Cell Res, 2016, 1863, 2436-2442). TZDs also inhibit mitochondrial complex I (see Diabetes 2004, 53, 1052-1059), although at higher and potentially supraphysiological concentrations relative to their effects on MPC. Despite decades of use of pioglitazone in humans with T2DM, the full picture of the target of pioglitazone and its precise mechanism of action is only now beginning to be elucidated.

[0007] All TZDs, including pioglitazone, are mixtures of enantiomers characterized by the presence of a chiral center. This chiral center is prone to rapid, non-enzymatic configurational inversion. Thus, the instability of the chiral center hinders the development of differential pharmacological potential between TZD enantiomers. For example, while the levorotatory or (S)-enantiomer of rosiglitazone was identified as the most potent PPARy agonist, (S)-rosiglitazone rapidly equilibrates to produce a 1 : 1 mixture of (R)- and (S)-rosiglitazone, preventing further in vivo characterization of the enantiomers (see Bioorg. Med. Chem. Lett., 1998, 8, 3657-8). Moreover, the anti-inflammatory effects of pioglitazone were shown to be uniquely associated with the (R)-enantiomer in a rat model of chronic obstructive pulmonary disease. This was achieved only after stabilization of the enantiomers in acidic solution, followed by immediate intranasal administration, which limited the inversion during the course of the study (see International Patent Application WO2010015818A1).

[0008] Due to the increasing number of patients suffering from conditions such as those described above, and the limitations of existing therapies (e.g., side effects), there is a need for new therapeutic drugs to treat medical diseases in which modulation of PPARy, anti-inflammatory, and / or MPC activity is expected to be beneficial.

[0009] The use of deuterium-enriched enantiomers of pioglitazone to treat such medical conditions has generated great interest, as they are believed to provide additional therapeutic efficacy and reduce the incidence and severity of side effects compared to pioglitazone. Recently, the characterization of unique pharmacological and pharmacokinetic properties of the deuterium-enriched (R) and / or (S)-enantiomers of pioglitazone has been reported (see Hepatol. Commun. 2021, Apr 10 doi.org / 10.1002 / hep4.1723). Preclinical studies indicated that (R)-pioglitazone retained the efficacy of pioglitazone in nonalcoholic steatohepatitis (NASH), including reduced liver triglycerides, free fatty acids, cholesterol, steatosis, inflammation, hepatocyte enlargement, and fibrosis. Although both enantiomers inhibited MPC, deuterium-enriched (R)-pioglitazone (PXL065) showed no PPARy activity, while (S)-pioglitazone appeared responsible for PPARy activity and associated weight gain. In preclinical mouse models, both enantiomers could reduce plasma glucose and liver fibrosis to the same extent as pioglitazone. In a phase la clinical study, PXL065 (7.5, 22.5, 30 mg) demonstrated safety and tolerability, as well as preferential exposure to the (R)-enantiomer, compared to 45 mg pioglitazone. These results led to the conclusion that PXL065 at doses lower than 22.5 mg is expected to show efficacy in NASH equal to or greater than 45 mg pioglitazone, without potentially deleterious weight gain and edema. In comparison, PXL065 (7.5, 22.5, 30 mg) demonstrated safety and tolerability, as well as preferential exposure to the (R)-enantiomer, compared to 45 mg pioglitazone. These results led to the conclusion that PXL065 at doses lower than 22.5 mg is expected to show efficacy in NASH equal to or greater than 45 mg pioglitazone, without potentially deleterious weight gain and edema.

[0010] However, developing solid-state forms of these deuterium-enriched pioglitazone enantiomers to provide the physicochemical properties required for manufacturing commercial pharmaceuticals with the desired efficacy remains a significant challenge. This is due to the unpredictability of the results of solid-state screening for any given compound, and the unpredictability of the physicochemical properties of any subsequently discovered solid-state form. Therefore, new solid-state forms of deuterium-enriched pioglitazone derivatives are needed to achieve the physicochemical properties required to provide efficacy superior to pioglitazone.

[0011] Overview

[0012] On the one hand, the present invention provides a salt form (e.g., crystalline salt form) of deuterium-enriched (R)-pioglitazone (PXL065).

[0013] In various embodiments of the present invention, deuterated hydrochlorides of deuterium-enriched compounds of formula (I) are provided:

[0014]

[0015] Where R 1 It is H or D, provided that the total deuterium abundance in the compound of formula (I) is about 1.3 to about 4.

[0016] In various embodiments of the present invention, crystalline deuterated hydrochlorides of deuterium-enriched compounds of formula (I) are provided.

[0017]

[0018] Where R 1 It is H or D, provided that the total deuterium abundance in the compound of formula (I) is from about 1.3 to about 4, and wherein the crystalline deuterated hydrochloride is characterized by X-ray powder diffraction patterns containing peaks at the following diffraction angles (2θ): 15.8°±0.2°, 22.8°±0.2° and 26.0°±0.2°.

[0019] In various embodiments of the present invention, crystalline hydrochlorides of compounds of formula (IA) are provided:

[0020]

[0021] In various embodiments of the present invention, crystalline hydrochlorides of compounds of formula (IA) are provided:

[0022]

[0023] The crystalline hydrochloride is characterized by X-ray powder diffraction patterns containing peaks at the following diffraction angles (2θ): 15.8°±0.2°, 22.8°±0.2°, and 26.0°±0.2°.

[0024] On the other hand, the present invention provides pharmaceutical materials comprising particles of deuterium-enriched (R)-pioglitazone crystalline salts (e.g., deuterated hydrochloride, hydrochloride).

[0025] In various embodiments of the present invention, the pharmaceutical material comprises crystalline deuterated hydrochloride particles of a deuterium-enriched compound of formula (I).

[0026]

[0027] Where R 1 It is H or D, provided that the total deuterium abundance (I) in the compound of formula (I) is about 1.3 to about 4, and wherein the particles in the composition have a crystal shape selected from hexagonal, rod-shaped and combinations thereof.

[0028] In various embodiments of the present invention, the pharmaceutical material comprises crystalline deuterated hydrochloride particles of a deuterium-enriched compound of formula (I).

[0029]

[0030] Where R 1 It is H or D, provided that the total deuterium abundance (I) in the compound of formula (I) is from about 1.3 to about 4, and wherein the particles have a particle size distribution defined by d(0.9) from about 10 μm to about 800 μm, preferably less than 500 μm.

[0031] In various embodiments of the present invention, the pharmaceutical material comprises crystalline hydrochloride particles of a compound of formula (IA).

[0032]

[0033] The particles in the composition have a needle-like crystal shape.

[0034] In various embodiments of the present invention, the pharmaceutical material comprises crystalline hydrochloride particles of a compound of formula (IA).

[0035]

[0036] The particles have a particle size distribution defined by d(0.9) from about 10 μm to about 800 μm, preferably less than 500 μm.

[0037] In another aspect, the present application provides pharmaceutical compositions comprising a crystalline salt of deuterium-enriched (R)-pioglitazone described herein or a pharmaceutical material described herein, and a pharmaceutically acceptable excipient. In various embodiments, the pharmaceutical composition comprises a crystalline deuterated hydrochloride salt of deuterium-enriched (R)-pioglitazone and a pharmaceutically acceptable excipient. In various embodiments, the pharmaceutical composition comprises a crystalline hydrochloride salt of deuterium-enriched (R)-pioglitazone and a pharmaceutically acceptable excipient.

[0038] In another aspect, the present application provides crystalline salt forms, pharmaceutical materials, and pharmaceutical compositions of deuterium-enriched (R)-pioglitazone useful for treating various conditions, diseases, and disorders described herein. In certain embodiments, the condition, disease, or disorder is a metabolic disorder. In certain embodiments, the condition, disease, or disorder is type 2 diabetes and / or nonalcoholic steatohepatitis. In certain embodiments, the condition, disease, or disorder is a neurological disorder. In some embodiments, the neurological disorder is adrenoleukodystrophy or adrenomyeloneuropathy. BRIEF DESCRIPTION OF DRAWINGS

[0039] Figure 1A is an exemplary X-ray powder diffraction (XRPD) pattern of a crystalline deuterated hydrochloride salt of deuterium-enriched (R)-pioglitazone.

[0040] Figure 1B is an overlay of an exemplary X-ray powder diffraction (XRPD) pattern of a crystalline hydrochloride salt of deuterium-enriched (R)-pioglitazone with an X-ray powder diffraction (XRPD) pattern of a crystalline hydrochloride salt of pioglitazone.

[0041] Figure 2 is an exemplary optical photomicrograph of a crystalline deuterated hydrochloride salt of deuterium-enriched (R)-pioglitazone at (A) 10x magnification and (B) 20x magnification.

[0042] Figure 3 is an exemplary differential scanning calorimetry (DSC) curve of a crystalline deuterated hydrochloride salt of deuterium-enriched (R)-pioglitazone.

[0043] Figure 4A is an exemplary thermogravimetric analysis (TGA) curve of a crystalline deuterated hydrochloride salt of deuterium-enriched (R)-pioglitazone.

[0044] Figure 4B is an exemplary thermogravimetric mass spectroscopy (TGMS) plot of a crystalline deuterated hydrochloride salt of deuterium-enriched (R)-pioglitazone.

[0045] Figure 5is an exemplary proton nuclear magnetic resonance (1H-NMR) spectrum of a crystalline deuterated hydrochloride salt of deuterium-enriched (R)-pioglitazone. 1 H-NMR) spectrum.

[0046] Figure 6 is an exemplary X-ray powder diffraction (XRPD) pattern of a crystalline hydrochloride salt of deuterium-enriched (R)-pioglitazone.

[0047] Figure 7 is an exemplary optical photomicrograph of a crystalline hydrochloride salt of deuterium-enriched (R)-pioglitazone at (A) 10x magnification and (B) 20x magnification.

[0048] Figure 8 is an exemplary differential scanning calorimetry (DSC) curve of a crystalline hydrochloride salt of deuterium-enriched (R)-pioglitazone.

[0049] Figure 9A is an exemplary thermogravimetric analysis (TGA) curve of a crystalline hydrochloride salt of deuterium-enriched (R)-pioglitazone.

[0050] Figure 9B is an exemplary thermogravimetric mass spectroscopy (TGMS) pattern of a crystalline hydrochloride salt of deuterium-enriched (R)-pioglitazone.

[0051] Figure 10 is an exemplary 1 H-NMR spectrum of a crystalline hydrochloride salt of deuterium-enriched (R)-pioglitazone.

[0052] Figure 11 is an exemplary X-ray powder diffraction (XRPD) pattern of a crystalline free base of deuterium-enriched (R)-pioglitazone.

[0053] Figure 12 is an exemplary differential scanning calorimetry (DSC) curve of a crystalline free base form of deuterium-enriched (R)-pioglitazone.

[0054] Figure 13A is an exemplary thermogravimetric analysis (TGA) curve of a crystalline free base form of deuterium-enriched (R)-pioglitazone.

[0055] Figure 13B is an exemplary thermogravimetric mass spectroscopy (TGMS) pattern of a crystalline free base form of deuterium-enriched (R)-pioglitazone.

[0056] Figure 14 is an overlay of pH-dependent solubility curves of a crystalline DC1 salt and a hydrochloride salt of deuterium-enriched (R)-pioglitazone and a crystalline DC1 salt of deuterium-enriched pioglitazone and a crystalline hydrochloride salt of pioglitazone.

[0057] Figure 15is an example plot of tablet hardness (N) vs. compression force (kN) for batches of tablets having different particle size distributions (PSD) in units of pm for an active pharmaceutical ingredient (API).

[0058] Figure 16 is an example plot of tablet hardness (N) vs. compression force (kN) for batches of tablets having different particle size distributions (PSD) in units of pm for an active pharmaceutical ingredient (API).

[0059] Figure 17 is an example plot of total pioglitazone plasma levels (sum of deuterated and protiated (R)- and (S)-enantiomers) vs. time following dose of PXL065 (deuterium-enriched (R) pioglitazone) in dogs.

[0060] Figure 18 is an example plot of total pioglitazone plasma levels (sum of deuterated and protiated (R)- and (S)-enantiomers) vs. time following dose of PXL061 (deuterium-enriched pioglitazone) in dogs.

[0061] Figure 19 is an example plot of total pioglitazone plasma levels (sum of deuterated and protiated (R)- and (S)-enantiomers) vs. time following dose of PXL064 (deuterium-enriched (S)-pioglitazone) in dogs.

[0062] Figure 20 is an example plot of total pioglitazone plasma levels (sum of deuterated and protiated (R)- and (S)-enantiomers) vs. time following dose of pioglitazone and PXL065 in dogs.

[0063] Figure 21 is an overlay plot of total pioglitazone (sum of deuterated and protiated (R)- and (S)-enantiomers) dose-normalized exposure curves for crystalline hydrochloride salt of deuterium-enriched (R)-pioglitazone (22.5 mg doses) and (pioglitazone hydrochloride, 45 mg doses) in humans, as further described in Example 11.

[0064] Figure 22 is an overlay plot of total pioglitazone (sum of deuterated and protiated (R)- and (S)-enantiomers) dose-normalized exposure curves for crystalline hydrochloride salt of deuterium-enriched (R)-pioglitazone (15 mg and 30 mg doses) and (pioglitazone hydrochloride, 45 mg doses) in humans, as further described in Example 12.

[0065] DETAILED DESCRIPTION

[0066] As generally described herein, the present application provides pharmaceutically acceptable salts of deuterium-enriched (R)-pioglitazone (also referred to herein as a compound of Formula I), e.g., crystalline salts of deuterium-enriched (R)-pioglitazone, pharmaceutical compositions comprising the same, and methods of using the salt forms of deuterium-enriched (R)-pioglitazone to treat medical conditions, diseases, and disorders (e.g., neurological disorders, cancers, respiratory disorders, metabolic disorders, hepatitis, cardiovascular diseases, inflammatory disorders, immune-mediated disorders, skin diseases, or skin defects) in a subject in need thereof. In particular, the present application provides crystalline hydrochloride salts of deuterium-enriched (R)-pioglitazone and deuterated hydrochloride salts, which have unexpectedly improved solubility at physiologically relevant pH and in vivo bioavailability compared to commercially available pioglitazone hydrochloride

[0067] Definitions

[0068] To facilitate the understanding of this application, a number of terms and phrases are defined below.

[0069] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Abbreviations used herein follow conventions known in the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to standard rules of chemical valence known in the chemical arts.

[0070] Throughout this specification, unless otherwise indicated, singular forms such as "a," "an," and "said" include plural referents unless the context clearly dictates otherwise. By "comprising" or "containing" or "including" it is meant that at least the named compound, element, or method step is present in the composition or method, but does not exclude the presence of other compounds, elements, materials, and / or method steps. Throughout this specification, unless otherwise indicated, all ranges are inclusive of the recited endpoints, and single values are inclusive of both the recited value and the endpoints.

[0071] In this application, words to the effect that one element or component "includes," "has," "possesses," "contains" or "comprises" another element or component means that the element or component includes, has, possesses, contains or comprises the other element or component, but does not exclude the presence of additional elements or components.

[0072] Further, it should be understood that the full scope of combinations of elements and / or features of compositions or methods described herein are not limited to only those combinations described or shown in the specification. For example, when referring to a particular compound, that compound can be used in various embodiments of compositions of the present application and / or methods of the present application, unless otherwise understood from the context. In other words, in this application, embodiments have been described in clear and concise language, and it is intended that the applicant's / s' teachings be understood not only as the preferred embodiments, but also as a broad methodology, algorithm, and means for solving the technical and technical problems described herein.​

[0073] The articles "a" and "an" are used herein to refer to one or more (i.e., at least one) of the grammatical object of the article. By way of example, "an element" means one element or more elements.

[0074] The term "and / or," as used in the present disclosure, unless otherwise stated, should be taken as a specific disclosure of each of the conjunctive terms and the disjunctive term.

[0075] It will be understood that the expression "at least one of" followed by a list of two or more items, covers all of the individual items in the list individually as well as in any combination of two or more of the items. The expression "at least one of," when preceding the presentation of a list of two or more items, should be understood to have the same meaning.

[0076] It should be understood that the use of the term "including" "includes" "included," "has," "have," "had," "having," "contains," "contain," "contained," or "contains," including grammatical equivalents thereof, is generally understood to be the broadest term and should be read to mean "comprising" or "including" and / or "consisting of" and / or "consisting essentially of," depending on the specific context.

[0077] When the term "about" is used in reference to a numerical value, the present invention also includes the specific numerical value itself, unless otherwise specifically stated. As used herein, the term "about" refers to a ±10% variation from the nominal value, unless otherwise stated or inferred from the context.

[0078] Throughout this specification, variables or parameters are disclosed in groups or ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, the integers in the range of 0 to 40 are specifically intended to be individually disclosed as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and the integers in the range of 1 to 20 are specifically intended to be individually disclosed as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0079] The use of any and all examples, or exemplary language (e.g., "such as" or "including") provided herein, is intended merely to better illuminate the application and does not pose a limitation on the scope of the application unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the application.

[0080] Deuterium is also denoted herein as 2 H and / or D, is 1 H is the stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.014. Hydrogen exists naturally as a mixture of isotopes 1 H hydrogen (i.e., protium), deuterium ( 2 H), and tritium ( 3 H). Deuterium has a natural abundance of about 0.015%. One of ordinary skill in the art recognizes that in all compounds having H atoms, the H atoms actually represent 1 H hydrogen, deuterium ( 2 H), and tritium ( 3 H), about 0.015% of which is deuterium. In various embodiments, compounds having enriched levels of deuterium above the natural abundance of about 0.015% are considered non-natural and, therefore, novel compared to their non-enriched counterparts. In certain embodiments, compounds having enriched levels of deuterium above its natural abundance of about 0.015% are deuterium-enriched compounds.

[0081] As used herein, "total deuterium content" or "total deuterium abundance" refers to the number of deuterium present in a molecule (if the molecule is a salt, then the counterion is also counted, e.g., HCl or DCI salt of deuterium-enriched (R)- pioglitazone). The total deuterium content can be determined, for example, by 2 H-NMR. For example, the deuterium content of a chiral center of a molecule (e.g., deuterium-enriched pioglitazone) can be determined using 1 H-NMR.

[0082] In general, specified percentages of compositions are by weight unless otherwise stated. Further, if a variable is not defined, the previous definition of the variable applies.

[0083] As used herein, "pharmaceutical composition" or "pharmaceutical formulation" refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0084] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or state governments or the corresponding agency in countries other than the United States, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0085] As used herein, "pharmaceutically acceptable excipient" refers to a substance that aids in the administration of an active agent to and / or absorption by a subject and can include in the compositions of the present application without posing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, solutions of physiological salts (e.g., phosphate buffered saline solution), emulsions (e.g., such as oil / water or water / oil emulsions), lactated Ringer's solution, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorants, salt solutions (e.g., Ringer's solution), alcohols, oils, gelatins, carbohydrates (such as lactose, amylose or starch), fatty acids esters, hyrmethylcellulose, polyvinylpyrrolidone and colorants, and the like. These formulations can be sterilized and, if desired, mixed with auxiliary agents that do not deleteriously react with the compounds of the present application, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, and / or aromatizing agents, and the like. For examples of excipients, see Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).

[0086] As used herein, "solid dosage form" refers to a solid form of a pharmaceutical agent, such as a tablet, capsule, granule, powder, sachet, reconstitutable powder, dry powder inhaler, and chewable.

[0087] As used herein, "administering" means orally administering, administering in a suppository, contacting topically, intravenously administering, parenterally administering, intraperitoneally administering, intramuscularly administering, intralesionally administering, intrathecally administering, intracranially administering, intranasally administering, or subcutaneously administering to a subject, or implanting a slow-release device, such as a microosmotic pump. Administration is by any route, including parenterally and transmucosally (e.g., buccal, sublingual, palatine, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. "Co-administration" means administration of the compositions described herein simultaneously with, just prior to, or just after administration of one or more additional therapies (e.g., an anti-cancer agent, a chemotherapeutic agent, or a treatment for a neurodegenerative disease).(R) 2 The H-pioglitazone or a pharmaceutically acceptable salt thereof can be administered alone or can be co-administered to a patient. Co-administration is intended to include administration of the compounds simultaneously or sequentially, either individually or in combination (more than one compound or agent). Thus, if desired, these formulations can also be used in combination with other active substances (e.g., to reduce metabolic degradation).

[0088] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0089] As used herein, unless otherwise noted, the terms "treat," "treating" and "treatment" encompass actions that occur when a subject is suffering from a particular disease, disorder or condition and that reduce the severity of the disease, disorder or condition or delay or slow the progression of the disease, disorder or condition (e.g., "therapeutic treatment").

[0090] Generally, an "effective amount" of a compound refers to an amount that is sufficient to elicit the desired biological response (e.g., to treat a disorder, disease or condition described herein). One of ordinary skill in the art will appreciate that the effective amount of a compound of the present disclosure can vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health and condition of the subject.

[0091] As used herein, "pioglitazone" refers to the following compound (A), which is a racemic (1 : 1) mixture of (R)- and (S)-enantiomers and has about the natural abundance of deuterium at each hydrogen atom position as a starting material. Analogues and / or enantiomers of pioglitazone can be specified herein, e.g., "deuterium-enriched (R)-pioglitazone.

[0092]

[0093] Deuterium-enriched (R)-pioglitazone

[0094] Deuterium-enriched (R)-pioglitazone of Formula (I) is an MPC inhibitor:

[0095]

[0096] wherein R 1 is H or D.

[0097] As described above, the deuterium-enriched (R)-pioglitazone described herein comprises deuterium enrichment at the chiral center of pioglitazone and optionally other positions of the compound (e.g., the nitrogen of the thiazolidinedione). Without wishing to be bound by theory, it is believed that the deuterium enrichment at the chiral center reduces or inhibits the rate at which the two enantiomers of pioglitazone can interconvert.

[0098] Methods for chemically synthesizing deuterium-enriched (R)-pioglitazone and preparing the crystalline salt forms described herein are provided in Examples 1, 2 and 3.

[0099] In certain embodiments, the deuterium abundance at a chiral center is about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 75% to about 100%, about 80% to about 100%, about 85% to about 100%, about 90% to about 100%, about 95% to about 100%, about 30% to about 95%, about 30% to about 90%, about 30% to about 85%, about 30% to about 80%, about 30% to about 75%, about 30% to about 70%, about 30% to about 60%, about 30% to about 50%, about 30% to about 40%, about 40% to about 95%, about 40% to about 90%, about 40% to about 85%, about 40% to about 80%, about 40% to about 75%, about 40% to about 70%, about 40% to about 60%, about 40% to about 50%, about 50% to about 95%, about 50% to about 90%, about 50% to about 85%, about 50% to about 80%, about 50% to about 75%, about 50% to about 70%, about 50% to about 60%, about 60% to about 95%, about 60% to about 90%, about 60% to about 85%, about 60% to about 80%, about 60% to about 75%, about 60% to about 70%, about 70% to about 95%, about 70% to about 90%, about 70% to about 85%, about 70% to about 80%, about 70% to about 75%, about 75% to about 95%, about 75% to about 90%, about 75% to about 85%, about 75% to about 80%, about 80% to about 95%, about 80% to about 90%, about 80% to about 85%, about 85% to about 95%, about 85% to about 90%, or about 90% to about 95%.

[0100] In certain embodiments, the deuterium abundance at a chiral center is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%.

[0101] In certain embodiments, the deuterium abundance at the chiral center is about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%.

[0102] In certain embodiments, R 1about 60% to about 50%, about 60% to about 40%, about 60% to about 30%, about 60% to about 20%, about 60% to about 10%, about 10% to about 95%, about 10% to about 90%, about 10% to about 85%, about 10% to about 80%, about 10% to about 75%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, about 20% to about 95%, about 20% to about 90%, about 20% to about 85%, about 20% to about 80%, about 20% to about 75%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 20% to about 30%, about 30% to about 95%, about 30% to about 90%, about 30% to about 85%, about 30% to about 80%, about 30% to about 75%, about 30% to about 70%, about 30% to about 60%, about 30% to about 50%, about 30% to about 40%, about 40% to about 95%, about 40% to about 90%, about 40% to about 85%, about 40% to about 80%, about 40% to about 75%, about 40% to about 70%, about 40% to about 60%, about 40% to about 50%, about 50% to about 95%, about 50% to about 90%, about 50% to about 85%, about 50% to about 80%, about 50% to about 75%, about 50% to about 70%, about 50% to about 60%, about 60% to about 95%, about 60% to about 90%, about 60% to about 85%, about 60% to about 80%, about 60% to about 75%, about 60% to about 70%, about 70% to about 95%, about 70% to about 90%, about 70% to about 85%, about 70% to about 80%, about 70% to about 75%, about 75% to about 95%, about 75% to about 90%, about 75% to about 85%, about 75% to about 80%, about 80% to about 95%, about 80% to about 90%, about 80% to about 85%, about 85% to about 95%, about 85% to about 90%, or about 90% to about 95%.

[0103] In certain embodiments, R 1at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%.

[0104] In certain embodiments, R 1 at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%.

[0105] In certain embodiments, the total deuterium abundance in the compound of Formula (I) is about 0.3 to about 4, about 0.5 to about 4, about 1 to about 4, about 1.2 to about 4, about 1.3 to about 4, about 1.4 to about 4, about 1.6 to about 4, about 1.8 to about 4, about 2 to about 4, about 2.2 to about 4, about 2.4 to about 4, about 2.6 to about 4, about 2.8 to about 4, about 3 to about 4, about 3.2 to about 4, about 3.4 to about 4, about 3.6 to about 4, about 3.8 to about 4, about 0.3 to about 3.8, about 0.3 to about 3.6, about 0.3 to about 3.4, about 0.3 to about 3.2, about 0.3 to about 3, about 0.3 to about 2.8, about 0.3 to about 2.6, about 0.3 to about 2.4, about 0.3 to about 2.2, about 0.3 to about 2, about 0.3 to about 1.8, about 0.3 to about 1.6, about 0.3 to about 1.4, about 0.3 to about 1.2, about 0.3 to about 1, about 0.3 to about 0.5, about 0.5 to about 3.8, about 0.5 to about 3.6, about 0.5 to about 3.4, about 0.5 to about 3.2, about 0.5 to about 3, about 0.5 to about 2.8, about 0.5 to about 2.6, about 0.5 to about 2.4, about 0.5 to about 2.2, about 0.5 to about 2, about 0.5 to about 1.8, about 0.5 to about 1.6, about 0.5 to about 1.4, about 0.5 to about 1.2, about 0.5 to about 1, about 1 to about 3.8, about 1 to about 3.6, about 1 to about 3.4, about 1 to about 3.2, about 1 to about 3, about 1 to about 2.8, about 1 to about 2.6, about 1 to about 2.4, about 1 to about 2.2, about 1 to about 2, about 1 to about 1.8, about 1 to about 1.6, about 1 to about 1.4, about 1 to about 1.2, about 1.2 to about 3.8, about 1.2 to about 3.6, about 1.2 to about 3.4, about 1.2 to about 3.2, about 1.2 to about 3, about 1.2 to about 2.8, about 1.2 to about 2.6, about 1.2 to about 2.4, about 1.2 to about 2.2, about 1.2 to about 2, about 1.2 to about 1.8, about 1.2 to about 1.6, about 1.2 to about 1.4, about 1.2 to about 1.3, about 1.3 to about 3.8, about 1.3 to about 3.6, about 1.3 to about 3.4, about 1.3 to about 3.2, about 1.3 to about 3, about 1.3 to about 2.8, about 1.3 to about 2.6, about 1.3 to about 2.4, about 1.3 to about 2.2, about 1.3 to about 2, about 1.3 to about 1.8, about 1.3 to about 1.6, about 1.3 to about 1.4, about 1.4 to about 3.8, about 1.4 to about 3.6, about 1.4 to about 3.4, about 1.4 to about 3.2, about 1.4 to about 3, about 1.4 to about 2.8, about 1.4 to about 2.6, about 1.4 to about 2.4, about 1.4 to about 2.2, about 1.4 to about 2, about 1.4 to about 1.8, about 1.4 to about 1.6, about 1.6 to about 3.8, about 1.6 to about 3.6, about 1.6 to about 3.4, about 1.6 to about 3.2, about 1.6 to about 3, about 1.6 to about 2.8, about 1.6 to about 2.6, about 1.6 to about 2.4, about 1.6 to about 2.2, about 1.6 to about 2, about 1.6 to about 1.8, about 1.8 to about 3.8, about 1.8 to about 3.6, about 1.8 to about 3.4, about 1.8 to about 3.2, about 1.8 to about 3, about 1.8 to about 2.8, about 1.8 to about 2.6, about 1.8 to about 2.4, about 1.8 to about 2.2, about 1.8 to about 2, about 2 to about 3.8, about 2 to about 3.6, about 2 to about 3.4, about 2 to about 3.2, about 2 to about 3, about 2 to about 2.8, about 2 to about 2.6, about 2 to about 2.4, about 2 to about 2.2, about 2.2 to about 3.8, about 2.2 to about 3.6, about 2.2 to about 3.4, about 2.2 to about 3.2, about 2.2 to about 3, about 2.2 to about 2.8, about 2.2 to about 2.6, about 2.2 to about 2.4, about 2.4 to about 3.8, about 2.4 to about 3.6, about 2.4 to about 3.4, about 2.4 to about 3.2, about 2.4 to about 3, about 2.4 to about 2.8, about 2.4 to about 2.6, about 2.6 to about 3.8, about 2.6 to about 3.6, about 2.6 to about 3.4, about 2.6 to about 3.2, about 2.6 to about 3, about 2.6 to about 2.8, about 2.8 to about 3.8, about 2.8 to about 3.6, about 2.8 to about 3.4, about 2.8 to about 3.2, about 2.8 to about 3, about 3 to about 3.8, about 3 to about 3.6, about 3 to about 3.4, about 3 to about 3.2, about 3.2 to about 3.8, about 3.2 to about 3.6, about 3.2 to about 3.4, about 3.4 to about 3.8, about 3.4 to about 3.6, or about 3.6 to about 3.8. In certain embodiments, the total deuterium abundance in the compound of Formula (I) is about 1.3 to about 4. In certain embodiments, the total deuterium abundance in the compound of Formula (I) is about 1.8 to about 3.

[0106] In certain embodiments, the deuterium-enriched (R)-pioglitazone described herein has an enantiomeric excess of about 70% to about 100%, about 75% to about 100%, about 80% to about 100%, about 85% to about 100%, about 90% to about 100%, about 95% to about 100%, about 70% to about 95%, about 70% to about 90%, about 70% to about 85%, about 70% to about 80%, about 70% to about 75%, about 75% to about 95%, about 75% to about 90%, about 75% to about 85%, about 75% to about 80%, about 80% to about 95%, about 80% to about 90%, about 80% to about 85%, about 85% to about 95%, about 85% to about 90%, or about 90% to about 95%.

[0107] In certain embodiments, the deuterium-enriched (R)-pioglitazone described herein has an enantiomeric excess of at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%.

[0108] In certain embodiments, the deuterium-enriched (R)-pioglitazone described herein has an enantiomeric excess of about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%. In certain embodiments, the deuterium-enriched (R)-pioglitazone described herein is enantiomerically pure.

[0109] In various embodiments, provided herein is deuterium-enriched (R)-pioglitazone in free base form.

[0110] In various embodiments, provided herein is a pharmaceutically acceptable salt of deuterium-enriched (R)-pioglitazone. In certain embodiments, the pharmaceutically acceptable salt of deuterium-enriched (R)-pioglitazone is a deuterated hydrochloride salt. In certain embodiments, the pharmaceutically acceptable salt of deuterium-enriched (R)-pioglitazone is a hydrochloride salt.

[0111] Deuterated hydrochloride salt of deuterium-enriched (R)-pioglitazone (DCl)

[0112] In one aspect, the present application provides a deuterated hydrochloride salt of a deuterium-enriched compound of Formula (I):

[0113]

[0114] wherein R 1 is H or D, provided that the total deuterium abundance in the compound of Formula (I) is from about 1.3 to about 4.

[0115] In certain embodiments, the deuterated hydrochloride salt is a crystalline deuterated hydrochloride salt. In certain embodiments, the crystalline deuterated hydrochloride salt is an anhydrous crystalline deuterated hydrochloride salt.

[0116] In another aspect, the present application provides a crystalline deuterated hydrochloride salt of a deuterium-enriched compound of Formula (I)

[0117]

[0118] wherein R 1H or D, provided that the total deuterium abundance in the compound of Formula (I) is from about 1.3 to about 4, and

[0119] wherein the crystalline deuterated hydrochloride salt is characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 15.8° ± 0.2°, 22.8° ± 0.2°, and 26.0° ± 0.2°.

[0120] In certain embodiments, the crystalline deuterated hydrochloride salt is characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 20.0° ± 0.2°, 20.8° ± 0.2°, and 22.8° ± 0.2°. In certain embodiments, the crystalline deuterated hydrochloride salt is characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 15.8° ± 0.2°, 20.0° ± 0.2°, 20.8° ± 0.2°, 22.8° ± 0.2°, and 26.0° ± 0.2°. In certain embodiments, the crystalline deuterated hydrochloride salt is characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 8.6° ± 0.2°, 8.8° ± 0.2°, 12.8° ± 0.2°, 12.9° ± 0.2°, 15.8° ± 0.2°, 18.8° ± 0.2°, 18.9° ± 0.2°, 19.7° ± 0.2°, 20.0° ± 0.2°, 20.8° ± 0.2°, 22.8° ± 0.2°, 26.0° ± 0.2°, and 31.3° ± 0.2°.

[0121] In certain embodiments, the crystalline deuterated hydrochloride salt is characterized by an X-ray powder diffraction pattern expressed in terms of diffraction angles 2Q and optional relative intensities (expressed as a percentage relative to the most intense peak) as shown in Table 1.

[0122] Table 1 - X-ray powder diffraction data (XRPD) for crystalline DCl salt

[0123]

[0124]

[0125] In certain embodiments, the crystalline deuterated hydrochloride salt is characterized by an X-ray powder diffraction pattern substantially identical to that shown in FIG. 2. Figure 1A

[0126] In certain embodiments, the crystalline deuterated hydrochloride salt exists in the monoclinic crystal system and has a P21 / c space group. In certain embodiments, the crystalline deuterated hydrochloride salt is characterized by crystallographic unit cell parameters as listed in Table 2.

[0127] Table 2 - Unit cell parameters for crystalline Form of the compound of Formula (V)

[0128] In certain embodiments, the crystalline deuterated hydrochloride salt is characterized by an X-ray powder diffraction pattern substantially identical to that shown in FIG. 2.

[0129]

[0130] The crystalline deuterated hydrochloride salt can also be characterized by the onset temperature of the melting point. In certain embodiments, the crystalline deuterated hydrochloride salt has an onset melting point of about 190 °C to about 200 °C as determined by differential scanning calorimetry. In certain embodiments, the crystalline deuterated hydrochloride salt has an onset melting point of about 191 °C as determined by differential scanning calorimetry. In certain embodiments, the crystalline deuterated hydrochloride salt exhibits a melting endotherm having a peak at about 200 °C to about 210 °C. In certain embodiments, the crystalline deuterated hydrochloride salt exhibits a melting endotherm having a peak at about 204 °C. In certain embodiments, the crystalline deuterated hydrochloride salt has a differential scanning calorimetry profile substantially the same as that shown in FIG. 2. Figure 3

[0131] In certain embodiments, the chemical purity of the crystalline deuterated hydrochloride salt is about 70% to about 100%, about 75% to about 100%, about 80% to about 100%, about 85% to about 100%, about 90% to about 100%, about 95% to about 100%, about 70% to about 95%, about 70% to about 90%, about 70% to about 85%, about 70% to about 80%, about 70% to about 75%, about 75% to about 95%, about 75% to about 90%, about 75% to about 85%, about 75% to about 80%, about 80% to about 95%, about 80% to about 90%, about 80% to about 85%, about 85% to about 95%, about 85% to about 90%, or about 90% to about 95%.

[0132] In certain embodiments, the chemical purity of the crystalline deuterated hydrochloride salt is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9%.

[0133] ​In certain embodiments, the crystalline deuterated hydrochloride salt has a chemical purity of about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9%, or about 100%.

[0134] In various embodiments, the present application provides a pharmaceutical material comprising crystalline deuterated hydrochloride salt particles of deuterium-enriched compound of Formula (I),

[0135]

[0136] wherein R 1 is H or D, provided that the total deuterium abundance in the compound of Formula (I) is about 1.3 to about 4, and

[0137] wherein the particles in the composition have a crystal shape selected from the group consisting of hexagonal, rod, and combinations thereof.

[0138] In some embodiments, the particle size distribution defined by d(0.1) is approximately 10 μm to 200 μm, approximately 20 μm to 200 μm, approximately 40 μm to 200 μm, approximately 60 μm to 200 μm, approximately 80 μm to 200 μm, approximately 100 μm to 200 μm, approximately 120 μm to 200 μm, approximately 140 μm to 200 μm, approximately 160 μm to 200 μm, approximately 180 μm to 200 μm, approximately 10 μm to 180 μm, and approximately 10 μm to 160 μm. μm, approximately 10μm to 140μm, approximately 10μm to 120μm, approximately 10μm to 100μm, approximately 10μm to 80μm, approximately 10μm to 60μm, approximately 10μm to 40μm, approximately 10μm to 20μm, approximately 20μm to 180μm, approximately 20μm to 160μm, approximately 20μm to 140μm, approximately 20μm to 120μm, approximately 20μm to 100μm, approximately 20μm to 80μm, approximately 20μm to 60μm, approximately 20μm to 40μm μm, approximately 40μm to 180μm, approximately 40μm to 160μm, approximately 40μm to 140μm, approximately 40μm to 120μm, approximately 40μm to 100μm, approximately 40μm to 80μm, approximately 40μm to 60μm, approximately 60μm to 180μm, approximately 60μm to 160μm, approximately 60μm to 140μm, approximately 60μm to 120μm, approximately 60μm to 100μm, approximately 60μm to 80μm, approximately 80μm to 180μm, approximately 80μm Up to 160 μm, about 80 μm to 140 μm, about 80 μm to 120 μm, about 80 μm to 100 μm, about 100 μm to 180 μm, about 100 μm to 160 μm, about 100 μm to 140 μm, about 100 μm to 120 μm, about 120 μm to 180 μm, about 120 μm to 160 μm, about 120 μm to 140 μm, about 140 μm to 180 μm, about 140 μm to 160 μm, or about 160 μm to 180 μm. In some embodiments, the particle size distribution defined by d(0.1) is about 10 μm to about 200 μm.

[0139] In certain embodiments, the particle size distribution of the particles as defined by d(0.5) is about 10 pm to about 400 pm, about 50 pm to about 400 pm, about 75 pm to about 400 pm, about 100 pm to about 400 pm, about 125 pm to about 400 pm, about 150 pm to about 400 pm, about 175 pm to about 400 pm, about 200 pm to about 400 pm, about 225 pm to about 400 pm, about 250 pm to about 400 pm, about 275 pm to about 400 pm, about 300 pm to about 400 pm, about 325 pm to about 400 pm, about 350 pm to about 400 pm, about 375 pm to about 400 pm, about 10 pm to about 375 pm, about 10 pm to about 350 pm, about 10 pm to about 325 pm, about 10 pm to about 300 pm, about 10 pm to about 275 pm, about 10 pm to about 250 pm, about 10 pm to about 225 pm, about 10 pm to about 200 pm, about 50 pm to about 375 pm, about 50 pm to about 350 pm, about 50 pm to about 325 pm, about 50 pm to about 300 pm, about 50 pm to about 275 pm, about 50 pm to about 250 pm, about 50 pm to about 225 pm, about 50 pm to about 200 pm, about 50 pm to about 175 pm, about 50 pm to about 150 pm, about 50 pm to about 125 pm, about 50 pm to about 100 pm, about 50 pm to about 75 pm, about 75 pm to about 375 pm, about 75 pm to about 350 pm, about 75 pm to about 325 pm, about 75 pm to about 300 pm, about 75 pm to about 275 pm, about 75 pm to about 250 pm, about 75 pm to about 225 pm, about 75 pm to about 375 pm, about 75 pm to about 350 pm, about 75 pm to about 325 pm, about 75 pm to about 300 pm, about 75 pm to about 275 pm, about 75 pm to about 250 pm, about 75 pm to about 225 pm, about 75 pm to about 200 pm, about 75 pm to about 175 pm, about 75 pm to about 150 pm, about 75 pm to about 125 pm, about 75 pm to about 100 pm, about 100 pm to about 375 pm, about 100 pm to about 350 pm, about 100 pm to about 325 pm, about 100 pm to about 300 pm, about 100 pm to about 275 pm, about 100 pm to about 250 pm, about 100 pm to about 225 pm, about 100 pm to about 200 pm, about 100 pm to about 175 pm, about 100 pm to about 150 pm, about 100 pm to about 125 pm, about 125 pm to about 375 pm, about 125 pm to about 350 pm, about 125 pm to about 325 pm, about 125 pm to about 300 pm, about 125 pm to about 275 pm, about 125 pm to about 250 pm, about 125 pm to about 225 pm, about 125 pm to about 200 pm, about 125 pm to about 175 pm, about 125 pm to about 150 pm, about 150 pm to about 375 pm, about 150 pm to about 350 pm, about 150 pm to about 325 pm, about 150 pm to about 300 pm, about 150 pm to about 275 pm, about 150 pm to about 250 pm, about 150 pm to about 225 pm, about 150 pm to about 200 pm, about 150 pm to about 175 pm, about 175 pm to about 375 pm, about 175 pm to about 350 pm, about 175 pm to about 325 pm, about 175 pm to about 300 pm, about 175 pm to about 275 pm, about 175 pm to about 250 pm, about 175 pm to about 225 pm, about 175 pm to about 200 pm, about 200 pm to about 375 pm, about 200 pm to about 350 pm, about 200 pm to about 325 pm, about 200 pm to about 300 pm, about 200 pm to about 275 pm, about 200 pm to about 250 pm, about 200 pm to about 225 pm, about 225 pm to about 375 pm, about 225 pm to about 350 pm, about 225 pm to about 325 pm, about 225 pm to about 300 pm, about 225 pm to about 275 pm, about 225 pm to about 250 pm, about 250 pm to about 375 pm, about 250 pm to about 350 pm, about 250 pm to about 325 pm, about 250 pm to about 300 pm, about 250 pm to about 275 pm, about 275 pm to about 375 pm, about 275 pm to about 350 pm, about 275 pm to about 325 pm, about 275 pm to about 300 pm, about 300 pm to about 375 pm, about 300 pm to about 350 pm, about 300 pm to about 325 pm, about 325 pm to about 375 pm, about 325 pm to about 350 pm, about 350 pm to about 375 pm, or about 10 pm to about 400 pm.about 150 μm to about 375 μm, about 150 μm to about 350 μm, about 150 μm to about 325 μm, about 150 μm to about 300 μm, about 150 μm to about 275 μm, about 150 μm to about 250 μm, about 150 μm to about 225 μm, about 150 μm to about 200 μm, about 150 μm to about 175 μm, about 175 μm to about 375 μm, about 175 μm to about 350 μm, about 175 μm to about 325 μm, about 175 μm to about 300 μm, about 175 μm to about 275 μm, about 175 μm to about 250 μm, about 175 μm to about 225 μm, about 175 μm to about 200 μm, about 200 μm to about 375 μm, about 200 μm to about 350 μm, about 200 μm to about 325 μm, about 200 μm to about 300 μm, about 200 μm to about 275 μm, about 200 μm to about 250 μm, about 200 μm to about 225 μm, about 225 μm to about 375 μm, about 225 μm to about 350 μm, about 225 μm to about 325 μm, about 225 μm to about 300 μm, about 225 μm to about 275 μm, about 225 μm to about 250 μm, about 250 μm to about 375 μm, about 250 μm to about 350 μm, about 250 μm to about 325 μm, about 250 μm to about 300 μm, about 250 μm to about 275 μm, about 275 μm to about 375 μm, about 275 μm to about 350 μm, about 275 μm to about 325 μm, about 275 μm to about 300 μm, about 300 μm to about 375 μm, about 300 μm to about 350 μm, about 300 μm to about 325 μm, about 325 μm to about 375 μm, about 325 μm to about 350 μm, or about 350 μm to about 375 μm. In certain embodiments, the particle size distribution of the particles as defined by d(0.5) is about 10 μm to about 400 μm.

[0140] In certain embodiments, the particle size distribution of the particles as defined by d(0.9) is about 10 pm to about 800 pm, about 50 pm to about 800 pm, about 100 pm to about 800 pm, about 150 pm to about 800 pm, about 200 pm to about 800 pm, about 250 pm to about 800 pm, about 300 pm to about 800 pm, about 350 pm to about 800 pm, about 400 pm to about 800 pm, about 450 pm to about 800 pm, about 500 pm to about 800 pm, about 550 pm to about 800 pm, about 600 pm to about 800 pm, about 650 pm to about 800 pm, about 700 pm to about 800 pm, about 750 pm to about 800 pm, about 150 pm to about 750 pm, about 150 pm to about 700 pm, about 150 pm to about 650 pm, about 150 pm to about 600 pm, about 150 pm to about 550 pm, about 150 pm to about 500 pm, about 150 pm to about 450 pm, about 150 pm to about 400 pm, about 150 pm to about 350 pm, about 150 pm to about 300 pm, about 150 pm to about 250 pm, about 150 pm to about 200 pm, about 200 pm to about 750 pm, about 200 pm to about 700 pm, about 200 pm to about 650 pm, about 200 pm to about 600 pm, about 200 pm to about 550 pm, about 200 pm to about 500 pm, about 200 pm to about 450 pm, about 200 pm to about 400 pm, about 200 pm to about 350 pm, about 200 pm to about 300 pm, about 200 pm to about 250 pm, about 250 pm to about 750 pm, about 250 pm to about 700 pm, about 250 pm to about 650 pm, about 250 pm to about 600 pm, about 250 pm to about 550 pm, about 250 pm to about 500 pm, about 250 pm to about 450 pm, about 250 pm to about 400 pm, about 250 pm to about 350 pm, about 250 pm to about 300 pm, about 300 pm to about 750 pm, about 300 pm to about 700 pm, about 300 pm to about 650 pm, about 300 pm to about 600 pm, about 300 pm to about 550 pm, about 300 pm to about 500 pm, about 300 pm to about 450 pm, about 300 pm to about 400 pm, about 300 pm to about 350 pm, about 350 pm to about 750 pm, about 350 pm to about 700 pm, about 350 pm to about 650 pm, about 350 pm to about 600 pm, about 350 pm to about 550 pm, about 350 pm to about 500 pm, about 350 pm to about 450 pm, about 350 pm to about 400 pm, about 400 pm to about 750 pm, about 400 pm to about 700 pm, about 400 pm to about 650 pm, about 400 pm to about 600 pm, about 400 pm to about 550 pm, about 400 pm to about 500 pm, about 400 pm to about 450 pm, about 450 pm to about 750 pm, about 450 pm to about 700 pm, about 450 pm to about 650 pm, about 450 pm to about 600 pm, about 450 pm to about 550 pm, about 450 pm to about 500 pm, about 500 pm to about 750 pm, about 500 pm to about 700 pm, about 500 pm to about 650 pm, about 500 pm to about 600 pm, about 500 pm to about 550 pm, about 550 pm to about 750 pm, about 550 pm to about 700 pm, about 550 pm to about 650 pm, about 550 pm to about 600 pm, about 600 pm to about 750 pm, about 600 pm to about 700 pm, about 600 pm to about 650 pm, about 650 pm to about 750 pm, about 650 pm to about 700 pm, or about 650 pm to about 600 pm.about 400 μm to about 600 μm, about 400 μm to about 550 μm, about 400 μm to about 500 μm, about 400 μm to about 450 μm, about 450 μm to about 750 μm, about 450 μm to about 700 μm, about 450 μm to about 650 μm, about 450 μm to about 600 μm, about 450 μm to about 550 μm, about 450 μm to about 500 μm, about 500 μm to about 750 μm, about 500 μm to about 700 μm, about 500 μm to about 650 μm, about 500 μm to about 600 μm, about 500 μm to about 550 μm, about 550 μm to about 750 μm, about 550 μm to about 700 μm, about 550 μm to about 650 μm, about 550 μm to about 600 μm, about 600 μm to about 750 μm, about 600 μm to about 700 μm, about 600 μm to about 650 μm, about 650 μm to about 750 μm, about 650 μm to about 700 μm, or about 700 μm to about 750 μm. In certain embodiments, the particle size distribution of the particles, as defined by d(0.9), is about 10 μm to about 800 μm.

[0141] In various embodiments, the present application provides a pharmaceutical material comprising particles of a crystalline deuterated hydrochloride salt of a deuterium-enriched compound of Formula (I),

[0142]

[0143] wherein R 1 is H or D, provided that the total deuterium abundance in the compound of Formula (I) is about 1.3 to about 4, and

[0144] wherein the particle size distribution of the particles, as defined by d(0.9), is about 10 μm to about 800 μm, preferably less than 500 μm.

[0145] Deuterium-enriched pioglitazone hydrochloride (HCl)

[0146] In one aspect, the present application provides a crystalline hydrochloride salt of a deuterium-enriched compound of Formula (I-A):

[0147]

[0148] In certain embodiments, the crystalline hydrochloride salt is characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Θ): 15.8° ± 0.2°, 22.8° ± 0.2°, and 26.0° ± 0.2°. In certain embodiments, the crystalline hydrochloride salt is characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Θ): 20.0° ± 0.2°, 20.8° ± 0.2°, and 22.8° ± 0.2°.

[0149] In various embodiments, the present application provides a crystalline hydrochloride salt of the compound of Formula (I-A)

[0150]

[0151] wherein the crystalline hydrochloride salt is characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 15.8° ± 0.2°, 22.8° ± 0.2°, and 26.0° ± 0.2°.

[0152] In certain embodiments, the crystalline hydrochloride salt is characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 15.8° ± 0.2°, 20.0° ± 0.2°, 20.8° ± 0.2°, 22.8° ± 0.2°, and 26.0° ± 0.2°. In certain embodiments, the crystalline hydrochloride salt is characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 8.6° ± 0.2°, 8.8° ± 0.2°, 12.8° ± 0.2°, 12.9° ± 0.2°, 15.9° ± 0.2°, 18.8° ± 0.2°, 19.7° ± 0.2°, 20.0° ± 0.2°, 20.8° ± 0.2°, 22.8° ± 0.2°, 26.0° ± 0.2°, 28.1° ± 0.2°, and 31.3° ± 0.2°.

[0153] In certain embodiments, the crystalline hydrochloride salt is characterized by an X-ray powder diffraction pattern expressed in terms of diffraction angles 2Q and optional relative intensities (expressed in percent relative to the most intense peak) as shown in Table 3.

[0154] Table 3 - X-ray powder diffraction data for the crystalline hydrochloride salt

[0155]

[0156]

[0157] In certain embodiments, the crystalline hydrochloride salt is characterized by an X-ray powder diffraction pattern substantially identical to that shown in Figure 6 FIG. 2.

[0158] The crystalline hydrochloride salt can also be characterized according to the onset temperature of the melting point. In certain embodiments, the crystalline hydrochloride salt has an onset melting point of about 190 °C to about 210 °C as determined by differential scanning calorimetry. In certain embodiments, the crystalline hydrochloride salt has an onset melting point of about 190 °C as determined by differential scanning calorimetry. In certain embodiments, the crystalline deuterated hydrochloride salt exhibits a melting endotherm having a peak at about 195 °C to about 205 °C. In certain embodiments, the crystalline deuterated hydrochloride salt exhibits a melting endotherm having a peak at about 200 °C. In certain embodiments, the crystalline hydrochloride salt has an onset melting point of about 190 °C to about 210 °C as determined by differential scanning calorimetry and a melting endotherm having a peak at about 195 °C to about 205 °C as determined by differential scanning calorimetry. Figure 8substantially identical differential scanning calorimetry curves.

[0159] In certain embodiments, the crystalline hydrochloride salt is an anhydrous crystalline hydrochloride salt.

[0160] In certain embodiments, the crystalline hydrochloride salt has a chemical purity of about 70% to about 100%, about 75% to about 100%, about 80% to about 100%, about 85% to about 100%, about 90% to about 100%, about 95% to about 100%, about 70% to about 95%, about 70% to about 90%, about 70% to about 85%, about 70% to about 80%, about 70% to about 75%, about 75% to about 95%, about 75% to about 90%, about 75% to about 85%, about 75% to about 80%, about 80% to about 95%, about 80% to about 90%, about 80% to about 85%, about 85% to about 95%, about 85% to about 90%, or about 90% to about 95%.

[0161] In certain embodiments, the crystalline hydrochloride salt has a chemical purity of at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9%.

[0162] In certain embodiments, the crystalline hydrochloride salt has a chemical purity of about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9%, or about 100%.

[0163] In various embodiments, the present application provides a pharmaceutical material comprising particles of a crystalline hydrochloride salt of the compound of formula (I-A)

[0164]

[0165] wherein the particles in the composition have acicular crystalline shape.

[0166] In certain embodiments, the particle size distribution of the particles as defined by d(0.1) is about 10 μm to 200 μm, about 20 μm to 200 μm, about 40 μm to 200 μm, about 60 μm to 200 μm, about 80 μm to 200 μm, about 100 μm to 200 μm, about 120 μm to 200 μm, about 140 μm to 200 μm, about 160 μm to 200 μm, about 180 μm to 200 μm, about 10 μm to 180 μm, about 10 μm to 160 μm, about 10 μm to 140 μm, about 10 μm to 120 μm, about 10 μm to 100 μm, about 10 μm to 80 μm, about 10 μm to 60 μm, about 10 μm to 40 μm, about 10 μm to 20 μm, about 20 μm to 180 μm, about 20 μm to 160 μm, about 20 μm to 140 μm, about 20 μm to 120 μm, about 20 μm to 100 μm, about 20 μm to 80 μm, about 20 μm to 60 μm, about 20 μm to 40 μm, about 40 μm to 180 μm, about 40 μm to 160 μm, about 40 μm to 140 μm, about 40 μm to 120 μm, about 40 μm to 100 μm, about 40 μm to 80 μm, about 40 μm to 60 μm, about 60 μm to 180 μm, about 60 μm to 160 μm, about 60 μm to 140 μm, about 60 μm to 120 μm, about 60 μm to 100 μm, about 60 μm to 80 μm, about 80 μm to 180 μm, about 80 μm to 160 μm, about 80 μm to 140 μm, about 80 μm to 120 μm, about 80 μm to 100 μm, about 100 μm to 180 μm, about 100 μm to 160 μm, about 100 μm to 140 μm, about 100 μm to 120 μm, about 120 μm to 180 μm, about 120 μm to 160 μm, about 120 μm to 140 μm, about 140 μm to 180 μm, about 140 μm to 160 μm, or about 160 μm to 180 μm. In certain embodiments, the particle size distribution of the particles as defined by d(0.1) is about 10 μm to about 200 μm.

[0167] In certain embodiments, the particle size distribution of the particles as defined by d(0.5) is about 10 pm to about 400 pm, about 50 pm to about 400 pm, about 75 pm to about 400 pm, about 100 pm to about 400 pm, about 125 pm to about 400 pm, about 150 pm to about 400 pm, about 175 pm to about 400 pm, about 200 pm to about 400 pm, about 225 pm to about 400 pm, about 250 pm to about 400 pm, about 275 pm to about 400 pm, about 300 pm to about 400 pm, about 325 pm to about 400 pm, about 350 pm to about 400 pm, about 375 pm to about 400 pm, about 10 pm to about 375 pm, about 10 pm to about 350 pm, about 10 pm to about 325 pm, about 10 pm to about 300 pm, about 10 pm to about 275 pm, about 10 pm to about 250 pm, about 10 pm to about 225 pm, about 10 pm to about 200 pm, about 50 pm to about 375 pm, about 50 pm to about 350 pm, about 50 pm to about 325 pm, about 50 pm to about 300 pm, about 50 pm to about 275 pm, about 50 pm to about 250 pm, about 50 pm to about 225 pm, about 50 pm to about 200 pm, about 50 pm to about 175 pm, about 50 pm to about 150 pm, about 50 pm to about 125 pm, about 50 pm to about 100 pm, about 50 pm to about 75 pm, about 75 pm to about 375 pm, about 75 pm to about 350 pm, about 75 pm to about 325 pm, about 75 pm to about 300 pm, about 75 pm to about 275 pm, about 75 pm to about 250 pm, about 75 pm to about 225 pm, about 75 pm to about 375 pm, about 75 pm to about 350 pm, about 75 pm to about 325 pm, about 75 pm to about 300 pm, about 75 pm to about 275 pm, about 75 pm to about 250 pm, about 75 pm to about 225 pm, about 75 pm to about 200 pm, about 75 pm to about 175 pm, about 75 pm to about 150 pm, about 75 pm to about 125 pm, about 75 pm to about 100 pm, about 100 pm to about 375 pm, about 100 pm to about 350 pm, about 100 pm to about 325 pm, about 100 pm to about 300 pm, about 100 pm to about 275 pm, about 100 pm to about 250 pm, about 100 pm to about 225 pm, about 100 pm to about 200 pm, about 100 pm to about 175 pm, about 100 pm to about 150 pm, about 100 pm to about 125 pm, about 125 pm to about 375 pm, about 125 pm to about 350 pm, about 125 pm to about 325 pm, about 125 pm to about 300 pm, about 125 pm to about 275 pm, about 125 pm to about 250 pm, about 125 pm to about 225 pm, about 125 pm to about 200 pm, about 125 pm to about 175 pm, about 125 pm to about 150 pm, about 150 pm to about 375 pm, about 150 pm to about 350 pm, about 150 pm to about 325 pm, about 150 pm to about 300 pm, about 150 pm to about 275 pm, about 150 pm to about 250 pm, about 150 pm to about 225 pm, about 150 pm to about 200 pm, about 150 pm to about 175 pm, about 175 pm to about 375 pm, about 175 pm to about 350 pm, about 175 pm to about 325 pm, about 175 pm to about 300 pm, about 175 pm to about 275 pm, about 175 pm to about 250 pm, about 175 pm to about 225 pm, about 175 pm to about 200 pm, about 200 pm to about 375 pm, about 200 pm to about 350 pm, about 200 pm to about 325 pm, about 200 pm to about 300 pm, about 200 pm to about 275 pm, about 200 pm to about 250 pm, about 200 pm to about 225 pm, about 225 pm to about 375 pm, about 225 pm to about 350 pm, about 225 pm to about 325 pm, about 225 pm to about 300 pm, about 225 pm to about 275 pm, about 225 pm to about 250 pm, about 250 pm to about 375 pm, about 250 pm to about 350 pm, about 250 pm to about 325 pm, about 250 pm to about 300 pm, about 250 pm to about 275 pm, about 275 pm to about 375 pm, about 275 pm to about 350 pm, about 275 pm to about 325 pm, about 275 pm to about 300 pm, about 300 pm to about 375 pm, about 300 pm to about 350 pm, about 300 pm to about 325 pm, about 325 pm to about 375 pm, about 325 pm to about 350 pm, about 350 pm to about 375 pm, or about 10 pm to about 400 pm.about 150 μm to about 375 μm, about 150 μm to about 350 μm, about 150 μm to about 325 μm, about 150 μm to about 300 μm, about 150 μm to about 275 μm, about 150 μm to about 250 μm, about 150 μm to about 225 μm, about 150 μm to about 200 μm, about 150 μm to about 175 μm, about 175 μm to about 375 μm, about 175 μm to about 350 μm, about 175 μm to about 325 μm, about 175 μm to about 300 μm, about 175 μm to about 275 μm, about 175 μm to about 250 μm, about 175 μm to about 225 μm, about 175 μm to about 200 μm, about 200 μm to about 375 μm, about 200 μm to about 350 μm, about 200 μm to about 325 μm, about 200 μm to about 300 μm, about 200 μm to about 275 μm, about 200 μm to about 250 μm, about 200 μm to about 225 μm, about 225 μm to about 375 μm, about 225 μm to about 350 μm, about 225 μm to about 325 μm, about 225 μm to about 300 μm, about 225 μm to about 275 μm, about 225 μm to about 250 μm, about 250 μm to about 375 μm, about 250 μm to about 350 μm, about 250 μm to about 325 μm, about 250 μm to about 300 μm, about 250 μm to about 275 μm, about 275 μm to about 375 μm, about 275 μm to about 350 μm, about 275 μm to about 325 μm, about 275 μm to about 300 μm, about 300 μm to about 375 μm, about 300 μm to about 350 μm, about 300 μm to about 325 μm, about 325 μm to about 375 μm, about 325 μm to about 350 μm, or about 350 μm to about 375 μm. In certain embodiments, the particle size distribution of the particles as defined by d(0.5) is about 10 μm to about 400 μm.

[0168] In certain embodiments, the particle size distribution of the particles as defined by d(0.9) is about 10 pm to about 800 pm, about 50 pm to about 800 pm, about 100 pm to about 800 pm, about 150 pm to about 800 pm, about 200 pm to about 800 pm, about 250 pm to about 800 pm, about 300 pm to about 800 pm, about 350 pm to about 800 pm, about 400 pm to about 800 pm, about 450 pm to about 800 pm, about 500 pm to about 800 pm, about 550 pm to about 800 pm, about 600 pm to about 800 pm, about 650 pm to about 800 pm, about 700 pm to about 800 pm, about 750 pm to about 800 pm, about 150 pm to about 750 pm, about 150 pm to about 700 pm, about 150 pm to about 650 pm, about 150 pm to about 600 pm, about 150 pm to about 550 pm, about 150 pm to about 500 pm, about 150 pm to about 450 pm, about 150 pm to about 400 pm, about 150 pm to about 350 pm, about 150 pm to about 300 pm, about 150 pm to about 250 pm, about 150 pm to about 200 pm, about 200 pm to about 750 pm, about 200 pm to about 700 pm, about 200 pm to about 650 pm, about 200 pm to about 600 pm, about 200 pm to about 550 pm, about 200 pm to about 500 pm, about 200 pm to about 450 pm, about 200 pm to about 400 pm, about 200 pm to about 350 pm, about 200 pm to about 300 pm, about 200 pm to about 250 pm, about 250 pm to about 750 pm, about 250 pm to about 700 pm, about 250 pm to about 650 pm, about 250 pm to about 600 pm, about 250 pm to about 550 pm, about 250 pm to about 500 pm, about 250 pm to about 450 pm, about 250 pm to about 400 pm, about 250 pm to about 350 pm, about 250 pm to about 300 pm, about 300 pm to about 750 pm, about 300 pm to about 700 pm, about 300 pm to about 650 pm, about 300 pm to about 600 pm, about 300 pm to about 550 pm, about 300 pm to about 500 pm, about 300 pm to about 450 pm, about 300 pm to about 400 pm, about 300 pm to about 350 pm, about 350 pm to about 750 pm, about 350 pm to about 700 pm, about 350 pm to about 650 pm, about 350 pm to about 600 pm, about 350 pm to about 550 pm, about 350 pm to about 500 pm, about 350 pm to about 450 pm, about 350 pm to about 400 pm, about 400 pm to about 750 pm, about 400 pm to about 700 pm, about 400 pm to about 650 pm, about 400 pm to about 600 pm, about 400 pm to about 550 pm, about 400 pm to about 500 pm, about 400 pm to about 450 pm, about 450 pm to about 750 pm, about 450 pm to about 700 pm, about 450 pm to about 650 pm, about 450 pm to about 600 pm, about 450 pm to about 550 pm, about 450 pm to about 500 pm, about 500 pm to about 750 pm, about 500 pm to about 700 pm, about 500 pm to about 650 pm, about 500 pm to about 600 pm, about 500 pm to about 550 pm, about 550 pm to about 750 pm, about 550 pm to about 700 pm, about 550 pm to about 650 pm, about 550 pm to about 600 pm, about 600 pm to about 750 pm, about 600 pm to about 700 pm, about 600 pm to about 650 pm, about 650 pm to about 750 pm, about 650 pm to about 700 pm, or about 650 pm to about 600 pm.about 400 μm to about 600 μm, about 400 μm to about 550 μm, about 400 μm to about 500 μm, about 400 μm to about 450 μm, about 450 μm to about 750 μm, about 450 μm to about 700 μm, about 450 μm to about 650 μm, about 450 μm to about 600 μm, about 450 μm to about 550 μm, about 450 μm to about 500 μm, about 500 μm to about 750 μm, about 500 μm to about 700 μm, about 500 μm to about 650 μm, about 500 μm to about 600 μm, about 500 μm to about 550 μm, about 550 μm to about 750 μm, about 550 μm to about 700 μm, about 550 μm to about 650 μm, about 550 μm to about 600 μm, about 600 μm to about 750 μm, about 600 μm to about 700 μm, about 600 μm to about 650 μm, about 650 μm to about 750 μm, about 650 μm to about 700 μm, or about 700 μm to about 750 μm. In certain embodiments, the particle size distribution of the particles, as defined by d(0.9), is about 10 μm to about 800 μm, preferably less than 500 μm.

[0169] In various embodiments, the present application provides a pharmaceutical material comprising particles of crystalline hydrochloride salt of the compound of formula (I-A)

[0170]

[0171] wherein the particle size distribution of the particles, as defined by d(0.9), is about 10 μm to about 800 μm, preferably less than 500 μm.

[0172] In certain embodiments, the particles in the composition have acicular crystalline shape.

[0173] In certain embodiments, the total deuterium abundance in the compound of Formula (I-A) is about 0.3 to about 2, about 0.4 to about 2, about 0.6 to about 2, about 0.8 to about 2, about 1 to about 2, about 1.2 to about 2, about 1.4 to about 2, about 1.6 to about 2, about 1.8 to about 2, about 0.3 to about 1.8, about 0.3 to about 1.6, about 0.3 to about 1.4, about 0.3 to about 1.2, about 0.3 to about 1, about 0.3 to about 0.8, about 0.3 to about 0.6, about 0.3 to about 0.4, about 0.4 to about 1.8, about 0.4 to about 1.6, about 0.4 to about 1.4, about 0.4 to about 1.2, about 0.4 to about 1, about 0.4 to about 0.8, about 0.4 to about 0.6, about 0.6 to about 1.8, about 0.6 to about 1.6, about 0.6 to about 1.4, about 0.6 to about 1.2, about 0.6 to about 1, about 0.6 to about 0.8, about 0.8 to about 1.8, about 0.8 to about 1.6, about 0.8 to about 1.4, about 0.8 to about 1.2, about 0.8 to about 1.0, about 1 to about 1.8, about 1 to about 1.6, about 1 to about 1.4, about 1 to about 1.2, about 1.2 to about 1.8, about 1.2 to about 1.6, about 1.2 to about 1.4, about 1.4 to about 1.8, about 1.4 to about 1.6, or about 1.6 to about 1.8.

[0174] Pharmaceutical compositions

[0175] In one aspect, the present application provides a pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A as described herein, including any pharmaceutical material, and a pharmaceutically acceptable excipient, for use in the treatment of a condition, disease, or disorder described herein (e.g., a neurological disorder, cancer, a respiratory disease, a metabolic disorder, hepatitis, a cardiovascular disease, an inflammation or immune-mediated disorder, a skin disease, a wound, a skin defect, etc.). In certain embodiments, the pharmaceutically acceptable salt form of the compound of Formula I or Formula I-A is a deuterated hydrochloride salt. In certain embodiments, the pharmaceutically acceptable salt form of the compound of Formula I or Formula I-A is a hydrochloride salt.

[0176] In various embodiments, the pharmaceutical composition comprises a deuterated hydrochloride salt of a compound of Formula I and a pharmaceutically acceptable excipient. In certain embodiments, the deuterated hydrochloride salt of a compound of Formula I is a crystalline deuterated hydrochloride salt.

[0177] In various embodiments, the pharmaceutical composition comprises a crystalline deuterated hydrochloride salt of a compound of Formula I and a pharmaceutically acceptable excipient.

[0178] In various embodiments, the pharmaceutical composition comprises a hydrochloride salt of a compound of Formula I-A and a pharmaceutically acceptable excipient. In certain embodiments, the hydrochloride salt of a compound of Formula I-A is a crystalline hydrochloride salt.

[0179] In various embodiments, the pharmaceutical composition comprises particles of a crystalline hydrochloride salt of a deuterium-enriched compound of Formula (I-A) and a pharmaceutically acceptable excipient.

[0180] In various embodiments, the present application provides a pharmaceutical composition comprising (i) particles of a crystalline deuterated hydrochloride salt of a deuterium-enriched compound of Formula (I),

[0181] and,

[0182] (ii) a pharmaceutically acceptable excipient,

[0183] wherein R 1 is H or D, provided that the deuterium abundance in R 1 is at least 80%, and wherein the particles in the composition have a crystal shape selected from the group consisting of hexagonal, rod, and combinations thereof.

[0184] In various embodiments, the present application provides a pharmaceutical composition comprising

[0185] (i) particles of a crystalline deuterated hydrochloride salt of a deuterium-enriched compound of Formula (I)

[0186] and

[0187] (ii) a pharmaceutically acceptable excipient,

[0188] wherein R 1 is H or D, provided that the deuterium abundance in R 1 is at least 80%, and wherein the particle size distribution of the particles, defined by d(0.9), is from about 10 pm to about 800 pm, preferably below 500 pm.

[0189] In various embodiments, the present application provides a pharmaceutical composition comprising

[0190] (i) particles of a crystalline hydrochloride salt of a compound of Formula (I-A)

[0191] and

[0192] (ii) a pharmaceutically acceptable excipient,

[0193] The particles in the pharmaceutical composition have a needle-like crystal shape.

[0194] In various embodiments, the present application provides a pharmaceutical composition comprising

[0195] (i) particles of a crystalline hydrochloride salt of a compound of Formula (I-A)

[0196] and

[0197] (ii) a pharmaceutically acceptable excipient,

[0198] The particle size distribution of the particles, ultimately defined by d(0.9), is about 10 pm to 800 pm, preferably below 500 pm.

[0199] In certain embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A. In certain embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a deuterated hydrochloride salt of a compound of Formula I. In certain embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a crystalline deuterated hydrochloride salt of a compound of Formula I. In certain embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a hydrochloride salt of a compound of Formula I-A. In certain embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a crystalline hydrochloride salt of a compound of Formula I-A.

[0200] In certain embodiments, the crystalline deuterated hydrochloride salt of a compound of Formula I is a crystalline deuterated hydrochloride salt described herein.

[0201] In certain embodiments, the crystalline hydrochloride salt of a compound of Formula I-A is a crystalline hydrochloride salt described herein.

[0202] The pharmaceutical compositions provided herein can be administered by a variety of routes, including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration. In some embodiments, the pharmaceutical compositions disclosed herein are administered orally.

[0203] The pharmaceutical compositions provided herein can also be administered chronically (“chronic administration”). Chronic administration refers to administration of a compound or a pharmaceutical composition thereof over an extended period of time, e.g., over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can continue indefinitely, e.g., for the remainder of the subject’s life. In certain embodiments, chronic administration is intended to provide a constant level of the compound in the blood, e.g., within a therapeutic window, over an extended period of time.

[0204] The pharmaceutical compositions provided herein can exist in unit dosage form to facilitate accurate administration. The term “unit dosage form” refers to physically discrete units suitable for unitary dosing to human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampules of liquid compositions or syringes, or in the case of solid compositions, pills, tablets, capsules, and the like.

[0205] While the description of pharmaceutical compositions provided herein is primarily concerned with pharmaceutical compositions that are suitable for administration to humans, the skilled artisan will understand that such compositions are typically suitable for administration to animals of all sorts. Modifications can be made in the pharmaceutical compositions described herein to account for factors such as the kind of animal, its size, its weight, and its general health or immune status. Such modifications are well known to those skilled in the art, and are generally found in the pertinent texts and references. General considerations in formulating and / or manufacturing pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21stEd., Lippincott Williams & Wilkins, 2005. st ed., Lippincott Williams & Wilkins, 2005.

[0206] Formulations

[0207] Pharmaceutical compositions can be used to prepare individual unit dosage forms. The pharmaceutical compositions and dosage forms provided herein comprise a compound provided herein, or a pharmaceutically acceptable salt, solvate, or enantiomer thereof. The pharmaceutical compositions and dosage forms can also comprise one or more excipients.

[0208] The pharmaceutical compositions and dosage forms provided herein can comprise one or more additional active ingredients. Examples of optional second or additional active ingredients are described above.

[0209] The single unit dosage forms provided herein are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus, intramuscular, or intra-arterial), topical (e.g., eye drops or other ophthalmic preparation), transdermal, or other percutaneous administration to a patient. Examples of dosage forms include, but are not limited to, tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; lozenges; troches; dispersions; suppositories; powders; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; eye drops or other ophthalmic preparations suitable for topical administration; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.

[0210] The composition, shape, and type of the dosage form will generally vary depending on its use. For example, a dosage form used for acute treatment of a disease can contain larger amounts of one or more active ingredients than a dosage form used for long-term treatment of the same disease. Similarly, a parenteral dosage form can contain smaller amounts of one or more active ingredients than an oral dosage form used for treatment of the same disease. These and other ways in which particular dosage forms will differ from one another will be apparent to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).

[0211] In another aspect, the pharmaceutical compositions and dosage forms of the present application contain one or more excipients. Suitable excipients are well known to those skilled in the art of pharmaceutical formulation, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the manner in which the dosage form will be administered to a patient. For example, an oral dosage form such as a tablet can contain excipients that are unsuitable for a parenteral dosage form. The suitability of a particular excipient can also depend on the particular active ingredient in the dosage form. For example, the decomposition of some active ingredients can be accelerated by some excipients or when exposed to water. Active ingredients that contain primary or secondary amines are particularly susceptible to such accelerated decomposition. Thus, the provided pharmaceutical compositions and dosage forms contain little or no lactose, other monosaccharides, or disaccharides. As used herein, the term "lactose-free" means that the amount of lactose present, if any, is insufficient to significantly increase the rate of degradation of the active ingredient.

[0212] Lactose-free compositions can contain excipients well known in the art, such as those listed in the U.S. Pharmacopeia (USP) 25-NF20 (2002). Typically, lactose-free compositions contain a pharmaceutically compatible and pharmaceutically acceptable amount of active ingredient, a binder / filler, and a lubricant. In another aspect, lactose-free dosage forms contain an active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0213] Anhydrous pharmaceutical compositions and dosage forms include those that are devoid of water, or comprise less than about 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05% or 0.01% water, by weight. Anhydrous pharmaceutical compositions and dosage forms can be prepared using anhydrous or low moisture ingredients (i.e., ingredients having a water content of less than about 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05% or 0.01% water, by weight) and low moisture or low humidity conditions. If substantial contact with water or moisture is expected during manufacturing, packaging, and / or storage, the pharmaceutical compositions and dosage forms including lactose and at least one active ingredient comprising a primary or secondary amine are preferably anhydrous.

[0214] Anhydrous pharmaceutical compositions and dosage forms can be prepared using anhydrous or low moisture ingredients (i.e., ingredients having a water content of less than about 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05% or 0.01% water, by weight) and low moisture or low humidity conditions. If substantial contact with water or moisture is expected during manufacturing, packaging, and / or storage, the pharmaceutical compositions and dosage forms including lactose and at least one active ingredient comprising a primary or secondary amine are preferably anhydrous.

[0215] Anhydrous pharmaceutical compositions should be prepared and stored to maintain their anhydrous nature. In another aspect, the anhydrous compositions are packaged using materials known to prevent exposure to water, such that they can be contained in appropriate formulation containers. Examples of suitable packaging include, but are not limited to, foil, plastic, dosage containers (e.g., vials), blister packs, and strip packs.

[0216] Also provided are pharmaceutical compositions and dosage forms that include one or more compounds that reduce the rate of degradation of the active ingredient. Such compounds, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants (e.g., ascorbic acid), pH buffers, or salt buffers.

[0217] As with the amount and type of excipient, the amount and specific type of active ingredient in a dosage form can vary depending on factors such as, but not limited to, the route by which it is to be administered to a patient. In another aspect, the dosage forms include an amount of a compound provided herein of about 0.10 to about 500 mg. Examples of dosages include, but are not limited to, 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.

[0218] In another aspect, the dosage form comprises the second active ingredient in an amount of 1 to about 1000 mg, about 5 to about 500 mg, about 10 to about 350 mg, or about 50 to about 200 mg. Of course, the specific amount of the second active agent will depend on the specific agent used, the disease or condition being treated or managed, the amount of the compound provided herein, and any optional additional second active agents being concurrently administered to the patient.

[0219] Pharmaceutical compositions adapted for oral administration can be presented in discrete dosage forms such as, but not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and can be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington’s Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).

[0220] Oral dosage forms provided herein are prepared according to conventional pharmaceutical dosage form techniques. The excipients can take a variety of forms depending on the desired form of the formulation for administration. For example, excipients suitable for use in liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants.

[0221] In another aspect, the present application provides oral dosage forms that are tablets or capsules, in which case solid excipients are used. In another aspect, the tablets can be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by any pharmaceutical dosage form method. Generally, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately mixing the active ingredients with the liquid carriers, finely divided solid carriers, or both, and then, if necessary in the case of a liquid carrier, shaping the product into the desired

[0222] For example, tablets can be prepared by compression or molding. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder such as a gelatin or starch. Molded tablets can be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.

[0223] Examples of excipients that can be used in the oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, polyvinyl pyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose (such as No. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

[0224] Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. One particular binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103 TM and Starch 1500 LM.

[0225] Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, talc, calcium carbonate (e.g., granular or powdered), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. In one aspect, the binder or filler in the pharmaceutical composition comprises about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.

[0226] Disintegrants can be used in the compositions to provide tablets which disintegrate when exposed to an aqueous environment. Tablets containing too much disintegrant can disintegrate in storage, while tablets containing too little can fail to disintegrate at the required rate or under the required conditions. Thus, a sufficient amount of disintegrant can be used to form the solid oral dosage form that is neither too much nor too little to avoid adversely affecting the release of the active ingredient. The amount of disintegrant used varies according to the type of formulation and is readily discernible to one of ordinary skill in the art. In one aspect, the pharmaceutical composition comprises about 0.5 to about 15 weight percent of a disintegrant, or about 1 to about 5 weight percent of a disintegrant.

[0227] Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, agar agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrillin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

[0228] Lubricants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, for example, Silicon dioxide (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (sold by the Degussa Co. of Piano, TX), CAB-O-SIL (a pyrogenic silicon dioxide product sold by the Cabot Co. of Boston, MA), and mixtures thereof. If used, lubricants can comprise less than about 2% by weight of the pharmaceutical composition or dosage form into which they are incorporated.

[0229] In another aspect, the present application provides a solid oral dosage form comprising a compound provided herein, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, and gelatin.

[0230] The active ingredients provided herein can also be administered through controlled release means or delivery devices well known to those of ordinary skill in the art. Examples include, but are not limited to, U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each incorporated herein by reference in its entirety. Such dosage forms can be used to provide sustained or controlled release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticulates, liposomes, microspheres, or a combination thereof to provide the desired release profile. Suitable controlled release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active agents provided herein. In another aspect, the present application provides single unit dosage forms suitable for oral administration, such as, but not limited to, tablets, capsules, gelcaps, and caplets suitable for controlled release.

[0231] Controlled release pharmaceutical products improve the efficacy of drug treatment regimes beyond that which is achieved with uncontrolled counterparts. In another aspect, the present application provides the use of a controlled release formulation in medical treatment characterized by the healing or control of a condition using the minimum drug substance in the shortest possible time. Advantages of controlled release formulations include prolonged drug activity, reduced dosage frequency, and increased patient compliance. In addition, controlled release formulations can be used to affect the onset time or other characteristics, such as blood concentration of a drug, to affect the occurrence of side effects (e.g., adverse effects).

[0232] In another aspect, controlled release formulations are designed to initially release an amount of drug (active ingredient) to rapidly produce the desired therapeutic or prophylactic effect, and gradually and continually release other amounts of the drug to maintain the level of such effect over an extended period of time. In another aspect, to maintain constant levels of drugs in the body, a drug can be released from a dosage form at a rate that replaces the amount of drug that is metabolized and excreted from the body. Controlled release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0233] Parenteral dosage forms can be administered to a patient by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Administration of parenteral dosage forms bypasses the patient’s natural defenses against contaminants, and thus, in these respects, parenteral dosage forms are sterile or can be sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions for injection, dry products dissolved or suspended in a pharmaceutically acceptable injectable medium, suspensions for injection, and emulsions.

[0234] Suitable vehicles that can be used to provide parenteral dosage forms are well known to those of ordinary skill in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, Ethanol, Polyethylene glycol, and Polypropylene glycol; and non-aqueous vehicles such as, but not limited to, Corn Oil, Cottonseed Oil, Peanut Oil, Sesame Oil, Ethyl Oleate, Isopropyl Myristate, and Benzyl Benzoate.

[0235] Compounds that increase the solubility of one or more active ingredients disclosed herein can also be incorporated into parenteral dosage forms. For example, cyclodextrins and their derivatives can be used to increase the solubility of the compounds provided herein. See, e.g., U.S. Patent No. 5,134,127, the entire contents of which are incorporated herein by reference.

[0236] Topical and mucosal dosage forms provided herein include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, eye drops or other ophthalmic preparations, or other forms known to those of ordinary skill in the art. See, e.g., Remington’s Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton PA (1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treatment of oral mucosal tissue can be formulated as mouthwashes or oral gels.

[0237] Suitable excipients (e.g., carriers and diluents), and other materials that can be used to provide topical and mucosal dosage forms encompassed herein are well known to those in the pharmaceutical arts, and depend on the particular pharmaceutical composition or dosage form desired. In general, the excipient is a material that is nontoxic to the patient in the amounts and concentrations employed and is suitable for use in humans. In certain embodiments, excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, 1,3-butanediol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form solutions, emulsions, or gels, which are nontoxic and pharmaceutically acceptable. Moisturizers or humectants can also be added to the pharmaceutical compositions and dosage forms. Examples of additional ingredients are well known to those in the art. See, e.g., Remington’s Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton PA (1980 & 1990).

[0238] The pH of the pharmaceutical composition or dosage form can also be adjusted to improve delivery of one or more active ingredients. In addition, the polarity, ionic strength, or tonicity of the solvent vehicle can be adjusted to improve delivery. Compounds such as stearates can also be added to the pharmaceutical composition or dosage form to alter the hydrophilicity or lipophilicity of one or more active ingredients to improve delivery. In other aspects, stearates can act as lipid vehicles for the formulation, as emulsifiers or surfactants, or as delivery or penetration enhancers. In other aspects, salts, solvates, prodrugs, or enantiomers of the active ingredients can be used to further adjust the properties of the resulting composition.

[0239] In another aspect, the active ingredients provided herein are not administered to the patient at the same time or by the same route of administration. In another aspect, kits are provided that can simplify administration of appropriate amounts of the active ingredients.

[0240] In another aspect, the present application provides kits comprising dosage forms of the compounds provided herein. The kits can also comprise additional active ingredients.

[0241] In other aspects, the kits can also include devices for administering the active ingredients. Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers.

[0242] The kits can also comprise cells or blood for transplantation and pharmaceutically acceptable vehicles that can be used to administer one or more of the active ingredients. For example, if the active ingredients are provided in solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredients can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: water for injection USP; aqueous vehicles such as, but not limited to, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer's injection; water-miscible vehicles such as, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0243] In one aspect, a pharmaceutical composition is provided comprising the deuterium- enriched pioglitazone hydrochloride or deuterated hydrochloride salt described herein, lactose, carboxymethylcellulose, hydroxypropylcellulose, and stearate.

[0244] Methods of use and treatment

[0245] Provided herein are methods of treating a condition, disease, or disorder (e.g., a neurological disorder, a cancer, a respiratory disorder, an endocrine disorder, a metabolic disorder, a kidney disorder, hepatitis, a cardiovascular disease, an inflammation or immune-mediated disorder, a skin disease, a wound, a skin defect, etc.) comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A (e.g., a compound of Formula I or Formula I-A in the deuterated hydrochloride salt or hydrochloride salt form described herein) to treat the condition, disease, or disorder. In various embodiments, the method comprises administering to a patient in need thereof a therapeutically effective amount of a deuterated hydrochloride salt of a compound of Formula I (e.g., the crystalline deuterated hydrochloride salt form described herein) to treat the condition, disease, or disorder. In various embodiments, the method comprises administering to a patient in need thereof a therapeutically effective amount of a hydrochloride salt of a compound of Formula I-A (e.g., the crystalline hydrochloride salt form described herein) to treat the condition, disease, or disorder.

[0246] In certain embodiments, the condition, disease, or disorder is a neurological disorder. In certain embodiments, the condition, disease, or disorder is a cancer. In certain embodiments, the condition, disease, or disorder is a respiratory disorder. In certain embodiments, the condition, disease, or disorder is an endocrine or metabolic disorder. In certain embodiments, the condition, disease, or disorder is a metabolic disorder. In certain embodiments, the condition, disease, or disorder is hepatitis. In certain embodiments, the condition, disease, or disorder is a cardiovascular disease. In certain embodiments, the condition, disease, or disorder is a kidney disease. In certain embodiments, the condition, disease, or disorder is an inflammation or immune-mediated disorder. In certain embodiments, the condition, disease, or disorder is a skin disease. In certain embodiments, the condition, disease, or disorder is a wound. In certain embodiments, the condition, disease, or disorder is a skin defect.

[0247] Also provided herein are methods of modulating the amount and / or function of an endogenous biomolecule (e.g., a triglyceride, a fatty acid, a carbohydrate or sugar, a low-density lipoprotein, a high-density lipoprotein, a cytokine, etc.) to prevent or treat a condition, disease, or disorder described herein, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A (e.g., a compound of Formula I or Formula I-A in the deuterated hydrochloride salt or hydrochloride salt form described herein) to modulate the endogenous biomolecule. In various embodiments, the method comprises administering to a patient in need thereof a therapeutically effective amount of a deuterated hydrochloride salt of a compound of Formula I (e.g., the crystalline deuterated hydrochloride salt form described herein) to modulate the endogenous biomolecule. In various embodiments, the method comprises administering to a patient in need thereof a therapeutically effective amount of a hydrochloride salt of a compound of Formula I-A (e.g., the crystalline hydrochloride salt form described herein) to modulate the endogenous biomolecule.

[0248] In certain embodiments, the endogenous biomolecule is a triglyceride. In certain embodiments, the endogenous biomolecule is a fatty acid. In certain embodiments, the endogenous biomolecule is a carbohydrate or sugar. In certain embodiments, the endogenous biomolecule is low density lipoprotein. In certain embodiments, the endogenous biomolecule is high density lipoprotein. In certain embodiments, the endogenous biomolecule is a cytokine.

[0249] (i) treating a metabolic disorder

[0250] In another aspect, the present application provides a method of treating a metabolic disorder or a liver disorder selected from the group consisting of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, viral hepatitis, cirrhosis, liver fibrosis, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, beta cell exhaustion insulin resistance in patients with congenital adrenal hyperplasia treated with glucocorticoids, polycystic ovary syndrome, leukodystrophy including adrenoleukodystrophy and adrenomyeloneuropathy, metabolic abnormalities in patients on peritoneal dialysis, reduced insulin secretion, misallocation of brown and white adipocytes, obesity, or misregulated leptin levels. The method comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A (e.g., a deuterated hydrochloride salt or a hydrochloride salt of a compound of Formula I or Formula I-A as described herein) to treat the metabolic disorder. In certain embodiments, the method comprises administering to a patient in need thereof a therapeutically effective amount of a deuterated hydrochloride salt of a compound of Formula I (e.g., a crystalline deuterated hydrochloride salt form as described herein) to treat the metabolic disorder. In certain embodiments, the method comprises administering to a patient in need thereof a therapeutically effective amount of a hydrochloride salt of a compound of Formula I-A (e.g., a crystalline hydrochloride salt form as described herein) to treat the metabolic disorder. In certain embodiments, the metabolic disorder is further selected from diabetic complications. In certain embodiments, the metabolic disorder is nonalcoholic fatty liver disease, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, or beta cell exhaustion insulin resistance in patients with congenital adrenal hyperplasia treated with glucocorticoids. In certain embodiments, the metabolic disorder is nonalcoholic fatty liver disease, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, beta cell exhaustion, reduced insulin secretion, misallocation of brown and white adipocytes, obesity, or misregulated leptin levels. In certain other embodiments, the metabolic disorder is nonalcoholic fatty liver disease. In certain other embodiments, the metabolic disorder is nonalcoholic steatohepatitis. In certain other embodiments, the metabolic disorder is type II diabetes. In certain other embodiments, the metabolic disorder is beta cell loss that can be treated by B cell regeneration. In certain other embodiments, the metabolic disorder is central obesity, dyslipidemia, or prediabetes. In certain other embodiments, the metabolic disorder is polycystic ovary syndrome. In certain other embodiments, the metabolic disorder is leukodystrophy including adrenoleukodystrophy and adrenomyeloneuropathy.

[0251] nonalcoholic fatty liver disease

[0252] In certain embodiments, a method for treating nonalcoholic fatty liver disease is provided, the method comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A (e.g., a compound of Formula I or Formula I-A as the deuterated hydrochloride salt or hydrochloride salt described herein) to treat nonalcoholic fatty liver disease. The method of treatment is expected to provide particular benefits to patients with nonalcoholic fatty liver disease. Exemplary benefits include little to no occurrence of PPARy side effects (e.g., weight gain, edema, and / or bone loss) while achieving improvement in the patient’s nonalcoholic fatty liver disease (possibly including a reduction in liver fat mass as a result of treatment).

[0253] Nonalcoholic steatohepatitis

[0254] In certain embodiments, a method for treating nonalcoholic steatohepatitis is provided, the method comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A (e.g., a compound of Formula I or Formula I-A as the deuterated hydrochloride salt or hydrochloride salt described herein) to treat nonalcoholic steatohepatitis. The method of treatment is expected to provide particular benefits to patients with nonalcoholic steatohepatitis. Exemplary benefits include little to no occurrence of PPARy side effects (e.g., weight gain, edema, and / or bone loss) while achieving improvement in the patient’s nonalcoholic steatohepatitis (possibly including a reduction in liver fat mass as a result of treatment).

[0255] Type II diabetes

[0256] In certain embodiments, a method for treating Type II diabetes is provided, the method comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A (e.g., a compound of Formula I or Formula I-A as the deuterated hydrochloride salt or hydrochloride salt described herein) to treat Type II diabetes. The method of treatment is expected to provide particular benefits to patients with Type II diabetes. Exemplary benefits include little to no occurrence of PPARy side effects (e.g., weight gain, edema, and / or bone loss) while achieving improvement in the patient’s Type II diabetes (possibly including improvement in the patient’s glycemic control).

[0257] (ii) Treatment of cancer

[0258] Another aspect of the application provides a method of treating cancer. The method includes administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A (e.g., a deuterated hydrochloride salt or a hydrochloride salt of a compound of Formula I or Formula I-A as described herein) to treat cancer. In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a deuterated hydrochloride salt of a compound of Formula I (e.g., a crystalline deuterated hydrochloride salt form as described herein) to treat cancer. In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a hydrochloride salt of a compound of Formula I-A (e.g., a crystalline hydrochloride salt form as described herein) to treat cancer.

[0259] In certain embodiments, the cancer is lung cancer, hepatocellular carcinoma, astrocytoma, glioma, glioblastoma, meningioma, hepatocarcinoma, lymphoma, melanoma, multiple myeloma, pancreatic cancer, colorectal cancer, pituitary cancer, thyroid cancer, esophageal cancer, or prostate cancer. In certain embodiments, the cancer is non-small cell lung cancer or hepatocellular carcinoma.

[0260] In certain other embodiments, the cancer is lung cancer, hepatocellular carcinoma, astrocytoma, glioma, glioblastoma, meningioma, hepatoma, lymphoma, melanoma, multiple myeloma, pancreatic cancer, colorectal cancer, pituitary cancer, thyroid cancer, esophageal cancer, prostate cancer, nasal cancer, laryngeal cancer, kidney cancer, breast cancer, stomach cancer, or uterine cancer. In certain other embodiments, the cancer is brain cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, leukemia, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal cancer, stomach cancer, testicular cancer, or uterine cancer.In other embodiments, the cancer is a vascularized tumor, squamous cell carcinoma, adenocarcinoma, small cell carcinoma, melanoma, glioma, neuroblastoma, sarcoma (e.g., angiosarcoma or chondrosarcoma), laryngeal cancer, parotid cancer, biliary tract cancer, thyroid cancer, acral lentiginous melanoma, actinic keratosis, acute lymphoblastic leukemia, acute myeloid leukemia, adenoid cystic carcinoma, adenoma, adenosarcoma, adenosquamous carcinoma, anal canal cancer, anal cancer, anorectal cancer, astrocytic tumor, bartholin gland carcinoma, basal cell carcinoma, biliary tract cancer, bone cancer, bone marrow cancer, bronchial cancer, bronchial gland carcinoma, carcinoid, cholangiocarcinoma, choroid plexus papilloma / carcinoma, chronic lymphocytic leukemia, chronic myeloid leukemia, clear cell carcinoma, connective tissue cancer, cystadenoma, digestive system cancer, duodenal cancer, endocrine system cancer, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, endothelial cell carcinoma, ependymal carcinoma, epithelial cell carcinoma, Ewing’s sarcoma, eye and orbit cancer, female genital organ cancer, focal nodular hyperplasia, gallbladder cancer, gastric antrum cancer, gastric fundus cancer, gastrinoma, glioblastoma, glucagonoma, heart cancer, hemangioblastoma, hemangioendothelioma, hemangioma, hepatocellular adenoma, hepatocellular adenoma, hepatobiliary cancer, hepatocellular carcinoma, Hodgkin’s disease, ileal cancer, insulinoma, intraepithelial neoplasm, intraepithelial squamous cell neoplasm, intrahepatic bile duct cancer, invasive squamous cell carcinoma, jejunal cancer, joint cancer, Kaposi’s sarcoma, pelvic cancer, large cell carcinoma, large intestine cancer, leiomyosarcoma, lentigo maligna melanoma, lymphoma, male genital organ cancer, malignant melanoma, malignant mesothelioma, medulloblastoma, medulloepithelioma, meningeal cancer, mesothelial cancer, metastatic cancer, mouth cancer, mucoepidermoid carcinoma, multiple myeloma, muscle cancer, nasal cavity cancer, nervous system cancer, neuroepithelial adenocarcinoma, nodular melanoma, non-epithelial skin cancer, non-Hodgkin’s lymphoma, oat cell carcinoma, oligodendroglioma, oral cavity cancer, osteosarcoma, papillary serous adenocarcinoma, penile cancer, pharyngeal cancer, pituitary tumor, plasmacytoma, pseudosarcoma, pulmonary blastoma, rectal cancer, renal cell carcinoma, respiratory system cancer, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, sinus cancer, skin cancer, small cell carcinoma, small intestine cancer, smooth muscle cancer, soft tissue cancer, somatostatin-secreting tumor, spine cancer, squamous cell carcinoma, striated muscle carcinoma, submesothelial carcinoma, superficial spreading melanoma, T-cell leukemia, tongue cancer, undifferentiated carcinoma, ureteral cancer, urethral cancer, urinary bladder cancer, urinary system cancer, uterine cervix cancer, uterine corpus cancer, uveal melanoma, vaginal cancer, verrucous carcinoma, vasoactive intestinal peptide tumor (VIPoma), vulvar cancer, well-differentiated carcinoma, or Wilms’ tumor.

[0261] In certain other embodiments, the cancer is a non-Hodgkin lymphoma, e.g., a B-cell lymphoma or a T-cell lymphoma. In certain embodiments, the non-Hodgkin lymphoma is a B-cell lymphoma, e.g., diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, or primary central nervous system (CNS) lymphoma. In certain other embodiments, the non-Hodgkin lymphoma is a T-cell lymphoma, e.g., precursor T-lymphoblastic lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, angioimmunoblastic T-cell lymphoma, extranodal natural killer / T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma, or peripheral T-cell lymphoma.

[0262] (iii) Treatment of respiratory diseases

[0263] Another aspect of the application provides a method of treating a respiratory condition. The method includes administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A (e.g., a deuterated hydrochloride salt or a hydrochloride salt of a compound of Formula I or Formula I-A as described herein) to treat the respiratory condition. In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a deuterated hydrochloride salt of a compound of Formula I (e.g., a crystalline deuterated hydrochloride salt form as described herein) to treat the respiratory condition. In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a hydrochloride salt of a compound of Formula I-A (e.g., a crystalline hydrochloride salt form as described herein) to treat the respiratory condition.

[0264] In certain embodiments, the respiratory condition is chronic obstructive pulmonary disease, asthma, bronchitis, cystic fibrosis, pulmonary edema, pulmonary embolism, pulmonary hypertension, pneumonia, pulmonary sarcoidosis, silicosis, pulmonary fibrosis, respiratory failure, acute respiratory distress syndrome, emphysema, chronic bronchitis, tuberculosis, lung cancer, or a chronic respiratory condition. In certain embodiments, the respiratory condition is chronic obstructive pulmonary disease, asthma, or a chronic respiratory condition. In certain other embodiments, the respiratory condition is chronic obstructive pulmonary disease. In other embodiments, the respiratory condition is bronchitis, cystic fibrosis, pulmonary edema, pulmonary embolism, pneumonia, pulmonary sarcoidosis, silicosis, pulmonary fibrosis, respiratory failure, acute respiratory distress syndrome, emphysema, chronic bronchitis, tuberculosis, or lung cancer. In certain embodiments, the asthma is mild asthma, moderate asthma, severe asthma, or steroid-resistant asthma.

[0265] (iv) Treatment of neurological conditions

[0266] Accordingly, one aspect of the application provides a method of treating a neurological condition selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, autism spectrum disorder, depression, mild cognitive impairment, Down's syndrome, neurodegeneration, adrenoleukodystrophy, adrenomyeloneuropathy, Zellweger syndrome, Huntington's disease, stroke, traumatic brain injury, psychoactive substance abuse, spinal cord injury, neuronal injury, major depressive disorder or bipolar disorder with metabolic syndrome, and neurological diseases caused by functional mitochondrial impairment. The method comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A (e.g., a deuterated hydrochloride salt or a hydrochloride salt of a compound of Formula I or Formula I-A as described herein) to treat the neurological condition. In certain embodiments, the method comprises administering to a patient in need thereof a therapeutically effective amount of a deuterated hydrochloride salt of a compound of Formula I (e.g., a crystalline deuterated hydrochloride salt form as described herein) to treat the neurological condition. In certain embodiments, the method comprises administering to a patient in need thereof a therapeutically effective amount of a hydrochloride salt of a compound of Formula I-A (e.g., a crystalline hydrochloride salt form as described herein) to treat the neurological condition. In certain embodiments, the neurological condition is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, autism spectrum disorder, depression, mild cognitive impairment, neurodegeneration, adrenoleukodystrophy, adrenomyeloneuropathy, Huntington's disease, stroke, traumatic brain injury, psychoactive substance abuse, spinal cord injury, neuronal injury, and major depressive disorder or bipolar disorder with metabolic syndrome. In certain embodiments, the neurological condition is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, depression, mild cognitive impairment, neurodegeneration, adrenoleukodystrophy, adrenomyeloneuropathy, and Huntington's disease. In certain other embodiments, the neurological condition is Alzheimer's disease. In certain other embodiments, the neurological condition is Down's syndrome. In certain other embodiments, the neurological condition is adrenoleukodystrophy. In certain other embodiments, the neurological condition is adrenomyeloneuropathy.

[0267] In certain other embodiments, the neurological condition is a cognitive condition, e.g., a cognitive impairment and / or a memory impairment. For example, the cognitive impairment can be a cognitive impairment associated with Alzheimer's disease.

[0268] In certain embodiments, the psychoactive substance abuse is one or more of alcohol craving, heroin dependence, and nicotine dependence.

[0269] (v) Treatment of symptoms of hepatitis

[0270] Another aspect of the application provides a method of treating a symptom of liver inflammation. The method includes administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A (e.g., a compound of Formula I or Formula I-A as the deuterated hydrochloride salt or hydrochloride salt described herein) to treat liver inflammation. In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a deuterated hydrochloride salt of a compound of Formula I (e.g., a crystalline deuterated hydrochloride salt form described herein) to treat liver inflammation. In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a hydrochloride salt of a compound of Formula I-A (e.g., a crystalline hydrochloride salt form described herein) to treat liver inflammation.

[0271] (vi) Treatment of cardiovascular disease

[0272] Another aspect of the application provides a method of treating a cardiovascular disease. The method includes administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A (e.g., a compound of Formula I or Formula I-A as the deuterated hydrochloride salt or hydrochloride salt described herein) to treat the cardiovascular disease. In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a deuterated hydrochloride salt of a compound of Formula I (e.g., a crystalline deuterated hydrochloride salt form described herein) to treat the cardiovascular disease. In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a hydrochloride salt of a compound of Formula I-A (e.g., a crystalline hydrochloride salt form described herein) to treat the cardiovascular disease. In certain embodiments, the cardiovascular disease is hypertension, hyperlipidemia, atherosclerosis, vascular dysfunction, dyslipidemia, stenosis, restenosis, myocardial infarction, stroke, intracranial hemorrhage, acute coronary syndrome, stable angina, or unstable angina. In certain other embodiments, the cardiovascular disease is intracranial hemorrhage, acute coronary syndrome, stable angina, or unstable angina.

[0273] In another aspect, the application provides a method of preventing stroke in a patient. The method includes administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A (e.g., a compound of Formula I or Formula I-A as the deuterated hydrochloride salt or hydrochloride salt described herein) to prevent stroke in the patient. In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a deuterated hydrochloride salt of a compound of Formula I (e.g., a crystalline deuterated hydrochloride salt form described herein) to prevent stroke in the patient. In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a hydrochloride salt of a compound of Formula I-A (e.g., a crystalline hydrochloride salt form described herein) to prevent stroke in the patient.

[0274] The method of treatment or prevention can involve a patient at risk of ischemic stroke of the central nervous system, or can involve a patient at risk of stroke due to a cardiovascular disease.

[0275] (vii) reducing the amount of triglycerides or low density lipoprotein

[0276] Another aspect of the application provides a method of reducing the amount of triglycerides or low density lipoprotein (LDL) in a patient. The method includes administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A (e.g., a deuterated hydrochloride salt or a hydrochloride salt of a compound of Formula I or Formula I-A as described herein) to reduce the amount of triglycerides or low density lipoprotein (LDL) in the patient. In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a deuterated hydrochloride salt of a compound of Formula I (e.g., a crystalline deuterated hydrochloride salt form as described herein) to reduce the amount of triglycerides or low density lipoprotein (LDL) in the patient. In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a hydrochloride salt of a compound of Formula I-A (e.g., a crystalline hydrochloride salt form as described herein) to reduce the amount of triglycerides or low density lipoprotein (LDL) in the patient.

[0277] In certain embodiments, the method reduces the amount of triglycerides or low density lipoprotein (LDL) in the patient by at least 1%, 5%, 10%, or 25%.

[0278] (viii) increasing the amount of high density lipoprotein

[0279] Another aspect of the application provides a method of increasing the amount of high density lipoprotein (HDL) in a patient. The method includes administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A (e.g., a deuterated hydrochloride salt or a hydrochloride salt of a compound of Formula I or Formula I-A as described herein) to increase the amount of high density lipoprotein (HDL) in the patient. In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a deuterated hydrochloride salt of a compound of Formula I (e.g., a crystalline deuterated hydrochloride salt form as described herein) to increase the amount of high density lipoprotein (HDL) in the patient. In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a hydrochloride salt of a compound of Formula I-A (e.g., a crystalline hydrochloride salt form as described herein) to increase the amount of high density lipoprotein (HDL) in the patient.

[0280] In certain embodiments, the method increases the amount of high density lipoprotein (HDL) in the patient by at least 1%, 5%, 10%, or 25%.

[0281] (ix) treating an inflammatory or immune-mediated disorder

[0282] Another aspect of the application provides a method of treating an inflammatory or immune-mediated disorder selected from chronic kidney disease, arthritis, primary cicatricial alopecia, pulmonary fibrosis, multiple sclerosis, endotoxemia, sepsis, septic shock, laminitis, inflammatory bowel disease, colitis, Crohn's disease, rheumatoid arthritis, lupus, myasthenia gravis, vasculitis, chronic pancreatitis, hyperproliferative skin disorders, inflammatory skin disorders, rhinitis (e.g., allergic rhinitis), and dermatosis. The method comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A (e.g., a deuterated hydrochloride salt or a hydrochloride salt of a compound of Formula I or Formula I-A as described herein) to treat the inflammatory or immune-mediated disorder. In certain embodiments, the method comprises administering to a patient in need thereof a therapeutically effective amount of a deuterated hydrochloride salt of a compound of Formula I (e.g., a crystalline deuterated hydrochloride salt form as described herein) to treat the inflammatory or immune-mediated disorder. In certain embodiments, the method comprises administering to a patient in need thereof a therapeutically effective amount of a hydrochloride salt of a compound of Formula I-A (e.g., a crystalline hydrochloride salt form as described herein) to treat the inflammatory or immune-mediated disorder. In certain embodiments, the inflammatory or immune-mediated disorder is selected from chronic kidney disease, arthritis, primary cicatricial alopecia, pulmonary fibrosis, multiple sclerosis, endotoxemia, sepsis, septic shock, laminitis, inflammatory bowel disease, colitis, Crohn's disease, rheumatoid arthritis, lupus, myasthenia gravis, vasculitis, chronic pancreatitis, hyperproliferative skin disorders, inflammatory skin disorders, and dermatosis. In certain embodiments, the inflammatory or immune-mediated disorder is selected from chronic kidney disease, arthritis, primary cicatricial alopecia, pulmonary fibrosis, multiple sclerosis, endotoxemia, sepsis, septic shock, laminitis, inflammatory bowel disease, colitis, Crohn's disease, rheumatoid arthritis, lupus, myasthenia gravis, vasculitis, chronic pancreatitis, hyperproliferative skin disorders, inflammatory skin disorders, and dermatosis, and in certain embodiments, the chronic kidney disease can be, for example, polycystic kidney disease (such as autosomal dominant or autosomal recessive).

[0283] (x) treating a dermatosis

[0284] Another aspect of the application provides a method of treating a skin disorder selected from psoriasis, atopic dermatitis, acne, leukoderma, scleroderma, and skin malignancies. The method comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A (e.g., a compound of Formula I or Formula I-A as the deuterated hydrochloride salt or hydrochloride salt described herein) to treat the skin disorder. In certain embodiments, the method comprises administering to a patient in need thereof a therapeutically effective amount of the deuterated hydrochloride salt of a compound of Formula I (e.g., a crystalline deuterated hydrochloride salt form described herein) to treat the skin disorder. In certain embodiments, the method comprises administering to a patient in need thereof a therapeutically effective amount of the hydrochloride salt of a compound of Formula I-A (e.g., a crystalline hydrochloride salt form described herein) to treat the skin disorder. In certain embodiments, the administration is by topical administration.

[0285] (xi) modulating expression of a proinflammatory cytokine

[0286] Another aspect of the application provides a method of modulating expression of a proinflammatory cytokine (e.g., TNFa, IL-1b, IL-6, IL-17, IL-23, or MCP-1) in a patient having an inflammatory disease. The method comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A (e.g., a compound of Formula I or Formula I-A as the deuterated hydrochloride salt or hydrochloride salt described herein) to modulate expression of a proinflammatory cytokine (e.g., TNFa, IL-1b, or IL-6) in a patient having an inflammatory disease. In certain embodiments, the method comprises administering to a patient in need thereof a therapeutically effective amount of the deuterated hydrochloride salt of a compound of Formula I (e.g., a crystalline deuterated hydrochloride salt form described herein) to modulate expression of a proinflammatory cytokine (e.g., TNFa, IL-1b, or IL-6) in a patient having an inflammatory disease. In certain embodiments, the method comprises administering to a patient in need thereof a therapeutically effective amount of the hydrochloride salt of a compound of Formula I-A (e.g., a crystalline hydrochloride salt form described herein) to modulate expression of a proinflammatory cytokine (e.g., TNFa, IL-1b, or IL-6) in a patient having an inflammatory disease. In certain embodiments, the proinflammatory cytokine is TNFa.

[0287] Another aspect of the application provides a method of modulating anti-inflammatory cytokine expression in a patient having an inflammatory condition. The method includes administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A (e.g., a compound of Formula I or Formula I-A as the deuterated hydrochloride salt or hydrochloride salt described herein) to modulate anti-inflammatory cytokine expression in a patient having an inflammatory condition. In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a deuterated hydrochloride salt of a compound of Formula I (e.g., a crystalline deuterated hydrochloride salt form described herein) to modulate anti-inflammatory cytokine expression in a patient having an inflammatory condition. In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a hydrochloride salt of a compound of Formula I-A (e.g., a crystalline hydrochloride salt form described herein) to modulate anti-inflammatory cytokine expression in a patient having an inflammatory condition.

[0288] (xii) modulating macrophage function

[0289] Another aspect of the application provides a method of modulating macrophage function in a patient having an infection, an inflammatory condition, or an autoimmune disease. The method includes administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A (e.g., a compound of Formula I or Formula I-A as the deuterated hydrochloride salt or hydrochloride salt described herein) to modulate macrophage function in a patient having an infection. In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a deuterated hydrochloride salt of a compound of Formula I (e.g., a crystalline deuterated hydrochloride salt form described herein) to modulate macrophage function in a patient having an infection, an inflammatory condition, or an autoimmune disease. In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a hydrochloride salt of a compound of Formula I-A (e.g., a crystalline hydrochloride salt form described herein) to modulate macrophage function in a patient having an infection.

[0290] (xiii) methods of promoting wound healing

[0291] Another aspect of the application provides a method of promoting wound healing. The method includes administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A (e.g., a compound of Formula I or Formula I-A as the deuterated hydrochloride salt or hydrochloride salt described herein) to promote wound healing. In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a deuterated hydrochloride salt of a compound of Formula I (e.g., a crystalline deuterated hydrochloride salt form described herein) to promote wound healing. In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a hydrochloride salt of a compound of Formula I-A (e.g., a crystalline hydrochloride salt form described herein) to promote wound healing. In certain embodiments, the administration is by topical administration.

[0292] (xiv) treating skin defects

[0293] Another aspect of the application provides a method of treating skin defects caused by exposure to ultraviolet radiation. The method includes administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A (e.g., a deuterated hydrochloride salt or a hydrochloride salt of a compound of Formula I or Formula I-A as described herein) to treat skin defects caused by exposure to ultraviolet radiation. In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a deuterated hydrochloride salt of a compound of Formula I (e.g., a crystalline deuterated hydrochloride salt form as described herein) to treat skin defects caused by exposure to ultraviolet radiation. In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a hydrochloride salt of a compound of Formula I-A (e.g., a crystalline hydrochloride salt form as described herein) to treat skin defects caused by exposure to ultraviolet radiation.

[0294] (xv) methods of modulating stem cell differentiation

[0295] Another aspect of the application provides a method of modulating stem cell differentiation (e.g., in a patient). The method includes administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A (e.g., a deuterated hydrochloride salt or a hydrochloride salt of a compound of Formula I or Formula I-A as described herein) to modulate stem cell differentiation (e.g., in a patient). In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a deuterated hydrochloride salt of a compound of Formula I (e.g., a crystalline deuterated hydrochloride salt form as described herein) to modulate stem cell differentiation (e.g., in a patient). In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a hydrochloride salt of a compound of Formula I-A (e.g., a crystalline hydrochloride salt form as described herein) to modulate stem cell differentiation (e.g., in a patient).

[0296] (xvi) other medical conditions

[0297] Another aspect of the application provides a method of treating a disorder selected from the group consisting of: transplant rejection, impairment of liver function, Rabson-Mendenhall syndrome, Donohue syndrome, Leber's hereditary optic neuropathy, myotonic dystrophy, ototoxicity, Niemann-Pick disease, autosomal dominant optic atrophy, spinal and bulbar muscular atrophy, Mohr-Tranebjaerg syndrome, hereditary spastic paraplegia, MELAS syndrome, monoclonal immunoglobulin deposition disease (MIDD), deafness, insulin resistance in patients receiving growth hormone therapy, and chronic progressive external ophthalmoplegia with mitochondrial myopathy. The method includes administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A (e.g., a deuterated hydrochloride salt or a hydrochloride salt of a compound of Formula I or Formula I-A as described herein) to treat the disorder. In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a deuterated hydrochloride salt of a compound of Formula I (e.g., a crystalline deuterated hydrochloride salt form as described herein) to treat the disorder. In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a hydrochloride salt of a compound of Formula I-A (e.g., a crystalline hydrochloride salt form as described herein) to treat the disorder.

[0298] (xvii) prophylaxis of a medical disorder

[0299] Also provided is a method of preventing a medical disorder in a patient. The method includes administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A (e.g., a deuterated hydrochloride salt or a hydrochloride salt of a compound of Formula I or Formula I-A as described herein) to prevent the medical disorder. In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a deuterated hydrochloride salt of a compound of Formula I (e.g., a crystalline deuterated hydrochloride salt form as described herein) to prevent the medical disorder. In certain embodiments, the method includes administering to a patient in need thereof a therapeutically effective amount of a hydrochloride salt of a compound of Formula I-A (e.g., a crystalline hydrochloride salt form as described herein) to prevent the medical disorder. The medical disorder can be one or more of the medical disorders described above, e.g., a neurological disorder (e.g., Alzheimer's disease or Parkinson's disease), a cancer (e.g., non-small cell lung cancer or hepatocellular carcinoma), a metabolic disorder, a cardiovascular disease (e.g., in-stent restenosis in a diabetic patient, reinfarction in a diabetic patient, or cardiac allograft vasculopathy after heart transplantation), or a respiratory disease (e.g., chronic obstructive pulmonary disease).

[0300] (xviii) other medical uses

[0301] The present application provides methods of using the compounds and solid forms described herein for therapy, including regenerative medicine. Also provided herein are methods of treating veterinary conditions, such as laminitis. The methods include administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A (e.g., a deuterated hydrochloride salt or a hydrochloride salt of a compound of Formula I or Formula I-A as described herein) to treat a veterinary condition. In certain embodiments, the methods include administering to a patient in need thereof a therapeutically effective amount of a deuterated hydrochloride salt of a compound of Formula I (e.g., a crystalline deuterated hydrochloride salt form as described herein) to treat a veterinary condition. In certain embodiments, the methods include administering to a patient in need thereof a therapeutically effective amount of a hydrochloride salt of a compound of Formula I-A (e.g., a crystalline hydrochloride salt form as described herein) to treat a veterinary condition.

[0302] In certain embodiments, the pharmaceutically acceptable salts of a compound of Formula I or Formula I-A provided herein can be administered as the sole active agent, or they can be administered in combination with other therapeutically active agents (e.g., combination therapy).

[0303] It is contemplated that the combination therapies of the present application described herein can act synergistically in the treatment of the particular conditions, diseases, or disorders described herein and / or one or more symptoms associated with such conditions, diseases, or disorders. It is also contemplated that the pharmaceutically acceptable salts of a compound of Formula I or Formula I-A provided herein can also be useful in mitigating side effects associated with a second therapeutically active agent, and vice versa.

[0304] In various embodiments, one or more second therapeutically active agents can be used in the methods and compositions provided herein. In certain embodiments, the one or more second therapeutically active agents can be a macromolecule (e.g., a protein) or a small molecule (e.g., a synthetic inorganic, organometallic, or organic molecule).

[0305] In certain embodiments, the combination therapy comprises a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A described herein and a second therapeutically active agent for treating a condition, disease, or disorder described herein (e.g., a neurological disorder, a cancer, a respiratory disorder, a metabolic disorder, hepatitis, a cardiovascular disease, an inflammation or immune-mediated disorder, a skin disease, a wound, a skin defect, etc.).

[0306] In certain embodiments, the second therapeutically active agent can be a drug useful for treating a metabolic disorder, such a therapeutically active agent can include, but is not limited to, metformin, imeglimin, a dipeptidyl peptidase IV inhibitor (e.g., sitagliptin, vildagliptin, etc.), a statin (e.g., an HMG-CoA reductase inhibitor such as atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, simvastatin, rosuvastatin, pravastatin, or a combination thereof), an AMPK activator, a thyroid beta agonist, a GLP-1 agonist, a GLP-2 agonist, or an SGLT2 inhibitor.

[0307] In certain embodiments, the second therapeutically active agent is a diuretic (e.g., hydrochlorothiazide).

[0308] In certain embodiments, the second therapeutically active agent can be a drug useful in the treatment of hypertension, diabetes, or an inflammatory disease. In certain embodiments, the second therapeutically active agent can be a drug that limits the activity of the renin-angiotensin system, such as an angiotensin-converting enzyme inhibitor (e.g., an ACE inhibitor, such as ramipril, captopril, enalapril, etc.), an angiotensin receptor blocker (e.g., candesartan, losartan, olmesartan, etc.), or a renin inhibitor. In certain embodiments, the second therapeutic agent can limit hypertension by alternative means, such as a beta-adrenergic receptor blocker or a calcium channel blocker (e.g., amlodipine).

[0309] In certain embodiments, the second therapeutically active agent is a glucocorticoid agonist. In certain embodiments, a combination therapy comprising a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A described herein and a glucocorticoid agonist can be used to treat an inflammatory disease, such as for the suppression of immune responses, prevention of transplant rejection, and treatment of autoimmune diseases. Exemplary conditions include, for example, rheumatoid arthritis, lupus, myasthenia gravis, vasculitic muscle dystrophy, multiple sclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, treatment of acute anaphylaxis, and transplant rejection.

[0310] In certain embodiments, combination therapy comprising a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A described herein and a second therapeutically active agent that increases cAMP or a beta-adrenergic agonist can be used to treat a kidney disease. Exemplary beta-adrenergic agonists include, but are not limited to, a beta-1 -adrenergic agonist, a beta-2-adrenergic agonist, a beta-3-adrenergic agonist, or a combination thereof. In certain embodiments, the second therapeutically active agent is norepinephrine, isoproterenol, dobutamine, salbutamol, levalbuterol, terbutaline, pirbuterol, procaterol, metaproterenol, fenoterol, bitolterol mesylate, salmeterol, formoterol, bambuterol, clenbuterol, indacaterol, L-796568, amibegron, solabegron, isoproterenol, salbutamol, metaproterenol, alprenolol, benofloxate, bromoacetyl alprenolol menthane, broxaterol, cimaterol, cilarizine, denopamine, dopropizine, epinephrine, etilefrine, hexoprenaline, and urapidil, isoxsuprine, isokoxamine, mabuterol, methoxyphenamine, nylidrin, oxifenoxate, prenalterol, rimiterol, ritodrine, tretazoline, tulobuterol, zanolterol, zilpaterol, xintrol, or a pharmaceutically acceptable salt thereof; or a combination of any of the foregoing.

[0311] In certain embodiments, combination therapy comprises a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A described herein and a second therapeutically active agent useful in the treatment of cancer. Exemplary second therapeutically active agents useful in the treatment of cancer include, but are not limited to, an alkylating agent, an antimetabolite (e.g., a molecule that blocks DNA and / or RNA synthesis), an anti-microtubule agent, a topoisomerase inhibitor, a cytotoxic antibiotic, a tyrosine kinase inhibitor, a tumor necrosis factor alpha inhibitor, an anti-neoplastic radiotherapy, or a programmed death protein-1 (PD-1) modulator (e.g., inhibitor). In certain embodiments, the second therapeutically active agent useful in the treatment of cancer is azacitidine, azathioprine, bleomycin, carboplatin, capecitabine, carmustine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, etoposide, fluorouracil, fulvestrant, gemcitabine, hydroxycarbamide, idarubicin, imatinib, lomustine, mechlorethamine, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, procarbazine, raloxifene, teniposide, temozolomide, tamoxifen, toremifene, valrubicin, vinblastine, vincristine, vindesine, vinorelbine, or a pharmaceutically acceptable salt thereof; or a combination of any of the foregoing.

[0312] In certain embodiments, the second therapeutically active agent useful in the treatment of cancer is albumin-bound paclitaxel (Abraxane); accutin; aclarubicin; acodazole hydrochloride; acribline; adozelesin; aldesleukin; altretamine; ambopterin; amsidine; anagrelide; anastrozole; anthramycin; asparaginase; augmentin; azacitidine; azatioprine; azetepa; balsalazide; batimastat; benzodepa; bicalutamide; bietanautine; bisnafide dimesylate; bizelesin; bleomycin sulfate; bortezomib; bromoctoril; busulfan; calicheamicin; calusterone; carbetimer; carboplatin; carmustine; carzinophilin; cedefmgol; celecoxib; chlorambucil; chlorsulfuron; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; diaziquone; dienestrol; diethylstilbestrol dimesylate; dihydroxy anthracin dione; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; enalapril maleate; enloplatm; enpromate; epirubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; exemestane; exemestane; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; flurocitrins; fosquidnon-sodium; fostripton sodium; gemcitabine; gemcitabine hydrochloride; gemtuzumab ozogamicin; hydroxycarbamide; idarubicin hydrochloride; ifosfamide; iimofosine; ifosfamide; irinotecan; irinotecan hydrochloride; lanreotide acetate; lapatinib; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; mitocarcin; mitobinite; mitocarcin; mitocromin; mitomycin; mitopodozide; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nafostine; nogalamycin; ormaplatin; oxaliplatin; paclitaxel; pegaspargase; peloruside A; pentamustine; pentostatin; phenamet; pirarubicin hydrochloride; plicamycin; plomestane; porfimer sodium; portiromycin; prednimustine; procarbazine hydrochloride; puromycin hydrochloride; pyrazofurin; riboprine; roglethopride; safingol hydrochloride; semustine; sparsaphen sodium; sparsomycin;Germanium spiroamine hydrochloride; Spiromustin; Spiroplatin; Stem cell therapy; Streptocin; Streptozotocin; Sulfochlorfenapyr; Talithromycin; Ticogallan sodium; Taxotere; Tegafur; Teloanthraquinone hydrochloride; Temoporfin; Teniposide; Tiroxicoron; Testrolide; Thiomipril; Thioguanine; Thiotepa; Thiazole carboxylamine nucleoside; Tirazamine; Toremifene citrate; Tritoprolol acetate; Tricerebroside phosphate; Trimethoprim; Trimethoprim gluconate; Triptorelin; Tobradex hydrochloride; Uracil nitrogen mustard; Uretipa; Vaportide; Vertepofen; Vincristine sulfate; Vincristine sulfate; Vincristine sulfate; Vinpicidin sulfate; Vincristine sulfate; Vincristyl sulfate; Vincrylexin sulfate; Vinorelbine tartrate; Vinrodine sulfate; Vinridine sulfate; Vorticillium; Zonipram; Netostatin; Zoraboxin hydrochloride, or combinations thereof.

[0313] Administering a pharmaceutically acceptable salt of a compound of formula I or IA described herein, and a second therapeutic active agent, to a patient may occur simultaneously or sequentially via the same or different routes of administration. The suitability of a particular route of administration for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without dissolving before entering the bloodstream) and the disease being treated. One route of administration for the compounds provided herein is oral administration. Routes of administration for the second active agent or ingredient are known to those skilled in the art. See, for example, Physicians' Desk Reference (60 th Ed., 2006). Example

[0314] To provide a fuller understanding of the disclosure herein, the following examples are provided. The synthetic and biological examples described in this application are for illustrative purposes only and should not be construed as limiting the scope thereof.

[0315] Example 1: Synthesis of deuterium-enriched (R)-pioglitazone L-dibenzoyl tartrate

[0316] The reaction temperature is reported as an internal temperature. Chemical intermediates, reagents, and solvents are obtained from commercial sources.

[0317] Filtration: Solid products were separated by filtration through a PTFE Büchner funnel using MN 617G (rapid filtration, phosphate-free; ref: MN 494024) and MN640m (ref: MN 203015) filter paper (unless otherwise specified), and washed with 1:1 MeOD:D2O (v / v) by plug flow method (partial; 2x / 3x) (unless otherwise specified).

[0318] Drying: After filtration, the solids are first air dried under vacuum for several hours (3-4h) and then dried in a 50°C / 42°C drying oven equipped with a vacuum pump (24-72h).

[0319] NMR: Proton spectra were recorded on a Bruker Avance 300MHz or higher spectrometer. Chemical shifts were referenced to the residual solvent signal at δ 2.50 (DMSO-d6) and, when applied, relative to TMS as an internal standard.

[0320] HPLC: For %d.e. / %e.e. measurements, all samples were dissolved in MeOH to make a 1 mg / mL solution.

[0321] HPLC for identification and chemical purity measurements: Samples were run on a 150mm x 4.6mm, 5μm YMC triart C18 column. The mobile phase was an isocratic elution system containing 1 : 1 0.1 M NH4OAc:CH3CN plus 2% HOAc. The flow rate was 0.75 mL / min; the run time, 35 minutes; and the detector wavelength, 269 nm.

[0322] In the following examples, when details of the example run are shown, notes in square brackets ([]) are used to indicate optional changes that are not part of the example run but can be performed or performed in another run.

[0323] Step 1: Preparation of racemic deuterium-enriched pioglitazone (Compound B)

[0324]

[0325] Pioglitazone HCI (Compound A HCI salt) is dissolved in D2O at elevated temperature. After stirring at 90°C to 100°C for at least 5h, a small amount of DCI is added and then cooled to ambient temperature. After aging the suspension at 15°C to 25°C for several hours, the product is filtered off as Compound B DCI salt. After the first cycle, approximately 95% of the hydrogen at the chiral center is replaced by deuterium.

[0326] If desired, the crude product is then subjected to a second cycle of the same treatment to further increase the deuterium substitution level in Compound (B) to 98+%, as 1 determined by H-NMR.

[0327] Example run:

[0328] First Deuteration Cycle: 19.96 kg of pioglitazone (Compound (A)) was charged into a 100 L glass lined vessel. Then 79.54 kg (71.86 L; 4.0 equivalents w / w) of D2O was charged into the same vessel. The reaction mixture was heated and stirred to about 95 °C and stirred at this temperature for 5 h [temperature can be from about 90 °C to about 100 °C (preferably 95 °C) for at least 5 h. Temperatures of 95 °C or less will result in lower deuterium levels, while temperatures from about 95 °C to about 100 °C work better. Lower amounts of D2O were tried, but the reaction mixture was difficult to stir with less than 4 w / w equivalents, and there was minimal increase in deuteration above 5 w / w equivalents. A significant increase in deuterium level was observed at elevated temperatures, up to 3 to 4 h.]. A thin white suspension was observed and 0.13 kg (0.10 L, 0.005 v / w equivalents) of 35% DC1 in D2O was added and the transfer line was rinsed with approximately 0.25 L D2O (0.0125 v / w equivalents). The reaction mixture was cooled to about 25 °C over about 240 min [cooling time is at least 3 h to a final temperature of about 15 °C to about 25 °C]. The reaction mixture was then stirred at 15 °C for about 13 h [hold time is at least 5 h from about 15 °C to about 25 °C. If the cooling is over 3 h or more, rather than just 1 h, the resulting solids are more easily stirred and filtered]. The crude product was filtered on a 140 L stainless steel nutsche filter. The product was washed with 5.52 kg (4.99 L; 0.25 v / w equivalents) of D2O. The crude product was blown dry under a stream of nitrogen for about 3 h [drying time should be at least 1 h]. The wet crude product was isolated and a monitor sample was taken for 1 H-NMR. The sample was then subjected to a second round of deuteration to increase the deuterium content. [In three runs, the % deuterium on the chiral center was observed to be 96.5%, 97.2% and 96.9% at this stage.]

[0329] Second Deuterium Cycle: Charge the vessel with the entire amount of wet crude product. Then add 75.57 kg (68.26 L) of D2O. Heat the reaction mixture to about 95 °C for about 5 h [the heating temperature can range from about 90 °C to about 100 °C (preferably 95 °C) for at least 5 h]. A thin white suspension is observed. Then add 0.12 kg (0.09 L) of 35% DC1 in D2O and rinse the transfer line with about 0.25 L of D2O. Cool the reaction mixture to 25 °C over a period of 4 h [the cooling ramp should be at least 3 h to a temperature from about 15 °C to about 25 °C]. Stir the reaction mixture at about 20 °C for 9 h [the stirring can be at 15 °C to 25 °C for at least 5 h]. Then filter the crude product on a 140 L stainless steel nutsche filter and rinse with 5.52 kg (4.99 L) of D2O. Deuterium NMR shows more than 2 deuterium per molecule. Dry the compound (B) DC1 salt product (or optionally a mixture of HC1 and DC1 salts) in a 140 L stainless steel nutsche filter to LOD (loss on drying) < 2% at about a maximum of 60 °C under vacuum (about 48 h) [the drying temperature should not exceed a maximum of 60 °C].

[0330] Step 2: Preparation of deuterium-enriched (R)-pioglitazone L-dibenzoyltartrate (Compound (C))

[0331]

[0332] The synthesis starts with dissolving compound (B) or a salt thereof with L-dibenzoyl tartaric acid in a mixture of MeOD (methanol-d1) and D2O at elevated temperature. The mixture is then cooled to about 55 °C. Optionally seed crystals are added (2% or less w / w relative to (compound B)) followed by a rather slow cooling ramp and extended aging time. Eventually, the product compound (C) is filtered off, washed with a mixture of MeOD and D2O and dried in vacuum.

[0333] Example runs:

[0334] A 1000 L glass vessel was charged with 28.10 kg of racemic deuterium enriched pioglitazone (Compound (B)) DCl salt, followed by 25.49 kg of L,L-dibenzoyltartaric acid (1 molar equivalent) and 187.3 kg of MeOD (230.4 L; 6.67 w / w equivalents) [0.6 molar equivalents of L,L-dibenzoyltartaric acid can be used resulting in slightly lower yield but comparable %ee]. The reaction mixture was warmed to a temperature of about 60 °C to about 70 °C (to 65 °C) and 280.9 kg of D2O (253.7 L; 10.0 w / w equivalents) was added. The reaction was warmed to 70 °C to 80 °C (to 76 °C) and the mixture was stirred at this temperature for at least 30 minutes. An almost clear solution was obtained. The mixture was then cooled to 55 °C over 66 minutes [the cooling time should be at least one hour to a temperature of about 52 °C to about 58 °C]. The mixture was then stirred at 56 °C for 2 hours [the stirring can be for at least 2 hours at a temperature of about 52 °C to about 58 °C] during which time seed crystals of Compound (C) were added (0.25 kg) [the seed crystals can be crystals of Compound (C) or (C')]. The suspension was cooled to 25 °C over 7.5 hours [the cooling to a temperature of about 22 °C to about 28 °C should be for at least 5 hours]. The suspension was then stirred for 37 hours [the stirring at 22 °C to 28 °C is required for at least 15 hours].

[0335] The product was filtered off on a stainless steel centrifuge and washed with a pre-mixed mixture of D2O ((13.38 kg; 12.08 L; 0.48 w / w equivalents) and MeOD (9.82 kg; 12.08 L; 0.35 w / w equivalents). The product was blown dry under a nitrogen steam for at least 1 hour. The product Compound (C) was then vacuum dried on a Hastelloy vacuum tray dryer at a maximum temperature of 60 °C. Deuterium NMR showed approximately 2 deuterium per molecule.

[0336] Step 3: Recrystallization of enantiomer (R)-enriched-deuterium-enriched pioglitazone L- dibenzoyltartrate (Compound (C) recrystallized to recrystallized Compound (C)) Preparation of HCI salt derivative:

[0337]

[0338] Example run:

[0339] X-ray powder diffraction characterizationForty six point eight eight kilograms of enantiomerically (R) enriched - deuterium enriched pioglitazone dibenzoyl tartrate (compound (C)) was charged into a 1000 L glass vessel followed by the addition of one hundred eighty five point six kilograms of MeOH ((234.4 L; 4.0 w / w equivalents), fifty five point zero kilograms of D2O (49.7 L; 1.17 w / w equivalents) and one point one kilograms of a 35% DCl solution in D2O (5.6 L; 0.15 w / w equivalents). The reaction mixture was warmed to 60°C to 70°C (63°C was reached) and two hundred eighteen point zero kilograms of D2O (196.9 L; 4.65 w / w equivalents) was added. The reaction was warmed to 70°C to 80°C and the mixture was stirred at this temperature for at least 30 minutes. A nearly clear solution was obtained. The mixture was then cooled to 55°C over 85 minutes [the cooling time should be at least one hour]. The mixture was then stirred at 55°C for 120 minutes and seed crystals of (compound C') (0.14 kg) were added [the stirring can be carried out at 52-58°C for at least 2 hours during which time seed crystals of compound (C) or (C') can be added if necessary]. The suspension was cooled to 26°C over 10 hours 50 minutes [the cooling ramp to 22°C to 28°C should be at least 5 hours]. The suspension was then stirred at 25°C for 34 hours 20 minutes [the suspension should be stirred at 22°C to 28°C for at least 15 hours].

[0340] The product was filtered off on a stainless steel centrifuge and washed with a pre-mixed mixture of D2O (17.1 kg; 15.5 L; 0.36 w / w equivalents) and MeOD (12.3 kg; 15.5 L; 0.26 w / w equivalents). The product compound (C') was blown dry under a stream of nitrogen for at least 1 hour. The product was then sent to HPLC for optical purity measurement. If the optical purity was sufficient (higher than 91%), the compound (C') was vacuum dried on a Hastelloy vacuum tray dryer at a maximum temperature of 60°C. If not, a second recrystallization was performed (actual example: 93% ee; no second recrystallization). Deuterium NMR showed approximately 2 deuterium per molecule.

[0341] If a second or further recrystallization is required, the above steps can be repeated and the recrystallized material isolated and vacuum dried on a Hastelloy vacuum tray dryer at a maximum temperature of 60°C as described above.

[0342] It should be noted that the details given below include the procedures for steps b) and c).

[0343] Preparation of the DCl salt derivative: It is necessary to use solvents which are replaced only with deuterium.

[0344] Example 2: Preparation and characterization of deuterium enriched (R)-pioglitazone crystalline DCl salt

[0345] A solution of 278.5 g of deuterium-enriched (R)-pioglitazone L-benzoyl tartrate (prepared as in Example 1), 450 mL of MeOD, and approximately 38% DCl in D2O (36 g, 2.9 equivalents) was heated to 50 °C. The slightly turbid solution was filtered through a Büchner funnel (100 mL) fitted with a porcelain-1 filter, and the filtrate was reheated to 50 °C. Ethyl acetate (1500 mL) was then added in seven portions (temperature reduced to 30 °C), and the mixture was brought to 20 °C. After stirring at this temperature for 2 hours, the deuterium-enriched (R)-pioglitazone crystalline DCl salt was separated by filtration through a Büchner funnel (250 mL) fitted with a porcelain-4 filter. After thorough washing (in batches) with ethyl acetate (5 x 250 mL), the separated wet cakes were vacuum dried overnight at 50 °C to obtain 44.6 g (Y = 89.9%) of deuterated hydrochloride, a white crystalline material. The enantiomeric excess was 97.1% (HPLC), and the chiral center D content was 99.0%. 1 H-NMR). Note: Other samples synthesized using the exact same process were analyzed by H-NMR. 2 Analyzed by H-NMR, using 2 The deuterium content of H-NMR indicates that there are approximately three deuteriums on the molecule (one at the chiral center, DCl, and one at the exchangeable NH position).

[0346] Chiral HPLC method: Samples were run on a 250 mm x 4.6 mm, 3 μm Chiralpak IC or equivalent apparatus. The mobile phase was an isocratic elution system using 70:30 (v / v) hexane / IPA. The flow rate was 1.0 mL / min; the run time was 30 min; and the detector wavelength was 225 nm.

[0347] 1 H-NMR method: Dissolve approximately 5 to 10 mg of sample in DMSO D6 for use. 1 ¹H-NMR analysis was performed using a Bruker Avance 300MHz or higher spectrometer. 1 H-NMR analysis.

[0348] Figure 1A

[0349] Figure 1A X-ray powder diffraction patterns of deuterium-enriched crystalline DCl salts of (R)-pioglitazone are provided. The diffraction was performed using a D8 Advance diffractometer with CuK at room temperature (e.g., about 21°C to about 23°C). a1 radiation X-ray powder diffraction data were collected using a germanium monochromator. Detector scanning was performed on a solid-state LynxEye detector at a step size of 0.016° and a scan rate of 5 seconds per step. The sample was analyzed in an 8-mm long glass capillary with an outer diameter of 0.3mm. Figure 1B The list of characteristics of the medium X-ray powder diffraction pattern is provided in Table 4 below, which lists the diffraction angle 2θ, interplane distance d, and relative intensity (expressed as a percentage relative to the strongest peak).

[0350] Table 4 – X-ray powder diffraction data of deuterium-enriched (R)-pioglitazone crystalline deuterated hydrochloride

[0351]

[0352]

[0353] like Single crystal X-ray diffraction characterization As shown, it can be noted that the X-ray powder diffraction (XRPD) pattern (upper trace) of (R)-2H-pioglitazone hydrochloride is different from that of pioglitazone hydrochloride (lower trace), especially showing the doubling of several peaks.

[0354] Optical microscopy characterization

[0355] Single-crystal DCl salts of deuterium-enriched (R)-pioglitazone were analyzed by single-crystal X-ray diffraction. Data were collected at 296 K using a Nonius Kappa-CCD instrument.

[0356] Data reduction was performed using HKL Scalepack (Otwinowski & Minor 1997), and cell parameters were obtained using Denzo and Scalepak (Otwinowski & Minor 1997).

[0357] The crystal structure of the deuterium-enriched (R)-pioglitazone crystalline DCl salt was resolved using the SHELXT-2014 / 7 direct method (Sheldrick, GM, 2015a). The structure was refined using the SHELXL-2014 / 7 method (Sheldrick, GM, 2015b) via least-squares full-matrix refinement. All H atoms bonded to C were contained within the geometry, and the thermal parameters were kept constant. The H atoms involved in the hydrogen bond network were identified in the Fourier difference plot and an isotropic refinement was performed.

[0358] The cell parameters of the deuterium-enriched (R)-pioglitazone crystalline DCl salt, as well as the data collection and structure refinement methods, are shown in Table 5.

[0359] Table 5 - Cell parameters, data collection and structure refinement methods for crystalline DC1 salt of deuterium-enriched (R)-pioglitazone

[0360]

[0361]

[0362] Figure 2

[0363] An optical micrograph of crystalline DC1 salt of deuterium-enriched (R)-pioglitazone is shown in Differential scanning calorimetry characterization The optical micrograph was obtained using a Leica DM2500M optical microscope. The crystals exhibited hexagonal and rod-like crystal shapes.

[0364] Figure 3

[0365] Characterization by thermogravimetric analysis and thermogravimetric mass spectrometry A differential scanning calorimetry (DSC) curve of crystalline DC1 salt of deuterium-enriched (R)-pioglitazone is provided. DSC data were collected using a heat flux DSC 3+ STARe system. The sample (-2 mg) was sealed in a standard 40 pL aluminum pan, pierced with a pin, and heated in the DSC at a heating rate of 10 °C / min from 25 °C to 300 °C. During the measurement, the sample chamber was purged with dry N2 gas at a flow rate of 50 mL / min. The DSC curve shows an endothermic event corresponding to the melting of the crystalline DC1 salt form of deuterium-enriched (R)-pioglitazone with onset and peak values of about 191 °C and about 202 °C, respectively.

[0366] Figure 4A

[0367] Thermogravimetric analysis (TGA) and thermogravimetric mass spectrometry (TGMS) data for the crystalline DC1 salt form of deuterium-enriched (R)-pioglitazone are provided in Figure 4B and NMR spectroscopy characterization The TGA data were collected using a TGA / DSC 3+ STARe system (Mettler-Toledo GmbH, Switzerland) which was temperature calibrated using indium and aluminum samples. The sample was weighed into a 100 pL aluminum crucible and sealed. The seal was pierced with a pin and the crucible was heated at a heating rate of 10 °C from 25 °C to 300 °C. During the measurement, a purge with dry N2 gas was used. Volatiles produced upon heating of the TGA sample were analyzed by an Omnistar GSD 301 T2 (Pfeiffer Vacuum GmbH, Germany) mass spectrometer. The TGA and TGMS data indicate that the crystalline DC1 salt form of deuterium-enriched (R)-pioglitazone is anhydrous with a mass loss of 0.07% between 40 °C and 170 °C and thermal decomposition above 190 °C.

[0368] Figure 5

[0369] At room temperature, deuterium-enriched (R)-pioglitazone crystalline DCl salts were collected on a 500 MHz Bruker instrument using a standard pulse sequence. 1 ¹H-NMR spectra. The sample, in the form of deuterium-enriched (R)-pioglitazone crystalline DCl salt, was dissolved in DMSO-d6. Deuterium-enriched (R)-pioglitazone crystalline DCl salt form. 1 The ¹H-NMR chemical shifts (ppm) are as follows: 1.25 (t, 3H), 2.79 (q, 2H), 3.07 (d, 1H), 3.30–3.34 (m, 1H), 3.43 (t, 2H), 4.38 (t, 2H), 6.83–6.93 (m, 2H), 7.11–7.24 (m, 2H), 7.94 (br d, 1H), 8.37 (br d, 1H), 8.66–8.80 (m, 1H), 12.04 (s, 1H). X-ray powder diffraction characterization Provides representative examples of crystalline DCl salts 1 H-NMR spectrum.

[0370] Example 3: Preparation and characterization of deuterium-enriched (R)-pioglitazone in crystalline HCl salt form

[0371] 2.2 g of deuterium-enriched (R)-pioglitazone L-benzoyl tartrate (prepared as in Example 1), 11 mL of MeOH, and an aqueous solution of 37% HCl in H₂O (0.308 g, 2.9 equivalents) were heated to 40 °C. Subsequently, 40 mL of ethyl acetate was added to the slightly turbid solution, and the mixture was cooled to 20 °C. After stirring at this temperature for 2 hours, the deuterium-enriched (R)-pioglitazone in HCl form was separated by filtration (using a P-4 Büchner funnel with filter paper) and thoroughly washed with ethyl acetate (5 x 20 mL). After drying under vacuum overnight at 50 °C, 1.1 g (Y = 90.9%) of a white crystalline material was obtained. The enantiomeric excess was 97.2% (HPLC), and the D content was >98%. 1 H-NMR). Note: 2 The deuterium content detected by H-NMR indicates that there is approximately one deuterium molecule on the molecule. 1 H-NMR confirmed that the molecule is located at a chiral center.

[0372] Chiral HPLC method: Samples were run on a 250 mm x 4.6 mm, 3 μm Chiralpak IC or equivalent apparatus. The mobile phase was an isocratic elution system using 70:30 (v / v) hexane / IPA. The flow rate was 1.0 mL / min; the run time was 30 min; and the detector wavelength was 225 nm.

[0373] 1 H-NMR Method: About 5 to 10 mg of sample was dissolved in DMSO D6 for 1 H-NMR analysis. H-NMR analysis was performed using a Bruker Avance 300 MHz or higher spectrometer. 1

[0374] Figure 6

[0375] Figure 6 An X-ray powder diffraction pattern of a crystalline HC1 salt of deuterium- enriched (R)-pioglitazone is provided. The X-ray powder diffraction data was collected as described in Example 2. Optical microscopy characterization A list of the characteristic features of the X-ray powder diffraction pattern is provided in Table 6 below, where the diffraction angles 2 theta, interplanar distances d, and relative intensities (expressed as a percentage relative to the strongest peak) are listed.

[0376] Table 6 - X-ray powder diffraction pattern data of a crystalline HC1 salt form of deuterium-enriched (R)-pioglitazone

[0377]

[0378]

[0379] Figure 7

[0380] An optical photomicrograph of a crystalline DC1 salt of deuterium-enriched (R)- pioglitazone is shown in Differential scanning calorimetry characterization The optical photomicrograph was obtained using a Leica DM2500M optical microscope. The crystals exhibited hexagonal and rod-like crystal shapes.

[0381] Figure 8

[0382] Characterization by thermogravimetric analysis / simultaneous differential thermal analysis and thermogravimetric mass spectrometry A differential scanning calorimetry (DSC) curve of a crystalline HC1 salt of deuterium-enriched (R)-pioglitazone is provided. The DSC data was collected using the method described in Example 2. The DSC curve shows an endothermic event corresponding to the melting of a crystalline HC1 salt form of deuterium-enriched (R)-pioglitazone with an onset and peak value of about 190 °C and about 200 °C, respectively.

[0383] Figure 9A

[0384] Thermogravimetric analysis (TGA) and thermogravimetric mass spectrometry (TGMS) data of a crystalline HC1 salt form of deuterium-enriched (R)-pioglitazone are provided in Figure 9B and NMR spectroscopy characterization ​The TGA and TGMS data were collected using the method described in Example 2. The TGA and TGMS data indicate that the crystalline HC1 salt form of deuterium-enriched (R)- pioglitazone is anhydrous with a mass loss of 0.1% between 40 °C and 180 °C and thermal decomposition occurs above 220 °C.

[0385] Figure 10

[0386] The TGA and TGMS data were collected using the method described in Example 2. The TGA and TGMS data indicate that the crystalline HC1 salt form of deuterium-enriched (R)- pioglitazone is anhydrous with a mass loss of 0.1% between 40 °C and 180 °C and thermal decomposition occurs above 220 °C. 1 H-NMR Spectrum. A sample of the crystalline HC1 salt form of deuterium-enriched (R)- pioglitazone was dissolved in DMSO-d6. The H-NMR spectrum of the crystalline HC1 salt form of deuterium-enriched (R)-pioglitazone is shown in Figure 1. 1 The H-NMR chemical shifts (ppm) are as follows: 1.25 (t, 3H), 2.79 (q, 2H), 3.07 (d, 1H), 3.30-3.34 (m, 1H), 3.43 (t, 2H), 4.38 (t, 2H), 6.83-6.93 (m, 2H), 7.11-7.24 (m, 2H), 7.94 (br d, 1H), 8.37 (br d, 1H), 8.66-8.80 (m, 1H), 12.04 (s, 1H). X-ray powder diffraction characterization A representative X-ray powder diffraction pattern of the crystalline HC1 salt is provided in Figure 2. 1 H-NMR Spectrum. A sample of the crystalline HC1 salt form of deuterium-enriched (R)- pioglitazone was dissolved in DMSO-d6. The H-NMR spectrum of the crystalline HC1 salt form of deuterium-enriched (R)-pioglitazone is shown in Figure 1.

[0387] Example 4: Preparation and characterization of the crystalline free base form of deuterium-enriched (R)-pioglitazone

[0388] The free base form of deuterium-enriched R-pioglitazone was prepared by incubating the crystalline DC1 salt of deuterium-enriched R-pioglitazone in water at 50 °C for 2 weeks.

[0389] The enantiomeric excess was determined to be 43% by HPLC. The HPLC method used is described in Examples 2 and 3.

[0390] The D content on the chiral center was determined to be about 66% by H-NMR. The H-NMR method used is described in Examples 2 and 3. 1 The D content on the chiral center was determined to be about 66% by H-NMR. The H-NMR method used is described in Examples 2 and 3. 1 The H-NMR method used is described in Examples 2 and 3.

[0391] Figure 11

[0392] Figure 11 An X-ray powder diffraction pattern of the crystalline free base form of deuterium-enriched R-pioglitazone is provided. The X-ray powder diffraction data were collected as shown in Example 2. Differential scanning calorimetry characterization Representative diffraction peaks of the X-ray powder diffraction pattern in Example 4 are provided below in Table 7 in terms of diffraction angle (2 theta).

[0393] Table 7 – X-ray powder diffraction data of deuterium-enriched R-pyridine in its crystalline free base form.

[0394]

[0395]

[0396] Figure 12

[0397] Characterization by thermogravimetric analysis / simultaneous differential thermal analysis and thermogravimetric mass spectrometry Differential scanning calorimetry (DSC) curves of the deuterium-enriched R-pioglitazone in its crystalline free base form are provided. The DSC data were collected using the method described in Example 2. The DSC curves show endothermic events corresponding to the melting of the deuterium-enriched R-pioglitazone in its crystalline free base form, with initial and peak values ​​of approximately 174 °C and approximately 178 °C, respectively.

[0398] Figure 13A

[0399] Thermogravimetric analysis (TGA) and thermogravimetric mass spectrometry (TGMS) data of deuterium-enriched R-pioglitazone in its crystalline free base form were obtained from [data missing]. Figure 13B and NMR spectroscopy characterization Provided in [the document]. TGA and TGMS data were collected using the method described in Example 2. The TGA and TGMS data indicate that the deuterium-enriched R-pioglitazone in its crystalline free base form is anhydrous and undergoes thermal decomposition above 160°C.

[0400] Solvent

[0401] The deuterium-enriched (R)-pioglitazone crystalline free base form was collected using the method described in Example 2. 1 ¹H-NMR spectra. The sample, in its deuterium-enriched (R)-pioglitazone crystalline free base form, was dissolved in DMSO-d6. Deuterium-enriched (R)-pioglitazone crystalline free base form... 1 The ¹H-NMR chemical shifts (ppm) are as follows: 1.20 (t, 3H), 2.56–2.70 (m, 2H), 3.06 (d, 1H), 3.17 (t, 2H), 3.24–3.33 (m, 1H), 4.32 (t, 2H), 4.88 (dd, 1H), 6.80–6.93 (m, 2H), 7.15 (m, 2H), 7.35 (br d, 1H), 7.66 (br d, 1H), 8.41 (s, 1H), 12.03 (s, 1H).

[0402] Example 5: Solubility of deuterium-enriched (R)-pioglitazone crystals in various organic solvents (DCl and HCl salts)

[0403] Crystalline DCI salt of deuterium-enriched (R)-pioglitazone: A suspension of the crystalline material in ethanol, methanol, 3-pentanone, 2-propanol, DMSO, t-butyl methyl ether, N,N-dimethylformamide, ethyl acetate, acetone, water, tetrahydrofuran, and chloroform was incubated at room temperature (about 21 °C to about 23 °C) for 24 hours. An aliquot of the mother liquor was then removed from each suspension and analyzed by HPLC to determine the concentration of deuterium-enriched (R)-pioglitazone in the different solvents. The HPLC method is shown in Table 8.

[0404] Table 8: HPLC Method

[0405]

[0406]

[0407] Crystalline HC1 salt of deuterium-enriched (R)-pioglitazone: Qualitative test: (i) about 5 mg of the crystalline HC1 salt was added to 1 mL of each solvent (DMSO, N,N-dimethylformamide, methanol, water, ethanol, tetrahydrofuran, ethyl acetate, toluene, and dichloromethane); (ii) the resulting mixture was then stirred at ambient temperature (about 21 °C to about 23 °C) for 5-10 minutes; (iii) the mixture was then visually inspected to determine if the crystalline HC1 salt was completely dissolved; (iv) if the crystalline HC1 salt was not completely dissolved, more solvent was added until complete dissolution. Quantitative test: (i) 100 mg of the crystalline HC1 salt was added to 4 volumes (0.4 mL) of each solvent (N,N-dimethylformamide, methanol, and DMSO); (ii) the resulting mixture was then stirred at ambient temperature (about 20 °C to about 25 °C) for 5-10 minutes; (iii) the mixture was then visually inspected to determine if the crystalline HC1 salt had completely dissolved; (iv) if the crystalline HC1 salt was not completely dissolved, more solvent was added until complete dissolution.

[0408] The solubility was then calculated using the total amount of crystalline HC1 salt and solvent used for each solvent.

[0409] Table 9 and Table 10 show the solubility data for the crystalline DCI and HC1 salts of deuterium-enriched (R)-pioglitazone in various organic solvents, respectively.

[0410] Table 9. Solubility of crystalline DCI salt form of deuterium-enriched (R)-pioglitazone in various organic solvents

[0411] Solubility (mg / mL) DMSO N,N-dimethylformamide 225.9 Methanol 46.4 Water 45.0 Ethanol 7.7 Chloroform 4.4 Tetrahydrofuran 2.0 3-pentanone 1.8 2-propanol 0.5 Acetone 0.5 tert-butyl methyl ether 0.5 Ethyl acetate <0.1 Figure 14 <0.1

[0412] Table 10. Solubility of crystalline HC1 salt form of deuterium-enriched (R)-pioglitazone in different organic solvents

[0413]

[0414]

[0415] Example 6: Effect of pH on solubility of crystalline DCI and HC1 salts of deuterium-enriched (R)-pioglitazone and crystalline pioglitazone HC1 salt

[0416] The pH-dependent solubility curves of the crystalline DCI salt form of deuterium-enriched (R)-pioglitazone and the crystalline pioglitazone HC1 salt were determined at room temperature (about 21 °C to about 23 °C) over a pH range of 0.3-7.6. For the crystalline HC1 salt form of deuterium-enriched (R)-pioglitazone, the pH-dependent solubility curve was measured at room temperature (about 21 °C to about 23 °C) over a pH range of 0.3-3.5.

[0417] For the crystalline DCI salt form of deuterium-enriched pioglitazone, the pH-dependent solubility curve was measured at room temperature (about 21 °C to about 23 °C) and over a pH range of 0.7-3.5.

[0418] Suspensions of the three crystalline forms in water or USP buffer solution were prepared. The pH of the suspensions was adjusted by the addition of 0.1 M HC1 or 0.1 M NaOH. To prepare suspensions with a pH of 0.5 or lower, the pH was adjusted using 1 M HC1.

[0419] The suspensions were then allowed to equilibrate at room temperature (about 21 °C to about 23 °C) for 48 hours. After equilibration, the solid phase was separated from the liquid phase by centrifugation, followed by drying, and then analyzed by XRPD. The concentration of deuterium-enriched (R)-pioglitazone or pioglitazone in the liquid phase (mother liquor) was determined by HPLC (see HPLC method described in Example 5).

[0420] The solubility data collected for the four crystalline forms are shown in Table 11, and overlays of the pH-dependent solubility curves for the crystalline DCI and HC1 salt forms of deuterium-enriched (R)-pioglitazone, the crystalline DCI salt form of deuterium-enriched pioglitazone, and the crystalline pioglitazone HC1 salt are shown in Figure 15

[0421] ​The crystalline DC1 and HC1 salts of deuterium-enriched (R)-pioglitazone exhibited similar pH-dependent solubility profiles: solubility was higher at very low pH values - 0.4-1.4, reaching a maximum solubility at pH 1.4 (4.54 mg / mL and 5.25 mg / mL for the DC1 and HC1 salts, respectively). Subsequent decrease in solubility was observed by increasing the pH. At pH 1.6, the solubility of the crystalline DC1 salt of deuterium-enriched (R)-pioglitazone decreased to 2.58 mg / mL, while the solubility of the crystalline HC1 salt of deuterium-enriched (R)-pioglitazone decreased to 3.47 mg / mL. The observed decrease in solubility was more pronounced at pH values of 2.4 and 3.0 (0.39 mg / mL and 0.20 mg / mL for the DC1 and HC1 salts, respectively). Both salts were observed to be almost insoluble at pH values higher than 4.

[0422] In contrast, the maximum solubility of pioglitazone HC1 salt was determined to be 4.00 mg / mL at pH 0.7. The solubility of pioglitazone HC1 salt was found to decrease with increasing solution pH: 2.88 mg / mL at pH 0.6 and 0.67 mg / mL at pH 1.2. Further decrease in solubility was observed at higher pH values. Pioglitazone HC1 salt was observed to be almost insoluble at pH values greater than 3. The crystalline DC1 salt form of deuterium-enriched pioglitazone exhibited similar behavior as pioglitazone HC1 salt.

[0423] For all four solid forms, no change in solid form was observed after equilibration at a pH range of 0.3-0.8. At a pH range of 1.2-1.4, partial or complete conversion of all three solid forms to the respective free base form was observed.

[0424] Table 11. pH-dependent solubility data for the crystalline DC1 and HC1 salt forms of deuterium-enriched (R)-pioglitazone and the crystalline pioglitazone HC1 salt

[0425]

[0426]

[0427]

[0428] a Average solubility values.

[0429] Example 7: Particle size distribution determination of the crystalline DC1 and HC1 salts of deuterium-enriched (R)-pioglitazone

[0430] The particle size distribution of crystalline DCl and HC1 salts of deuterium- enriched (R)-pioglitazone prepared using the methods described in Examples 2 and 3, respectively, was measured using laser diffraction method. Samples of crystalline DCl and HC1 salts (100-200 mg) were wetted and dispersed in 30 mL of heptane. Experimental details are given in Table 12.

[0431] Representative particle size distributions of HC1 (before and after milling) and DCl salts are given in Table 13.

[0432] The crystalline HC1 salt was milled using a fluidized air jet milling system or equivalent.

[0433] Table 12. Particle size distribution analysis - laser diffraction method

[0434]

[0435] Table 13. Representative particle size distribution of crystalline DCl and HC1 salts of deuterium-enriched (R)-pioglitazone

[0436]

[0437]

[0438] Example 8: Study to evaluate the impact of particle size distribution of crystalline HC1 salt of deuterium-enriched (R)-pioglitazone (API) on processability

[0439] PXL065 tablets of 15 mg strength were studied.

[0440] Table 14. Particle size distribution of PXL065 for the 3 micronized batches used in the study:

[0441]

[0442] The tablets contained 15 mg of PXL065, and lactose, carboxymethylcellulose calcium, hydroxypropylcellulose and magnesium stearate. The manufacturing process included steps of mixing, lubrication and compression. The particle size distribution of the 3 batches is shown in Table 14.

[0443] Flowability

[0444] The mixture of API manufactured with D90 < 10 pm was more sticky.

[0445] Mixing homogeneity

[0446] Table 15: Mixing homogeneity

[0447]

[0448]

[0449] Conclusions:

[0450] The blend uniformity (as shown in Table 15) for all three batches met the requirements (acceptance criteria = 90-110%). However, lower uniformity values were obtained for blends manufactured with API having D90 < 10 pm. Some loss can occur during manufacturing due to the stickiness of the API.

[0451] The average content uniformity values were < 97% for batch LF21026, while the average content uniformity values were > 97% for batches LF21027 and LF21028, which is consistent with the blend uniformity results.

[0452] Extensometric Study

[0453] Objective: To assess the tablet hardness (Critical Quality Attribute = CQA) as a function of pressure and speed. The tablet hardness is shown in Table 16.

[0454] Conclusions

[0455] As shown in Table 16, the lower the PSD of the API, the lower the maximum hardness. Tablet hardness was not specified and information at the time of release was analyzed. Figure 16 As shown in Table 16, tablets produced from blends of API having D90 < 10 pm were more affected by the change in speed of the compression machine.

[0456] Day

[0457] Table 16 - Tablet hardness in Newtons

[0458]

[0459] Example 9. Canine Pharmacokinetic (PK) Study

[0460] The objective of this study was to assess and compare the pharmacokinetic characteristics of the deuterium-enriched (R)- and (S)-enantiomers of pioglitazone (PXL064 and PXL065) and the deuterium-enriched pioglitazone (PXL061) after a single administration by the oral route (capsules). Three male beagle dogs were fasted prior to administration. All test drugs were then administered by the oral route using the API in capsules. The administration schedule is shown in Table 17.

[0461] Table 17. Administration of test drugs for canine PK study

[0462] Administration Dose (mg / kg) PXL065 1 PXL064 5 4 PXL061 5 8 Figures 17-19 10

[0463] ​​On treatment days, food was given no earlier than one hour after dose administration. Each administration was separated by a washout period of at least 2 days. Blood collections were performed for analysis of plasma concentrations and area under the curve (AUC) of d-R-pioglitazone, d-S-pioglitazone, h-R-pioglitazone, and h-S-pioglitazone. Quantitative time points: pre-dose (pre-administration), post-administration T0.25h, T0.5h, Tlh, T2h, T4h, T8h, T12h, and T24h.

[0464] Table 18. Mean plasma PK parameters for total pioglitazone and pioglitazone enantiomers following single oral PXL065, PXL064, PXL061, or pioglitazone in dogs

[0465]

[0466]

[0467] AUCo-24 = Area under the plasma concentration-time curve from 0 to 24 hours; Cmax = Maximum plasma concentration; pio = pioglitazone; SD = standard deviation; t 1 / 2 z = terminal elimination phase half-life; t max = time to maximum plasma concentration

[0468] Note: Tables show exposure to total pioglitazone (sum of deuterated and protonated (R)- and (S)-enantiomers of pioglitazone),

[0469] Note: Data are presented as mean ± SD values, t max Except that it is presented as median [min, max].

[0470] Note: Data are shown as n = 3, unless otherwise indicated.

[0471] a Data are presented for n = 2 rather than n = 3. Data are presented as mean (individual animal values).

[0472] Mean plasma PK parameters are shown in Table 18, and plasma exposure and relative bioavailability are shown in Table 19.

[0473] Plasma PK profiles over time are shown in Figure 20 .

[0474] Table 19. Plasma exposure (AUCo-24) of total pioglitazone in dogs and relative bioavailability of deuterium-enriched (R)-pioglitazone (PXL065) and deuterium-enriched (S)-pioglitazone (PXL064) compared to deuterium-enriched pioglitazone (PXL061)

[0475]

[0476] AUC0 -24 = area under the plasma concentration-time curve from 0 to 24 hours; Frel = relative oral bioavailability; geo = geometric; total pioglitazone (sum of deuterated and protonated (R)- and (S)-enantiomers of pioglitazone)

[0477] The results of these studies support the fact that an increase in total pioglitazone bioavailability (sum of protonated and deuterated (R)- and (S)-enantiomers) is observed with PXL065 compared to deuterium-enriched pioglitazone (PXL061) and not with deuterium-enriched (S)-enantiomer (PXL064), indicating that the bioavailability enhancement of PXL065 is not due to the presence of deuterium.

[0478] Example 10. 13-Week canine toxicology study

[0479] The objective of this study was to evaluate the potential toxicity and toxicokinetics of deuterium-enriched (R)-pioglitazone (PXL065) following 13 weeks of oral (capsule) administration to beagle dogs compared to pioglitazone. Four groups of beagle dogs included three or five animals / sex per group, administered orally 0 (placebo capsule), 1.5, 5, or 15 mg / kg / day of PXL065 (one capsule per day of API) for 13 weeks; another group was given 10 mg / kg / day of pioglitazone (one capsule per day of API). Blood was collected at various time points during dosing (pre-dose, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose) for toxicokinetic evaluation to determine plasma concentrations of d-R-pioglitazone, d-S-pioglitazone, h-R-pioglitazone, and h-S-pioglitazone.

[0480] A complete toxicology evaluation is not provided here, but relative bioavailability data based on total pioglitazone plasma concentrations at Day 91 are shown in Table 20 and Objectives

[0481] Table 20: Mean total pioglitazone exposure in dogs at Day 91

[0482]

[0483] AUC 0-24,SS = area under the plasma concentration-time curve from 0 to 24 hours at steady state; total pioglitazone (sum of deuterated and protonated (R)- and (S)-enantiomers of pioglitazone)

[0484] The results of these studies indicate that an increase in total pioglitazone bioavailability (sum of protonated and deuterated (R)- and (S)-enantiomers) is observed with PXL065 compared to pioglitazone.

[0485] ​Example 11: Assessment of PXL065 in comparison to pioglitazone hydrochloride Phase la study to assess safety, tolerability, and pharmacokinetics of repeated dosing of crystalline HC1 salt of deuterium-enriched (R)-pioglitazone (PXL065) in healthy human subjects in comparison to pioglitazone hydrochloride

[0486] Study methods

[0487] The primary objective of this study is to assess the safety and tolerability of single oral doses of PXL-065 (7.5 mg, 22.5 mg, and 30 mg capsules) in healthy subjects.

[0488] The second objective of this study is to assess the PK of PXL065 in comparison to The PK of PXL065 following single dose administration in healthy subjects, with particular focus on assessing the exposure of deuterated and protonated (R)- and (S)-pioglitazone to determine the extent, if any, of interconversion of PXL065 with the protonated (R)- and (S)-enantiomers in comparison to pioglitazone hydrochloride.

[0489] Diagnosis and inclusion criteria

[0490] This study is conducted in two parts. Part 1 uses an open-label, parallel-group design. Eligible subjects are enrolled in the clinical research unit within 21 days of screening. On study day 1, subjects are randomly assigned to receive a single dose of PXL065 22.5 mg (6 subjects) or a single dose of PXL065 45 mg (6 subjects). The study drug dose is administered in a fasted state at approximately 8 a.m. on day 1. Subjects remain in the clinical unit for 36 hours post administration. Subjects return to the clinical facility for follow-up assessments on days 4 and 7 as outpatients. Following review of the safety and tolerability of PXL065 in Part 1 and determination of comparative PK exposure of the enantiomers by the Data Review Committee (DRC), 6 healthy subjects are enrolled in Part 2.

[0491] Part 2 uses an open-label design in which a single dose of PXL065 7.5 mg is administered in a fasted state in the morning on day 1. Subjects remain in the clinical unit for at least 36 hours post administration and return to the clinical facility for follow-up assessments on days 4 and 7 as outpatients. Following review of the safety, tolerability, and PK data for the PXL065 7.5 mg dose group, an additional treatment group of 6 healthy subjects (PXL065 30 mg) is evaluated. The DRC reviews the safety and tolerability of the previous group prior to dosing of the additional group.

[0492] Test product, dose, and mode of administration

[0493] ​Subjects are healthy adult men or women, aged 18-40 years, inclusive, with a body mass index (BMI) > 17 to < 32 kg / m 2 . Female subjects are not pregnant or lactating.

[0494] Control product, dose, and mode of administration

[0495] PXL065, administered orally. Dose = 1 x 7.5 mg capsule, 1 x 22.5 mg capsule, or 1 x 30 mg capsule. PXL065 capsules contain 7.5 mg, 22.5 mg, or 30 mg of PXL065, and lactose.

[0496] Treatment duration

[0497] Administered orally. Dose = 1 x 45 mg, tablet.

[0498] Purchased as a brand product. The 45 mg tablet includes 45 mg pioglitazone HC1 salt, lactose, carboxymethylcellulose calcium, hydroxypropyl cellulose, and magnesium stearate.

[0499] Evaluation criteria

[0500] In Part 1, a single dose of PXL065 22.5 mg or a single dose of 45 mg is administered to each subject for evaluation, and they are evaluated 7 days after administration. In Part 2, each subject is administered a single dose of PXL065 7.5 mg or 30 mg, and they are evaluated 7 days after administration. The total study duration from the restriction time (-1 day) to the end of the study visit is 8 days.

[0501] Statistical methods

[0502] Safety: The investigator assesses safety using the following assessments: physical examination, electrocardiogram (ECG), vital sign measurements, clinical laboratory assessments, and reported or observed adverse events (AEs). Any AEs in the subject are monitored from the restriction through the end of the study.

[0503] Pharmacokinetics: Plasma PK parameters for the deuterated and protonated forms of (R)- and (S)-pioglitazone are calculated, including but not limited to t 1 / 2 , t max , C max , AUC 0-last , and AUC 0-inf .

[0504] Results

[0505] Generally, all data are summarized with descriptive statistics (number of participants, mean, standard deviation, minimum, median, and maximum) for continuous endpoints, and frequency and percentage for categorical endpoints. Within each part of the clinical study, data for each cohort and the treatment group within each cohort are presented separately.

[0506] Safety and Tolerability: All safety and tolerability data are listed. In the case of continuous variables, descriptive statistics are used to summarize treatment and time point outcomes and changes relative to baseline.

[0507] The categorized assessment values ​​were tabulated. Adverse events (AEs) were coded according to MedDRA.

[0508] Figure 21

[0509] As shown in Table 21 and Objectives As shown, with In comparison, PXL065 showed improved bioavailability after a single dose in healthy human subjects.

[0510] Table 21: Total pioglitazone exposure in Phase Ia human studies

[0511]

[0512] AUC inf = Area under the plasma concentration-time curve from time 0 to infinity; Total pioglitazone (the sum of deuterated and protonated (R)- and (S)-enantiomers of pioglitazone)

[0513] Example 12. Evaluation of the effect of pioglitazone HCl In comparison, a Phase Ib study of the safety, tolerability, and pharmacokinetics of repeatedly administered deuterium-enriched crystalline HCl salt of (R)-pioglitazone (PXL065) in healthy human subjects was conducted.

[0514] Study methods

[0515] The primary objective of this study was to evaluate its interaction with pioglitazone HCl. Safety and tolerability of repeated administration of different doses of PXL065 in healthy subjects compared to 45 mg.

[0516] The second objective of this study is to evaluate and... Compared to 45 mg, the pharmacokinetic (PK) of PXL065 in healthy subjects after single and multiple administrations focused particularly on assessing exposure to the deuterated and protonated (R)- and (S)-enantiomers of pioglitazone to determine the interconversion of PXL065 with the protonated (R)- and (S)-enantiomers (if any).

[0517] Diagnosis and inclusion criteria

[0518] Subjects were screened within 28 days prior to the first dose of study drug. They remained at the clinical site from 1 day prior to administration (Day -1) until at least 48 hours after the last trial drug administration (Day 11). Subjects returned to the clinical site for outpatient assessments and / or PK sampling on Day 12 (about 72 hours after administration), Day 13 (about 96 hours after administration), Day 14 (about 120 hours after administration), Day 15 (about 144 hours after administration) and for a follow-up visit 10 days (± 2 days) after the last administration.

[0519] Up to 30 healthy subjects were enrolled in the trial:

[0520] • Three (3) PXL065 dose groups: 8 subjects in each dose group (6 taking active drug, 2 taking placebo). Each dose group consisted of 4 males and 4 females, with an active drug / placebo ratio of 3: 1.

[0521] • One (1) PXL065 dose group: Group: 6 subjects (3 males and 3 females) received No placebo was given to any subject in this group.

[0522] The dose levels in Groups 1-4 were as follows (Table 22):

[0523] Table 22. Dose levels for Groups 1-4

[0524]

[0525] Subjects received a single oral dose of study drug (7.5, 15, or 30 mg PXL065 tablets or matching placebo tablets, or 45 mg tablets) under fasted conditions on Day 1. They then received repeated administrations of each study drug for 7 days, from Day 3 to Day 9. All study drugs were administered under fasted conditions.

[0526] PXL065 PK parameters for the three single oral doses on Day 1 and on Day 9 after 7 days of administration were compared to PK parameters on Day 1 and on Day 9 after 7 days of administration.

[0527] Test product, dose, and mode of administration

[0528] Subjects were healthy adult men or women, aged 18-45 years, inclusive, with a body mass index (BMI) of > 18.5 to < 32 kg / m 2Body weight > 60 kg. Female subjects were not pregnant or lactating.

[0529] Control product, dose, and mode of administration

[0530] PXL065, administered orally. Dose = 1 x 7.5 mg tablet, 1 x 15 mg tablet, or 1 x 30 mg tablet.

[0531] PXL065 tablets contain 7.5 mg, 15 mg, or 30 mg of PXL065, and lactose, carboxymethylcellulose calcium, hydroxypropyl cellulose, and magnesium stearate.

[0532] Treatment duration

[0533] Oral administration. Dose = 1 x 45 milligrams, tablet.

[0534] Purchased as brand product. 45 mg tablet contains 45 mg pioglitazone HCl salt, lactose, carboxymethylcellulose calcium, hydroxypropyl cellulose, and magnesium stearate.

[0535] Evaluation criteria

[0536] On Day 1, a single oral dose of PXL065 or matching placebo or Then multiple oral doses of PXL065 or matching placebo or

[0537] Safety

[0538] Pharmacokinetics: Plasma samples were analyzed using a validated assay. Samples from all evaluable subjects were analyzed. Samples from subjects who experienced emesis within 4 hours post-dose were not analyzed.

[0539] Plasma PK parameters include, but are not limited to:

[0540] • After single administration on Day 1 and Day 3 (for PXL065 groups): t max , t lag , C max , AUC 0-last , AUC 0-24 , AUC 0-inf , λ z , t 1 / 2 , %AUC ext , CL / F, Vz / F, C max / dose, AUC0-last / dose, AUC 0-inf / dose and MRT.

[0541] • Days 4 to 9: deuterated and protonated (R)- and (S)-enantiomers for pioglitazone;

[0542] • On Day 9, the following repeat dosing was performed: t max , C max , C avg , t lag , AUC 0-last , AUC 0-24 , AUC 0-inf , λ z , t 1 / 2 , %AUC ext , CL ss / F, Vz ss / F, MRT, PTF, R ac (AUC 0-24 ), R ac (C max )SR(AUC), C max / dose, AUC 0-last / dose, AUC 0-inf / dose, AUC 0-24 / dose.

[0543] Statistical methods

[0544] The investigators used the following assessments to evaluate safety: physical examination, vital sign measurements, clinical laboratory evaluations, electrocardiogram, and reported or observed adverse events (AEs). Any AEs in the subjects were monitored from the time of signing the informed consent form until the end of the study.

[0545] Results

[0546] In general, all data summarized descriptive statistics for continuous endpoints (number of subjects, mean, standard deviation, minimum, median, and maximum), and frequencies and percentages for categorical endpoints. Data for each cohort and data for treatment groups within each cohort were presented separately in each part of the clinical study.

[0547] Safety and tolerability: All safety and tolerability data were listed. In the case of continuous variables, descriptive statistics were used to summarize results at treatment and time points and changes from baseline. Values for categorical assessments were tabulated. Adverse events (AEs) were coded according to MedDRA.

[0548] Figure 18

[0549] Pharmacokinetic results: Compared to PXL065, the relative bioavailability of PXL065 in humans was increased by 55-65% (see Table 23 and Figure 22 ).

[0550] Table 23. Pharmacokinetic parameters of PXL065 and in humans

[0551]

[0552] As shown in Table 23 and ​ , PXL065 had improved bioavailability in healthy human subjects following repeat administration compared to .

[0553] Taken together, the results from the two canine and two human PK studies described in Examples 9-12 above indicate that the bioavailability of total pioglitazone (sum of protonated and deuterated (R)- and (S)-enantiomers) of PXL065 is independent of the formulation (capsule or tablet) compared to pioglitazone.

[0554] incorporated by reference

[0555] This application relates to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If any incorporated reference conflicts with the present specification, the present specification controls. In addition, any particular embodiment of the present disclosure falling within the scope of the prior art can be expressly excluded from any one or more claims. Because such embodiments are considered to be known to those of ordinary skill in the art, they can be excluded even if not expressly set forth in the present text. Any particular embodiment of the present disclosure can be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0556] equivalents

[0557] Various embodiments of the present invention can be used in combination with one or more other embodiments, unless technically incompatible.

[0558] The present invention can be embodied in other specific forms without departing from the spirit or essential characteristics thereof. Accordingly, the embodiments described above are to be considered in all respects as illustrative only and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. A crystalline hydrochloride salt of the compound of Formula (I-A): ###0001### (I-A) wherein the crystalline hydrochloride salt is characterized by an X-ray powder diffraction pattern comprising peaks at diffraction angles (2Θ) of 15.8° ± 0.2°, 22.8° ± 0.2°, and 26.0° ± 0.2°.

2. The crystalline hydrochloride salt of claim 1, wherein the crystalline hydrochloride salt is characterized by an X-ray powder diffraction pattern comprising peaks at diffraction angles (2Θ) of 15.8° ± 0.2°, 20.0° ± 0.2°, 20.8° ± 0.2°, 22.8° ± 0.2°, and 26.0° ± 0.2°.

3. The crystalline hydrochloride salt of claim 1, wherein the crystalline hydrochloride salt is characterized by an X-ray powder diffraction pattern comprising peaks at diffraction angles (2Θ) of 8.6° ± 0.2°, 8.8° ± 0.2°, 12.8° ± 0.2°, 12.9° ± 0.2°, 15.8° ± 0.2°, 18.8° ± 0.2°, 19.7° ± 0.2°, 20.0° ± 0.2°, 20.8° ± 0.2°, 22.8° ± 0.2°, 26.0° ± 0.2°, 28.1° ± 0.2°, and 31.3° ± 0.2°.

4. The crystalline hydrochloride salt of claim 1, wherein the crystalline hydrochloride salt is characterized by an X-ray powder diffraction pattern that is the same as shown in Figure 6.

5. The crystalline hydrochloride salt of claim 1, wherein the crystalline hydrochloride salt has an onset melting point of about 190 °C to about 210 °C as determined by differential scanning calorimetry, wherein the term "about" means ± 10% variation from the stated value.

6. The crystalline hydrochloride salt of claim 1, wherein the crystalline hydrochloride salt is an anhydrous crystalline hydrochloride salt.

7. A pharmaceutical composition comprising the crystalline hydrochloride salt of any one of claims 1-6, and a pharmaceutically acceptable excipient.

8. Use of the crystalline hydrochloride salt of any one of claims 1-6 in the manufacture of a medicament for the treatment of a metabolic disorder.

9. The use of claim 8, wherein the metabolic disorder is polycystic ovary syndrome.

10. Use of the crystalline hydrochloride salt of any one of claims 1-6 in the manufacture of a medicament for the treatment of type 2 diabetes.

11. Use of the crystalline hydrochloride salt of any one of claims 1-6 in the manufacture of a medicament for the treatment of nonalcoholic steatohepatitis.

12. Use of the crystalline hydrochloride salt of any one of claims 1-6 in the manufacture of a medicament for the treatment of nonalcoholic fatty liver disease.

13. Use of the crystalline hydrochloride salt of any one of claims 1-6 in the manufacture of a medicament for the treatment of a neurological disorder.

14. The use of claim 13, wherein the neurological disorder is adrenoleukodystrophy or adrenomyeloneuropathy. ​

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