Crystals of deuterium-enriched pioglitazone

Abstract

This invention provides the crystalline form and composition of deuterium-enriched (R)-pioglitazone, as well as methods for using them. [Solution] A crystalline hydrochloride salt of a compound represented by the following formula is provided, wherein the crystalline hydrochloride salt is characterized by an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 15.8°±0.2°, 22.8°±0.2°, and 26.0°±0.2°. JPEG2026143678000051.jpg2993

Description

[Technical Field]

[0001] Related applications This invention claims benefit and priority to U.S. Patent Application No. 17 / 314,538, filed 7 May 2021, U.S. Provisional Application No. 63 / 046,304, filed 30 June 2020, and U.S. Provisional Application No. 63 / 046,309, filed 30 June 2020, each of which is incorporated by reference in its entirety. [Background technology]

[0002] Thiazolidinediones (TZDs) are antidiabetic drugs that sensitize the body to insulin. These compounds have been empirically found to be agonists of peroxisome proliferator-activated receptors (PPARs) (including PPAR-γ (PPARγ)), ligand-activated nuclear receptors that promote a wide range of transcriptional programs related to adipogenesis, lipid metabolism, innate immune function, and metabolic homeostasis (see, e.g., J. Clin. Invest. 2000, 106, 1305-1307, Trends Endocrinol. Metab. 2012, 23, 205-215). Thus, the antidiabetic mechanism of action of TZDs has been thought to contribute to binding to and activation of PPARγ (see, e.g., J Biol Chem 1995, 270, 12953-12956, Nat Med 2013, 19, 557-566).

[0003] Therapies that modulate PPARs are marketed to treat medical disorders, such as metabolic disorders. One example is pioglitazone hydrochloride, a TZD 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 multiple clinical backgrounds. Pioglitazone hydrochloride is marketed under the registered trademark ACTOS®, and the prescribing information for ACTOS® states that pioglitazone is a PPARγ agonist. Adverse side effects associated with PPARγ in ACTOS® have been reported, including, for example, weight gain, edema, and increased fractures.

[0004] However, genetic and pharmacological evidence has shown that TZDs produce many beneficial effects independently of PPARγ activation (see Biochem. Pharmacol. 2005, 70, 177-188). For example, the liver and skeletal muscle remain responsive to TZDs despite tissue-specific PPARγ deficiency (see J Clin Invest 2003, 112, 608-618, J Biol Chem 2012, 287, 23537-23548), and the systemic insulin sensitization effect of rosiglitazone is maintained by the absence of PPARγ in mature adipocytes (see Mol Cell Biol 2018, 38, e00677-17). Pharmacological evidence also suggests that TZDs have PPARγ-dependent effects. These drugs can rapidly alter metabolic homeostasis for periods that are too rapid to be facilitated by broad-spectrum gene expression changes (see Am. J. Physiol. Endocrinol. Metab. 2006, 291, E175-81), and several in vitro and in vivo experiments have shown that affinity for PPARγ does not necessarily correlate with efficacy (see Biochem. Pharmacol. 2005, 70, 177-188). Pioglitazone and other TZDs have also been shown to possess anti-inflammatory activity that may be mediated, at least in part, by mechanisms unrelated to PPAR (Curr. Drug Targets Inflamm. Allergy 2002, 1, 243-248).

[0005] Recent studies have shown that the majority of the PPARγ-dependent effects of TZD may be due to the inhibition of mitochondrial pyruvate transporter (MPC), an inner mitochondrial membrane transporter involved in the uptake of cytoplasmic glucose-derived pyruvate into the mitochondrial matrix (see Biochim. Biophys. Acta - Mol Cell Res, 2016, 1863, 2436-2442). TZD is a rapidly specific inhibitor of MPC activity at clinically relevant concentrations (Proc. Natl. Acad. Sci. USA, 2013, 110, 5422-5427). TZD also inhibits mitochondrial complex I more effectively than MPC, and possibly even at hyperphysiological concentrations (see Diabetes 2004, 53, 1052-1059). Even in individuals with T2DM who have been using pioglitazone for many years, the targets of pioglitazone and the precise mechanisms of its action are only just beginning to be elucidated.

[0006] All TZDs, including pioglitazone, are enantiomeric mixtures characterized by the presence of a chiral center. This chiral center is prone to rapid, non-enzymatic inversion of its conformation. Therefore, the instability of the chiral center has hindered the exploration of the different pharmacological possibilities between TZD enantiomers. For example, while the levorotonic or (S)-enantiomer of rosiglitazone was identified as the most potent PPARγ agonist, (S)-rosiglitazone rapidly equilibrates to produce a 1:1 mixture of (R) and (S)-rosiglitazone, hindering further in vivo characterization of the enantiomer (see Bioorg. Med. Chem. Lett., 1998, 8, 3657-8). Furthermore, the anti-inflammatory effect of pioglitazone has been shown to be uniquely associated with the (R)-enantiomer in a rat model of chronic obstructive pulmonary disease. This was achieved by stabilizing the enantiomer in an acidic solution, followed by immediate intranasal administration, thereby limiting inversion during the test to only that (see International Patent Application WO2010015818A1).

[0007] Due to the increasing number of patients suffering from the disorders described above, and the limitations of existing treatments (e.g., adverse side effects), there is a need for new therapeutic agents to treat medical disorders in which PPARγ modulation, anti-inflammatory activity, and / or MPC activity are expected to be beneficial.

[0008] The use of deuterium-enriched enantiomers of pioglitazone to treat such medical disorders has attracted considerable interest because they are thought to offer greater therapeutic efficacy and potentially reduce the rate and severity of side effects compared to pioglitazone alone. In recent years, the unique pharmacological and pharmacokinetic properties of deuterium-enriched (R) and / or (S)-enantiomers of pioglitazone have been reported (see Hepatol. Commun. 2021, Apr 10 doi.org / 10.1002 / hep4.1723). Preclinical studies have shown that (R)-pioglitazone maintains the efficacy of pioglitazone in non-alcoholic fatty liver disease (NASH), including reductions in hepatic triglycerides, free fatty acids, cholesterol, fatty liver, inflammation, hepatocyte enlargement, and fibrosis. Both enantiomers inhibit MPC, but deuterium-enriched (R)-pioglitazone (PXL065) is shown to be limited to the absence of PPARγ activity, while (S)-pioglitazone appears to be associated with PPARγ activity and associated weight gain. Both enantiomers reduce plasma glucose and liver fibrosis to a similar degree as pioglitazone in preclinical mouse models. In Clinical Trial IA, the safety and tolerability of PXL065 (7.5, 22.5, 30 mg), as well as the preferred efficacy of the (R)-enantiomer compared to 45 mg of ACTOS®, were demonstrated. These results suggest that lower doses of PXL065 (22.5 mg or less) are expected to be effective for NASH with 45 mg or more of pioglitazone without potential adverse weight gain and edema.

[0009] However, developing solid-state forms of these deuterium-enriched pioglitazone enantiomers that provide the physicochemical properties required to manufacture commercially viable drugs with the desired efficacy remains a significant challenge. This is due to the unpredictability of screening results for solid-state forms of a given compound, and subsequently, the unpredictability of the physicochemical properties of the resulting solid-state form. Therefore, there is a need for novel solid-state forms of deuterium-enriched pioglitazone derivatives that achieve the physicochemical properties necessary to provide superior efficacy for pioglitazone. [Overview of the project]

[0010] overview In one embodiment, the present invention provides a salt form (e.g., a crystalline salt form) of deuterium-enriched (R)-pioglitazone (PXL065).

[0011] Various embodiments of the present invention, formula (I): [ka] (I) [In the formula, R 1 [wherein is H or D, but the total deuterium ratio in the compound of formula (I) is approximately 1.3 to 4.] This is a deuterium chloride salt of a deuterium-concentrated compound shown as [the formula].

[0012] Various embodiments of the present invention, Formula (I) [ka] (I) [In the formula, R 1 [wherein is H or D, but the total deuterium ratio in the compound of formula (I) is approximately 1.3 to 4.] A crystalline deuterium chloride salt of a deuterium-enriched compound represented by [formula], characterized by an X-ray powder diffraction pattern including peaks at the following diffraction angles (2θ): 15.8°±0.2°, 22.8°±0.2°, and 26.0°±0.2°.

[0013] Various embodiments of the present invention, formula (IA): [ka] (IA) It is a crystalline hydrochloride salt of the compound shown.

[0014] Various embodiments of the present invention, formula (IA) [ka] (IA) A crystalline hydrochloride salt of the compound represented by [formula], characterized by an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 15.8°±0.2°, 22.8°±0.2°, and 26.0°±0.2°.

[0015] In another embodiment, the present invention provides a pharmaceutical substance comprising particles of a crystalline salt (e.g., deuterium chloride salt, hydrochloride salt) of deuterium-enriched (R)-pioglitazone.

[0016] In various embodiments of the present invention, the pharmaceutical substance is of formula (I) [ka] (I) [In the formula, R 1 [wherein is H or D, but the total deuterium ratio in the compound of formula (I) is approximately 1.3 to 4.] The pharmaceutical substance contains particles of crystalline deuterium chloride salt of a deuterium-concentrated compound represented by [formula], wherein the particles have a crystalline shape selected from hexagonal, rod-shaped, and combinations thereof.

[0017] In various embodiments of the present invention, the pharmaceutical substance is of formula (I) [ka] (I) [In the formula, R 1[wherein is H or D, but the total deuterium ratio in the compound of formula (I) is approximately 1.3 to 4.] The material comprises particles of crystalline deuterium chloride salts of a deuterium-enriched compound represented by [formula], wherein the particles have a particle size distribution defined by d(0.9) of about 10 μm to about 800 μm, preferably less than 500 μm.

[0018] Various embodiments of the present invention, formula (IA) [ka] (IA) A pharmaceutical substance comprising particles of a crystalline hydrochloride salt of a compound represented by [formula], wherein the particles in the pharmaceutical substance have a needle-like crystalline shape.

[0019] Various embodiments of the present invention, formula (IA) [ka] (IA) A pharmaceutical substance comprising particles of a crystalline hydrochloride salt of a compound represented by , wherein the particles have a particle size distribution defined by d(0.9) of about 10 μm to about 800 μm, preferably less than 500 μm.

[0020] In another embodiment, the present invention provides a pharmaceutical composition comprising a crystalline salt of deuterium-concentrated(R)-pioglitazone as described herein, or a pharmaceutical substance as described herein, and a pharmaceutically acceptable excipient. In various embodiments, the pharmaceutical composition comprises a crystalline deuterium chloride salt of deuterium-concentrated(R)-pioglitazone and a pharmaceutically acceptable excipient. In various embodiments, the pharmaceutical composition comprises a crystalline hydrochloride salt of deuterium-concentrated(R)-pioglitazone and a pharmaceutically acceptable excipient.

[0021] In another embodiment, the present invention provides crystalline salt forms, pharmaceutical substances, and pharmaceutical compositions of deuterium-enriched (R)-pioglitazone useful for the treatment of various diseases, disorders, and disabilities described herein. In one embodiment, the disease, disorder, or disability is a metabolic disorder. In one embodiment, the disease, disorder, or disability is type 2 diabetes and / or non-alcoholic fatty liver disease. In one embodiment, the disease, disorder, or disability is a neurological disorder. In one embodiment, the neurological disorder is adrenoleukodystrophy or adrenal spinal neuropathy. [Brief explanation of the drawing]

[0022] [Figure 1A] Figure 1A shows a typical X-ray powder diffraction (XRPD) pattern of a crystalline deuterium chloride salt of deuterium-enriched (R)-pioglitazone. [Figure 1B] Figure 1B shows a representative X-ray powder diffraction (XRPD) pattern of deuterium-enriched (R)-pioglitazone crystalline hydrochloride superimposed on the X-ray powder diffraction (XRPD) pattern of pioglitazone crystalline hydrochloride. [Figure 2] Figure 2 shows representative optical microscope images of crystalline deuterium chloride salts of deuterium-enriched (R)-pioglitazone at (A) 10x magnification and (B) 20x magnification. [Figure 3] Figure 3 shows a typical differential scanning calorimetry (DSC) curve for a crystalline deuterium chloride salt of deuterium-enriched (R)-pioglitazone. [Figure 4A] Figure 4A shows a typical thermogravimetric analysis (TGA) curve for a crystalline deuterium chloride salt of deuterium-enriched (R)-pioglitazone. [Figure 4B] Figure 4B shows a typical thermogravimetric mass spectrometry (TGMS) plot of crystalline deuterium chloride salts of deuterium-enriched (R)-pioglitazone. [Figure 5] Figure 5 shows a typical proton nuclear magnetic resonance (1H-NMR) spectrum of a crystalline deuterium chloride salt of deuterium-enriched (R)-pioglitazone. [Figure 6]Figure 6 shows a typical X-ray powder diffraction (XRPD) pattern of a crystalline hydrochloride salt of deuterium-enriched (R)-pioglitazone. [Figure 7] Figure 7 shows representative optical micrographs of deuterium-enriched (R)-pioglitazone crystalline hydrochloride at (A) 10x magnification and (B) 20x magnification. [Figure 8] Figure 8 shows a typical differential scanning calorimetry (DSC) curve for the crystalline hydrochloride of deuterium-enriched (R)-pioglitazone. [Figure 9A] Figure 9A shows a typical thermogravimetric analysis (TGA) curve for the crystalline hydrochloride of deuterium-enriched (R)-pioglitazone. [Figure 9B] Figure 9B shows a typical thermogravimetric mass spectrometry (TGMS) plot of deuterium-enriched (R)-pioglitazone crystalline hydrochloride. [Figure 10] Figure 10 shows a typical 1H-NMR spectrum of the crystalline hydrochloride of deuterium-enriched (R)-pioglitazone. [Figure 11] Figure 11 shows a typical X-ray powder diffraction (XRPD) pattern of the crystalline free base of deuterium-enriched (R)-pioglitazone. [Figure 12] Figure 12 shows a typical differential scanning calorimetry (DSC) curve of the crystalline free base morphology of deuterium-enriched (R)-pioglitazone. [Figure 13A] Figure 13A shows a typical thermogravimetric analysis (TGA) curve of the crystalline free base form of deuterium-enriched (R)-pioglitazone. [Figure 13B] Figure 13B is a typical thermogravimetric mass spectrometry (TGMS) plot of the crystalline free base form of deuterium-enriched (R)-pioglitazone. [Figure 14] Figure 14 shows the overlapping pH-dependent solubility profiles of crystalline DCl and HCl salts of deuterium-enriched (R)-pioglitazone, crystalline DCl salt of deuterium-enriched pioglitazone, and crystalline HCl salt of pioglitazone. [Figure 15]Figure 15 shows typical plots of tablet hardness (N) against compressive force (kN) for various particle size distributions (PSD) (μm) of active pharmaceutical ingredient (API) batches. [Figure 16] Figure 16 shows typical plots of tablet hardness (N) against compressive force (kN) for various particle size distributions (PSD) (μm) of API batches at different tableting rates. [Figure 17] Figure 17 is a representative plot of plasma levels of total pioglitazone (sum of deuterated and hydrogenated (R)- and (S)-enantiomers) over time with administration of PXL065 (deuterium-concentrated (R) pioglitazone) in dogs. [Figure 18] Figure 18 is a representative plot of plasma levels of total pioglitazone (sum of deuterated and hydrogenated (R)- and (S)-enantiomers) over time with administration of PXL061 (deuterium-concentrated pioglitazone) in dogs. [Figure 19] Figure 19 is a representative plot of plasma levels of total pioglitazone (sum of deuterated and hydrogenated (R)- and (S)-enantiomers) over time with administration of PXL064 (deuterium-enriched (S)-pioglitazone) in dogs. [Figure 20] Figure 20 is a representative plot of total pioglitazone (sum of deuterated and hydrogenated (R)- and (S)-enantiomers) plasma levels over time with administration of pioglitazone and PXL065 in dogs. [Figure 21] Figure 21 shows the overlap of normalized exposure curves for total pioglitazone (the sum of deuterated and hydrogenated (R)- and (S)-enantiomers) doses of deuterium-enriched (R)-pioglitazone (22.5 mg dose) and crystalline hydrochloride of ACTOS® (pioglitazone HCl, 45 mg dose) in humans, as further described in Example 11. [Figure 22]Figure 22 shows the overlap of normalized exposure curves for total pioglitazone (total of deuterated and hydrogenated (R)- and (S)-enantiomers) doses of deuterium-enriched (R)-pioglitazone (15 mg and 30 mg doses) and crystalline hydrochloride of ACTOS® (pioglitazone HCl, 45 mg dose) in humans, as further described in Example 11. [Modes for carrying out the invention]

[0023] Detailed explanation As generally described herein, the present invention provides pharmaceutically acceptable salts of deuterium-concentrated(R)-pioglitazone (also referred herein as the compound of formula I) (e.g., crystalline salts of deuterium-concentrated(R)-pioglitazone), pharmaceutical compositions comprising the same, and methods of using the salt forms of deuterium-concentrated(R)-pioglitazone for the treatment of medical diseases, disorders and disorders (e.g., neurological disorders, cancer, respiratory diseases, metabolic disorders, hepatitis, cardiovascular diseases, inflammatory diseases, immune-mediated diseases, skin diseases, or cutaneous diseases) in subjects requiring treatment. In particular, the present invention provides crystalline hydrochloride and deuterium chloride salts of deuterium-concentrated(R)-pioglitazone having unexpectedly improved solubility and in vivo bioavailability at physiologically relevant pH compared to commercially available pioglitazone hydrochloride (ACTOS®).

[0024] definition To facilitate understanding of this invention, many terms and expressions are defined below.

[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art. Abbreviations used herein have their conventional meanings within the fields of chemistry and biology. Chemical structures and formulas shown herein are constructed according to standard rules of valence known in the field of chemistry.

[0026] Throughout this specification, compositions and kits are described as having, including, or containing specific components, or processes and methods are described as having, including, or containing specific steps, such that compositions and kits of the present invention exist that are essential from or consist of the listed components, or processes and methods of the present invention exist that are essential from or consist of the listed processing steps.

[0027] In this application, where a component or constituent is to be included in and / or selected from the enumerated components or constituent, it should be understood that the component or constituent may be any one of the enumerated components or constituent, or may be selected from a group consisting of two or more of the enumerated components or constituent.

[0028] Furthermore, it should be understood that the components and / or features of the compositions or methods described herein can be combined in various ways, either expressly or implicitly, without departing from the spirit and scope of the invention. For example, with reference to a particular compound, the compound can be used in various embodiments of the compositions and / or methods of the invention, unless otherwise understood from the context. That is, in this application, the embodiments are described and illustrated in a clear and concise manner, but it is intended and understood that the embodiments may be combined or separated in various ways without departing from the teachings and invention. For example, it should be understood that all features described and shown herein may be applicable to all embodiments described and shown herein.

[0029] The articles “a” and “an” are used in this disclosure to mean one or more (i.e., at least one) of the objects they refer to, unless the context makes it inappropriate. For example, “component” means one or more components.

[0030] The terms “and / or” are used in this disclosure to mean either “and” or “or” unless otherwise indicated.

[0031] The term "at least one" should be understood to include each of the objects listed after it, and any various combinations of two or more of the listed objects, unless otherwise understood from the context and usage. The term "and / or" combined with three or more listed objects should be understood to have the same meaning, unless otherwise understood from the context.

[0032] The use of the terms “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing” (including grammatically equivalent terms) should be understood as open-ended and unrestricted, for example, not excluding components or steps not further specified, unless otherwise specifically stated or understood from the context.

[0033] Where the term "about" is used before a quantitative value, the present invention also includes the specific quantitative value itself, unless otherwise specifically stated. As used herein, the term "about" means a variation of ±10% from the stated value, unless otherwise indicated or inferred.

[0034] In various positions throughout this specification, variables or parameters are disclosed in groups or ranges. It is specifically intended that this specification include each and every subcombination of members of such groups and ranges. For example, it is specifically intended to individually disclose 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 for integers in the range of 0 to 40, and it is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 for integers in the range of 1 to 20.

[0035] The use of any and all examples or exemplary language in this specification, for example, "such as" or "comprising", is merely intended to illustrate the present invention, and is not intended to limit the scope of the present invention, unless otherwise specified in the claims. No language in this specification should be construed as indicating any unclaimed element essential to the practice of the present invention.

[0036] Deuterium ( 2 which may also be referred to herein as H and / or D) is 1 a stable non-radioactive isotope of H hydrogen, and has an atomic weight of 2.014. Hydrogen exists as a mixture of the isotopes 1 H hydrogen (i.e., protium), deuterium ( 2 H), and tritium ( 3 H) in nature. The natural abundance of deuterium is about 0.015%. Those skilled in the art will appreciate that in all chemical compounds containing H atoms, H atoms exist as 1 H hydrogen, deuterium ( 2 H), and tritium ( 3The mixture of H) is shown, and it is understood that about 0.015% is deuterium. In various embodiments, compounds having a deuterium level concentrated to about 0.015% or more of their natural abundance are considered unnatural and, as a result, novel to their unconcentrated counterparts. In some embodiments, compounds having a deuterium level concentrated to about 0.015% or more are deuterium-concentrated compounds.

[0037] As used herein, “total deuterium content” or “total deuterium abundance” means the number of deuterium atoms present in the molecule (if the molecule is a salt (e.g., the HCl or DCl salt of deuterium-enriched (R)-pioglitazone), the counterions are also counted). Total deuterium content is, for example, 2 It may also be determined by 1H-NMR. The deuterium content at the chiral center of a molecule (e.g., deuterium-enriched pioglitazone) is, for example, 1 The determination may also be made using 1H-NMR.

[0038] As a general rule, unless otherwise specified, percentages of a composition are given by weight. Furthermore, if a variable is not included in the definition, it is defined in the aforementioned definition of the variable.

[0039] As used herein, “pharmaceutical composition” or “pharmaceutical preparation” means a combination of an active agent and an inactive or active carrier, particularly prepared for use in diagnostic or therapeutic applications in vivo or in vitro.

[0040] "Medically acceptable" means that it is approved or available for use in animals, more specifically in humans, by a federal or state regulatory authority or the equivalent authority in a country other than the United States, or is listed in the United States Pharmacopoeia or other generally recognized pharmacopoeias.

[0041] As used herein, “pharmaceutically acceptable excipients” means substances that can be included in the compositions of the present invention for the purpose of administering an active agent to and / or being absorbed by the subject without causing any significantly harmful toxicological effects in the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, sodium chloride, ordinary saline solutions (e.g., phosphate-buffered saline), emulsions (e.g., oil / water or water / oil emulsions), Ringer's lactate solution, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (e.g., Ringer's solution), alcohols, oils, gelatin, carbohydrates (e.g., lactose), amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and colorants. Such preparations may be sterilized and, if necessary, mixed with excipients such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts affecting osmotic pressure, buffers, colorants, and / or aromatics that do not react adversely with the compound. For examples of excipients, see Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).

[0042] As used herein, “solid formulation” means a pharmaceutical formulation in solid form, such as tablets, capsules, granules, powders, pouches, reconstituted powders, dry powder inhalants, and chewable tablets.

[0043] As used herein, “administer” means to a subject by oral administration, suppository administration, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intrafocal administration, subarachnoid administration, intracerebral administration, intranasal administration, or subcutaneous administration, or implantation of a delayed-release device (e.g., a mini osmotic pump). Administration is by any route including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, transnasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracerebral. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, and transdermal patch. “Co-administer” means that the compositions described herein are administered concurrently with, before, or after the administration of one or more therapies (e.g., anticancer agents, chemotherapy, or treatment for neurodegenerative diseases). (R)- 2 H-pioglitazone or its pharmaceutically acceptable salts may be administered to patients alone or in combination. Combination may involve simultaneous or sequential administration of each compound or combination (one or more compounds or drugs). Thus, the preparation may also be combined with other active substances as needed (e.g., to reduce metabolic degradation).

[0044] The terms “disease,” “disorder,” and “illness” are used interchangeably in this specification.

[0045] As used herein and unless otherwise indicated, the terms “to treat,” “to treat,” and “treatment” mean any action (e.g., “treatment procedure”) that reduces the severity of a particular disease, disorder, or illness, or slows or delays the progression of the disease, disorder, or illness.

[0046] Generally, the “effective amount” of a compound means an amount sufficient to produce a desired biological response (for example, to treat a disease, disorder, or disorder described herein). As can be appreciated by those skilled in the art, the effective amount of a compound in this disclosure may vary depending on the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and factors such as the age, weight, health, and condition of the subject.

[0047] As used herein, “pioglitazone” refers to a racemic (1:1) mixture of (R)- and (S)-enantiomers, and as a single substance, means the following compound (A) having the natural abundance of deuterium at each hydrogen atom position as appropriate. Analogues and / or enantiomers of pioglitazone may be specified herein, for example, “deuterium-enriched (R)-pioglitazone”. [ka]

[0048] Deuterium-enriched (R)-pioglitazone Deuterium-enriched (R)-pioglitazone, represented by formula (I), is an MCP inhibitor: [ka] (I) [In the formula, R 1 [is H or D] That is the case.

[0049] As described above, the deuterium-enriched (R)-pioglitazone described herein involves deuterium enrichment at the chiral center of pioglitazone, and optionally at other positions of the compound (e.g., the thiazolidinedione nitrogen). Without being bound by theory, it is thought that deuterium enrichment at the chiral center reduces or inhibits the rate at which the two enantiomers of pioglitazone can interconvert.

[0050] Methods for chemically synthesizing deuterium-enriched (R)-pioglitazone and producing the crystalline salt forms described herein are provided in Examples 1, 2, and 3.

[0051] In one embodiment, the abundance of deuterium in chiral centers was approximately 30% to 100%, 40% to 100%, 50% to 100%, 60% to 100%, 70% to 100%, 75% to 100%, 80% to 100%, 85% to 100%, 90% to 100%, 95% to 100%, and 30% to 95%. Approximately 30% to 90%, approximately 30% to 85%, approximately 30% to 80%, approximately 30% to 75%, approximately 30% to 70%, approximately 30% to 60%, approximately 30% to 50%, approximately 30% to 40%, approximately 40% to 95%, approximately 40% to 90%, approximately 40% to 85%, approximately 40% to 80%, approximately 40% to 75%, approximately 40% to 70%, approximately 40% to 60% %, approximately 40%~50%, approximately 50%~95%, approximately 50%~90%, approximately 50%~85%, approximately 50%~80%, approximately 50%~75%, approximately 50%~70%, approximately 50%~60%, approximately 60%~95%, approximately 60%~90%, approximately 60%~85%, approximately 60%~80%, approximately 60%~75%, approximately 60%~70%, approximately 70%~9 The percentages are 5%, approximately 70% to 90%, approximately 70% to 85%, approximately 70% to 80%, approximately 70% to 75%, approximately 75% to 95%, approximately 75% to 90%, approximately 75% to 85%, approximately 75% to 80%, approximately 80% to 95%, approximately 80% to 90%, approximately 80% to 85%, approximately 85% to 95%, approximately 85% to 90%, or approximately 90% to 95%.

[0052] In one embodiment, the abundance of deuterium in the 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%.

[0053] In one instance, the abundance of deuterium in chiral centers was approximately 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, and The percentages are approximately 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%.

[0054] One reason, R 1The abundance of deuterium in these samples is approximately 0.015% to 100%, approximately 10% to 100%, approximately 20% to 100%, approximately 30% to 100%, approximately 40% to 100%, approximately 50% to 100%, approximately 60% to 100%, approximately 70% to 100%, approximately 75% to 100%, approximately 80% to 100%, approximately 85% to 100%, approximately 90% to 100%, approximately 95% to 100%, 0.015% to 95%, 0.015% to 90%, 0.015% to 85%, 0.015% to 80%, 0.015% to 75%, 0.015% to 70%, and 0.015% to 60%. 0.015%~approx. 50%, 0.015%~approx. 40%, 0.015%~approx. 30%, 0.015%~approx. 20%, 0.015%~approx. 10%, approx. 10%~approx. 95%, approx. 10%~approx. 90%, approx. 10%~approx. 85%, approx. 10%~approx. 80%, approx. 10%~approx. 75%, approx. 10%~approx. 70%, approx. 10%~approx. 60%, approx. 10%~approx. 50%, approx. 10%~approx. 40%, approx. 10%~approx. 30%, approx. 10%~approx. 20%, approx. 20%~approx. 95%, approx. 20%~approx. 90%, approx. 20%~approx. 85%, approx. 20%~approx. 80%, approx. 20%~approx. 75%, approx. 20%~approx. 70%, approx. 20%~approx. 60%, approx. 2 0%~approx. 50%, approx. 20%~approx. 40%, approx. 20%~approx. 30%, approx. 30%~approx. 95%, approx. 30%~approx. 90%, approx. 30%~approx. 85%, approx. 30%~approx. 80%, approx. 30%~approx. 75%, approx. 30%~approx. 70%, approx. 30%~approx. 60%, approx. 30%~approx. 50%, approx. 30%~approx. 40%, approx. 40%~approx. 95%, approx. 40%~approx. 90%, approx. 40%~approx. 85%, approx. 40%~approx. 80%, approx. 40%~approx. 75%, approx. 40%~approx. 70%, approx. 40%~approx. 60%, approx. 40%~approx. 50%, approx. 50%~approx. 95%, approx. 50%~approx. 90%, approx. 50%~approx. 85%, approx. 50%~approx. 80%, approx. 50% The percentages are approximately 75%, 50% to 70%, 50% to 60%, 60% to 95%, 60% to 90%, 60% to 85%, 60% to 80%, 60% to 75%, 60% to 70%, 70% to 95%, 70% to 90%, 70% to 85%, 70% to 80%, 70% to 75%, 75% to 95%, 75% to 90%, 75% to 85%, 75% to 80%, 80% to 95%, 80% to 90%, 80% to 85%, 85% to 95%, 85% to 90%, or 90% to 95%.

[0055] One reason, R 1 The abundance of deuterium in is 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%.

[0056] One reason, R 1 The abundance of deuterium in these regions is approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, and 25%. %, approximately 26%, approximately 27%, approximately 28%, approximately 29%, approximately 30%, approximately 31%, approximately 32%, approximately 33%, approximately 34%, approximately 35%, approximately 36%, approximately 37%, approximately 38%, approximately 39%, approximately 40%, approximately 41%, approximately 42%, approximately 43%, approximately 44%, approximately 45%, approximately 46%, approximately 47%, approximately 48%, approximately 49%, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately 55%, approximately 56%, approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately 75%, approximately 76% The percentages are approximately 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%.

[0057] In one embodiment, the total deuterium abundance in the compound of formula (I) is approximately 0.3 to 4, approximately 0.5 to 4, approximately 1 to 4, approximately 1.2 to 4, approximately 1.3 to 4, approximately 1.4 to 4, approximately 1.6 to 4, approximately 1.8 to 4, approximately 2 to 4, approximately 2.2 to 4, approximately 2.4 to 4, approximately 2.6 to 4, approximately 2.8 to 4, approximately 3 to 4, approximately 3.2 to 4, approximately 3.4 to 4, approximately 3.6 to 4, approximately 3.8 to 4, approximately 0.3 to 3.8, approximately 0.3 to 3.6, approximately 0.3 to 3.4, approximately 0.3 to 3.2, approximately 0.3 to 3, approximately 0.3 to 2.8, approximately 0.3 to 2.6, approximately 0.3 to 2.4, approximately 0.3 to approximately 2.2, approximately 0.3 to approximately 2, approximately 0.3 to approximately 1.8, approximately 0.3 to approximately 1.6, approximately 0.3 to approximately 1.4, approximately 0.3 to approximately 1.2, approximately 0.3 to approximately 1, approximately 0.3 to approximately 0.5, approximately 0.5 to approximately 3.8, approximately 0.5 to approximately 3.6, approximately 0.5 to approximately 3.4, approximately 0.5 to approximately 3.2, approximately 0.5 to approximately 3, approximately 0.5 to approximately 2.8, approximately 0.5 to approximately 2.6, approximately 0.5 to approximately 2.4, approximately 0.5 to approximately 2.2, approximately 0.5 to approximately 2, approximately 0.5 to approximately 1.8, approximately 0.5 to approximately 1.6, approximately 0.5 to approximately 1.4, approximately 0.5 to approximately 1.2, approximately 0.5 to approximately 1, approximately 1 to approximately 3.8, approximately 1 to approximately 3.6, approximately 1 to approximately 3.4, approximately 1 to approximately 3. 2, approximately 1 to approximately 3, approximately 1 to approximately 2.8, approximately 1 to approximately 2.6, approximately 1 to approximately 2.4, approximately 1 to approximately 2.2, approximately 1 to approximately 2, approximately 1 to approximately 1.8, approximately 1 to approximately 1.6, approximately 1 to approximately 1.4, approximately 1 to approximately 1.2, approximately 1.2 to approximately 3.8, approximately 1.2 to approximately 3.6, approximately 1.2 to approximately 3.4, approximately 1.2 to approximately 3.2, approximately 1.2 to approximately 3. Approximately 1.2 to 2.8, approximately 1.2 to 2.6, approximately 1.2 to 2.4, approximately 1.2 to 2.2, approximately 1.2 to 2, approximately 1.2 to 1.8, approximately 1.2 to 1.6, approximately 1.2 to 1.4, approximately 1.2 to 1.3, approximately 1.3 to 3.8, approximately 1.3 to 3.6, approximately 1.3 to 3.4, approximately 1.3 to Approximately 3.2, approximately 1.3-3, approximately 1.3-2.8, approximately 1.3-2.6, approximately 1.3-2.4, approximately 1.3-2.2, approximately 1.3-2, approximately 1.3-1.8, approximately 1.3-1.6, approximately 1.3-1.4, approximately 1.4-3.8, approximately 1.4-3.6, approximately 1.4-3.4, approximately 1.4 ~approximately 3.2, approximately 1.4~approximately 3, approximately 1.4~approximately 2.8, approximately 1.4~approximately 2.6, approximately 1.4~approximately 2.4, approximately 1.4~approximately 2.2, approximately 1.4~approximately 2, approximately 1.4~approximately 1.8, approximately 1.4~approximately 1.6, approximately 1.6~approximately 3.8, approximately 1.6~approximately 3.6, approximately 1.6~approximately 3.4, approximately 1.6~approximately 3.2, approximately 1.6~approx. 3, approx. 1.6~approx. 2.8, approx. 1.6~approx. 2.6, approx. 1.6~approx. 2.4, approx. 1.6~approx. 2.2, approx. 1.6~approx. 2, approx. 1.6~approx. 1.8, approx. 1.8~approx. 3.8, approx. 1.8~approx. 3.6, approx. 1.8~approx. 3.4, approx. 1.8~approx. 3.2, approx. 1.8~approx. 3, approx. 1.8~approx. 2.8, approx. 1.8~approx. 2.6, approx. 1.8~approx. 2.4, approx. 1. 8~approx. 2.2, approx. 1.8~approx. 2, approx. 2~approx. 3.8, approx. 2~approx. 3.6, approx. 2~approx. 3.4, approx. 2~approx. 3.2, approx. 2~approx. 3, approx. 2~approx. 2.8, approx. 2~approx. 2.6, approx. 2~approx. 2.4, approx. 2~approx. 2.2, approx. 2.2~approx. 3.8, approx. 2.2~approx. 3.6, approx. 2.2~approx. 3.4, approx. 2.2~approx. 3.2, approx. 2.2~approx. 3, approx. 2.2~approx. 2.8, approx. 2 0.2~approx. 2.6, approx. 2.2~approx. 2.4, approx. 2.4~approx. 3.8, approx. 2.4~approx. 3.6, approx. 2.4~approx. 3.4, approx. 2.4~approx. 3.2, approx. 2.4~approx. 3, approx. 2.4~approx. 2.8, approx. 2.4~approx. 2.6, approx. 2.6~approx. 3.8, approx. 2.6~approx. 3.6, approx. 2.6~approx. 3.4, approx. 2.6~approx. 3.2, approx. 2.6~approx. 3, approx. 2.6~approx. 2.8, approx. The total deuterium ratios are approximately 2.8 to 3.8, 2.8 to 3.6, 2.8 to 3.4, 2.8 to 3.2, 2.8 to 3, 3 to 3.8, 3 to 3.6, 3 to 3.4, 3 to 3.2, 3.2 to 3.8, 3.2 to 3.6, 3.2 to 3.4, 3.4 to 3.8, 3.4 to 3.6, or 3.6 to 3.8. In one embodiment, the total deuterium ratio in the compound of formula (I) is approximately 1.3 to 4. In another embodiment, the total deuterium ratio in the compound of formula (I) is approximately 1.8 to 3.3.

[0058] In one embodiment, the deuterium-enriched (R)-pioglitazone described herein has an enantiomer 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%.

[0059] In one embodiment, the deuterium-enriched (R)-pioglitazone described herein has an enantiomer 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%.

[0060] In one embodiment, 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 one embodiment, the deuterium-enriched(R)-pioglitazone described herein is enantiopurine.

[0061] In various embodiments, the free base form of deuterium-enriched (R)-pioglitazone is provided herein.

[0062] In various embodiments, pharmaceutically acceptable salts of deuterium-concentrated(R)-pioglitazone are provided herein. In some embodiments, the pharmaceutically acceptable salt of deuterium-concentrated(R)-pioglitazone is a deuterium chloride salt. In some embodiments, the pharmaceutically acceptable salt of deuterium-concentrated(R)-pioglitazone is a hydrochloride salt.

[0063] Deuterium-concentrated (R) pioglitazone in deuterium (DCl) chloride In one embodiment, the present invention relates to formula (I): [ka] (I) [In the formula, R 1[wherein is H or D, but the total deuterium ratio in the compound of formula (I) is approximately 1.3 to 4.] This provides a deuterium chloride salt of a deuterium-concentrated compound shown in [the formula].

[0064] In one embodiment, the deuterium chloride is a crystalline deuterium chloride. In another embodiment, the crystalline deuterium chloride is anhydrous crystalline deuterium chloride.

[0065] In another embodiment, the present invention relates to formula (I) [ka] (I) [In the formula, R 1 [wherein is H or D, but the total deuterium ratio in the compound of formula (I) is approximately 1.3 to 4.] The present invention provides a crystalline deuterium chloride salt of a deuterium-enriched compound represented by [formula], wherein the crystalline deuterium chloride salt is characterized by an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 15.8°±0.2°, 22.8°±0.2°, and 26.0°±0.2°.

[0066] In one embodiment, the crystalline deuterium chloride is characterized by an X-ray powder diffraction pattern including peaks at the following diffraction angles (2θ): 20.0°±0.2°, 20.8°±0.2°, and 22.8°±0.2°. In another embodiment, the crystalline deuterium chloride is characterized by an X-ray powder diffraction pattern including peaks at the following diffraction angles (2θ): 15.8°±0.2°, 20.0°±0.2°, 20.8°±0.2°, 22.8°±0.2°, and 26.0°±0.2°. In one embodiment, the crystalline deuterium chloride is characterized by an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 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°.

[0067] In one embodiment, the crystalline deuterium chloride is characterized by an X-ray powder diffraction pattern shown with respect to the diffraction angle 2θ, as shown in Table 1, and, optionally, by relative intensity (shown as a percentage of the strongest peak). Table 1 - X-ray powder diffraction (XRPD) data of crystalline DCl salts [Table 1]

[0068] In one embodiment, the crystalline deuterium chloride is characterized by an X-ray powder diffraction pattern substantially identical to the X-ray powder diffraction pattern shown in Figure 1A.

[0069] In one embodiment, the crystalline deuterium chloride exists in a monoclinic system and has a P21 / c space group. In one embodiment, the crystalline deuterium chloride is characterized by the crystal unit cell parameters shown in Table 2. Table 2 - Unit cell parameters of the crystalline form of the compound of formula (V) [Table 2]

[0070] The crystalline deuterium chloride may also be characterized by the onset temperature of its melting point. In one embodiment, the crystalline deuterium chloride exhibits an onset of its melting point at about 190°C to about 200°C, as determined by differential scanning calorimetry. In one embodiment, the crystalline deuterium chloride exhibits an onset of its melting point at about 191°C, as determined by differential scanning calorimetry. In one embodiment, the crystalline deuterium chloride exhibits endothermic melting with a peak at about 200°C to about 210°C. In one embodiment, the crystalline deuterium chloride exhibits endothermic melting with a peak at about 204°C. In one embodiment, the crystalline deuterium chloride has a differential scanning calorimetry curve substantially identical to the differential scanning calorimetry curve shown in Figure 3.

[0071] In one embodiment, the crystalline deuterium chloride 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%.

[0072] In one embodiment, the crystalline deuterium chloride 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%.

[0073] In one embodiment, the crystalline deuterium chloride 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%.

[0074] In various embodiments, the present invention is based on formula (I) [ka] (I) [In the formula, R 1 [wherein is H or D, but the total deuterium ratio in the compound of formula (I) is approximately 1.3 to 4.] A pharmaceutical substance comprising a crystalline deuterium chloride salt of a deuterium-concentrated compound represented by, The present invention provides a pharmaceutical substance in which the particles have a crystal shape selected from hexagonal, rod-shaped, and combinations thereof.

[0075] In one embodiment, the particles are 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, approximately 10 μm to 160 μm, and approximately 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 16 0μm, approx. 20μm~140μm, approx. 20μm~120μm, approx. 20μm~100μm, approx. 20μm~80μm, approx. 20μm~60μm, approx. 20μm~40μm, approx. 40μm~180μm, approx. 40μm m~160μm, approx. 40μm~140μm, approx. 40μm~120μm, approx. 40μm~100μm, approx. 40μm~80μm, approx. 40μm~60μm, approx. 60μm~180μm, approx. 60μm~160μ m, approximately 60μm~140μm, approximately 60μm~120μm, approximately 60μm~100μm, approximately 60μm~80μm, approximately 80μm~180μm, approximately 80μm~160μm, approximately 80μm~140μm, approximately 80μm The particles have a particle size distribution defined by d(0.1) of approximately 10μm to 120μm, approximately 80μm to 100μm, approximately 100μm to 180μm, approximately 100μm to 160μm, approximately 100μm to 140μm, approximately 100μm to 120μm, approximately 120μm to 180μm, approximately 120μm to 160μm, approximately 120μm to 140μm, approximately 140μm to 180μm, approximately 140μm to 160μm, or approximately 160μm to 180μm. In one embodiment, the particles have a particle size distribution defined by d(0.1) of approximately 10μm to approximately 200μm.

[0076] In one embodiment, the particles are approximately 10 μm to 400 μm, 50 μm to 400 μm, 75 μm to 400 μm, 100 μm to 400 μm, 125 μm to 400 μm, 150 μm to 400 μm, 175 μm to 400 μm, 200 μm to 400 μm, 225 μm to 400 μm, 250 μm to 400 μm, 275 μm to 400 μm, 300 μm to 400 μm, 325 μm to 400 μm, 350 μm to 400 μm, 375 μm to 400 μm, 10 μm to 375 μm, and 10 μm to 350 μm. m, about 10 μm to about 325 μm, about 10 μm to about 300 μm, about 10 μm to about 275 μm, about 10 μm to about 250 μm, about 10 μm to about 2 25μm, about 10μm to about 200μm, about 50μm to about 375μm, about 50μm to about 350μm, about 50μm to about 325μm, about 50μm ~300μm, approximately 50μm~275μm, approximately 50μm~250μm, approximately 50μm~225μm, approximately 50μm~200μm, approximately 5 0 μm to approx. 175 μm, approx. 50 μm to approx. 150 μm, approx. 50 μm to approx. 125 μm, approx. 50 μm to approx. 100 μm, approx. 75μm to approx. 375μm, approx. 75μm to approx. 350μm, approx. 75μm to approx. 325μm, approx. 75μm to approx. 300μm, approx. 75μm to approx. 275μm m, about 75 μm to about 250 μm, about 75 μm to about 225 μm, about 75 μm to about 375 μm, about 75 μm to about 350 μm, about 75 μm to about 3 25μm, about 75μm to about 300μm, about 75μm to about 275μm, about 75μm to about 250μm, about 75μm to about 225μm, about 75μm ~ approx. 200 μm, approx. 75 μm ~ approx. 175 μm, approx. 75 μm ~ approx. 150 μm, approx. 75 μm ~ approx. 125 μm, approx. 75 μm ~ approx. 0 μm ~ approx. 375 μm, approx. 100 μm ~ approx. 350 μm, approx. 100 μm ~ approx. 325 μm, approx. 100 μm ~ approx. 300 μm, approx. 100 μm ~ approx. 2 75μm, about 100μm to about 250μm, about 100μm to about 225μm, about 100μm to about 200μm, about 100μm to about 175μm, about 100μm~about 150μm, about 100μm~about 125μm, about 125μm~about 375μm, about 125μm~about 350μm, about 125μm~ Approximately 325μm, approximately 125μm to approximately 300μm, approximately 125μm to approximately 275μm, approximately 125μm to approximately 250μm, approximately 125μm to approximately 225μm,Approximately 125μm to approximately 200μm, approximately 125μm to approximately 175μm, approximately 125μm to approximately 150μm, approximately 150μm to approximately 375μm, approximately 150μm to approximately 350μm, approximately 150μm to approximately 325μm, approximately 15 0μm~about 300μm, about 150μm~about 275μm, about 150μm~about 250μm, about 150μm~about 225μm, about 150μm~about 200μm, about 150μm~about 175μm, about 175μm~ Approximately 375μm, approximately 175μm to approximately 350μm, approximately 175μm to approximately 325μm, approximately 175μm to approximately 300μm, approximately 175μm to approximately 275μm, approximately 175μm to approximately 250μm, approximately 175μm to approximately 22 5μm, about 175μm to about 200μm, about 200μm to about 375μm, about 200μm to about 350μm, about 200μm to about 325μm, about 200μm to about 300μm, about 200μm to about 275μm, Approximately 200μm to approximately 250μm, approximately 200μm to approximately 225μm, approximately 225μm to approximately 375μm, approximately 225μm to approximately 350μm, approximately 225μm to approximately 325μm, approximately 225μm to approximately 300μm, approximately 22 5μm~about 275μm, about 225μm~about 250μm, about 250μm~about 375μm, about 250μm~about 350μm, about 250μm~about 325μm, about 250μm~about 300μm, about 250μm~ The particles have a particle size distribution defined by d(0.5) of approximately 275 μm, approximately 275 μm to approximately 375 μm, approximately 275 μm to approximately 350 μm, approximately 275 μm to approximately 325 μm, approximately 275 μm to approximately 300 μm, approximately 300 μm to approximately 375 μm, approximately 300 μm to approximately 350 μm, approximately 300 μm to approximately 325 μm, approximately 325 μm to approximately 375 μm, approximately 325 μm to approximately 350 μm, or approximately 350 μm to approximately 375 μm. In one embodiment, the particles have a particle size distribution defined by d(0.5) of approximately 10 μm to approximately 400 μm.

[0077] In one embodiment, the particles are approximately 10 μm to 800 μm, 50 μm to 800 μm, 100 μm to 800 μm, 150 μm to 800 μm, 200 μm to 800 μm, 250 μm to 800 μm, 300 μm to 800 μm, 350 μm to 800 μm, 400 μm to 800 μm, 450 μm to 800 μm, 500 μm to 800 μm, 550 μm to 800 μm, 600 μm to 800 μm, 650 μm to 800 μm, 700 μm to 800 μm, 750 μm to 800 μm, and 150 μm to 7 50μm, about 150μm to about 700μm, about 150μm to about 650μm, about 150μm to about 600μm, about 150μm to about 550μm, about 150μm~about 500μm, about 150μm~about 450μm, about 150μm~about 400μm, about 150μm~about 350μm, about 150μm~ Approximately 300μm, approximately 150μm to approximately 250μm, approximately 150μm to approximately 200μm, approximately 200μm to approximately 750μm, approximately 200μm to approximately 700μm , about 200μm to about 650μm, about 200μm to about 600μm, about 200μm to about 550μm, about 200μm to about 500μm, about 200μm ~450μm, approx. 200μm ~ approx. 400μm, approx. 200μm ~ approx. 350μm, approx. 200μm ~ approx. 300μm, approx. 200μm ~ approx. 250μ m, about 250 μm to about 750 μm, about 250 μm to about 700 μm, about 250 μm to about 650 μm, about 250 μm to about 600 μm, about 250 μm ~ approx. 550 μm, approx. 250 μm ~ approx. 500 μm, approx. 250 μm ~ approx. 450 μm, approx. 250 μm ~ approx. 400 μm, approx. 250 μm ~ approx. 35 0μm, about 250μm to about 300μm, about 300μm to about 750μm, about 300μm to about 700μm, about 300μm to about 650μm, about 30 0μm~about 600μm, about 300μm~about 550μm, about 300μm~about 500μm, about 300μm~about 450μm, about 300μm~about 4 00μm, approximately 300μm to approximately 350μm, approximately 350μm to approximately 750μm, approximately 350μm to approximately 700μm, approximately 350μm to approximately 650μm, approximately 350μm~about 600μm, about 350μm~about 550μm, about 350μm~about 500μm, about 350μm~about 450μm, about 350μm~ Approximately 400μm, approximately 400μm to approximately 750μm, approximately 400μm to approximately 700μm, approximately 400μm to approximately 650μm, approximately 400μm to approximately 600μm,Approximately 400μm to approximately 550μm, approximately 400μm to approximately 500μm, approximately 400μm to approximately 450μm, approximately 450μm to approximately 750μm, approximately 450μm to approximately 700μm, approximately 450μm to approximately 650μm, approximately 450μm~ Approximately 600μm, approximately 450μm to approximately 550μm, approximately 450μm to approximately 500μm, approximately 500μm to approximately 750μm, approximately 500μm to approximately 700μm, approximately 500μm to approximately 650μm, approximately 500μm to approximately 600μm, The particles have a particle size distribution defined by d(0.9) of approximately 500 μm to 550 μm, approximately 550 μm to 750 μm, approximately 550 μm to 700 μm, approximately 550 μm to 650 μm, approximately 550 μm to 600 μm, approximately 600 μm to 750 μm, approximately 600 μm to 700 μm, approximately 600 μm to 650 μm, approximately 650 μm to 750 μm, approximately 650 μm to 700 μm, or approximately 700 μm to 750 μm. In one embodiment, the particles have a particle size distribution defined by d(0.9) of approximately 10 μm to 800 μm.

[0078] In various embodiments, the present invention is based on formula (I) [ka] (I) [In the formula, R 1 [wherein is H or D, but the total deuterium ratio in the compound of formula (I) is approximately 1.3 to 4.] A pharmaceutical substance comprising particles of crystalline deuterium chloride salt of a deuterium-concentrated compound represented by, The present invention provides a pharmaceutical substance in which the particles have a particle size distribution defined by d(0.9) of about 10 μm to about 800 μm, preferably less than 500 μm.

[0079] Deuterium-concentrated pioglitazone hydrochloride (HCl) salt In one embodiment, the present invention is defined by formula (IA): [ka] (IA) This provides the crystalline hydrochloride salt of a deuterium-enriched compound represented by [the formula shown].

[0080] In one embodiment, the crystalline hydrochloride is characterized by an X-ray powder diffraction pattern including peaks at the following diffraction angles (2θ): 15.8°±0.2°, 22.8°±0.2°, and 26.0°±0.2°. In another embodiment, the crystalline hydrochloride is characterized by an X-ray powder diffraction pattern including peaks at the following diffraction angles (2θ): 20.0°±0.2°, 20.8°±0.2°, and 22.8°±0.2°.

[0081] In various embodiments, the present invention is expressed by formula (IA) [ka] (IA) The present invention provides a crystalline hydrochloride salt of a compound represented by [formula], wherein the crystalline hydrochloride salt is characterized by an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 15.8°±0.2°, 22.8°±0.2°, and 26.0°±0.2°.

[0082] In one embodiment, the crystalline hydrochloride is characterized by an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 15.8°±0.2°, 20.0°±0.2°, 20.8°±0.2°, 22.8°±0.2°, and 26.0°±0.2°. In one embodiment, the crystalline hydrochloride is characterized by an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 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°.

[0083] In one embodiment, the crystalline hydrochloride is characterized by an X-ray powder diffraction pattern shown with respect to the diffraction angle 2θ, as shown in Table 3, and, optionally, by relative intensity (shown as a percentage of the strongest peak). Table 3 - X-ray powder diffraction data of crystalline hydrochloride salts [Table 3]

[0084] In one embodiment, the crystalline hydrochloride is characterized by an X-ray powder diffraction pattern substantially identical to that shown in Table 6.

[0085] The crystalline hydrochloride salt may also be characterized by the onset temperature of its melting point. In one embodiment, the crystalline hydrochloride salt exhibits an onset of its melting point at about 190°C to about 210°C, as determined by differential scanning calorimetry. In one embodiment, the crystalline hydrochloride salt exhibits an onset of its melting point at about 190°C, as determined by differential scanning calorimetry. In one embodiment, the crystalline deuterium chloride salt exhibits endothermic melting with a peak at about 195°C to about 205°C. In one embodiment, the crystalline deuterium chloride salt exhibits endothermic melting with a peak at about 200°C. In one embodiment, the crystalline hydrochloride salt has a differential scanning calorimetry curve substantially identical to the differential scanning calorimetry curve shown in Table 8.

[0086] In one embodiment, the crystalline hydrochloride is an anhydrous crystalline hydrochloride.

[0087] In one embodiment, the crystalline hydrochloride 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%.

[0088] In one embodiment, the crystalline hydrochloride 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%.

[0089] In one embodiment, 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%.

[0090] In various embodiments, the present invention is expressed by formula (IA) [ka] (IA) The present invention provides a pharmaceutical substance comprising particles of a crystalline hydrochloride salt of a compound represented by [formula], wherein the particles in the pharmaceutical substance have a needle-like crystalline shape.

[0091] In one embodiment, the particles are 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, approximately 10 μm to 160 μm, and approximately 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 16 0μm, approx. 20μm~140μm, approx. 20μm~120μm, approx. 20μm~100μm, approx. 20μm~80μm, approx. 20μm~60μm, approx. 20μm~40μm, approx. 40μm~180μm, approx. 40μm m~160μm, approx. 40μm~140μm, approx. 40μm~120μm, approx. 40μm~100μm, approx. 40μm~80μm, approx. 40μm~60μm, approx. 60μm~180μm, approx. 60μm~160μ m, approximately 60μm~140μm, approximately 60μm~120μm, approximately 60μm~100μm, approximately 60μm~80μm, approximately 80μm~180μm, approximately 80μm~160μm, approximately 80μm~140μm, approximately 80μm The particles have a particle size distribution defined by d(0.1) of approximately 10μm to 120μm, approximately 80μm to 100μm, approximately 100μm to 180μm, approximately 100μm to 160μm, approximately 100μm to 140μm, approximately 100μm to 120μm, approximately 120μm to 180μm, approximately 120μm to 160μm, approximately 120μm to 140μm, approximately 140μm to 180μm, approximately 140μm to 160μm, or approximately 160μm to 180μm. In one embodiment, the particles have a particle size distribution defined by d(0.1) of approximately 10μm to approximately 200μm.

[0092] In one embodiment, the particles are approximately 10 μm to 400 μm, 50 μm to 400 μm, 75 μm to 400 μm, 100 μm to 400 μm, 125 μm to 400 μm, 150 μm to 400 μm, 175 μm to 400 μm, 200 μm to 400 μm, 225 μm to 400 μm, 250 μm to 400 μm, 275 μm to 400 μm, 300 μm to 400 μm, 325 μm to 400 μm, 350 μm to 400 μm, 375 μm to 400 μm, 10 μm to 375 μm, and 10 μm to 350 μm. m, about 10 μm to about 325 μm, about 10 μm to about 300 μm, about 10 μm to about 275 μm, about 10 μm to about 250 μm, about 10 μm to about 2 25μm, about 10μm to about 200μm, about 50μm to about 375μm, about 50μm to about 350μm, about 50μm to about 325μm, about 50μm ~300μm, approximately 50μm~275μm, approximately 50μm~250μm, approximately 50μm~225μm, approximately 50μm~200μm, approximately 5 0 μm to approx. 175 μm, approx. 50 μm to approx. 150 μm, approx. 50 μm to approx. 125 μm, approx. 50 μm to approx. 100 μm, approx. 75μm to approx. 375μm, approx. 75μm to approx. 350μm, approx. 75μm to approx. 325μm, approx. 75μm to approx. 300μm, approx. 75μm to approx. 275μm m, about 75 μm to about 250 μm, about 75 μm to about 225 μm, about 75 μm to about 375 μm, about 75 μm to about 350 μm, about 75 μm to about 3 25μm, about 75μm to about 300μm, about 75μm to about 275μm, about 75μm to about 250μm, about 75μm to about 225μm, about 75μm ~ approx. 200 μm, approx. 75 μm ~ approx. 175 μm, approx. 75 μm ~ approx. 150 μm, approx. 75 μm ~ approx. 125 μm, approx. 75 μm ~ approx. 0 μm ~ approx. 375 μm, approx. 100 μm ~ approx. 350 μm, approx. 100 μm ~ approx. 325 μm, approx. 100 μm ~ approx. 300 μm, approx. 100 μm ~ approx. 2 75μm, about 100μm to about 250μm, about 100μm to about 225μm, about 100μm to about 200μm, about 100μm to about 175μm, about 100μm~about 150μm, about 100μm~about 125μm, about 125μm~about 375μm, about 125μm~about 350μm, about 125μm~ Approximately 325μm, approximately 125μm to approximately 300μm, approximately 125μm to approximately 275μm, approximately 125μm to approximately 250μm, approximately 125μm to approximately 225μm,Approximately 125μm to approximately 200μm, approximately 125μm to approximately 175μm, approximately 125μm to approximately 150μm, approximately 150μm to approximately 375μm, approximately 150μm to approximately 350μm, approximately 150μm to approximately 325μm, approximately 15 0μm~about 300μm, about 150μm~about 275μm, about 150μm~about 250μm, about 150μm~about 225μm, about 150μm~about 200μm, about 150μm~about 175μm, about 175μm~ Approximately 375μm, approximately 175μm to approximately 350μm, approximately 175μm to approximately 325μm, approximately 175μm to approximately 300μm, approximately 175μm to approximately 275μm, approximately 175μm to approximately 250μm, approximately 175μm to approximately 22 5μm, about 175μm to about 200μm, about 200μm to about 375μm, about 200μm to about 350μm, about 200μm to about 325μm, about 200μm to about 300μm, about 200μm to about 275μm, Approximately 200μm to approximately 250μm, approximately 200μm to approximately 225μm, approximately 225μm to approximately 375μm, approximately 225μm to approximately 350μm, approximately 225μm to approximately 325μm, approximately 225μm to approximately 300μm, approximately 22 5μm~about 275μm, about 225μm~about 250μm, about 250μm~about 375μm, about 250μm~about 350μm, about 250μm~about 325μm, about 250μm~about 300μm, about 250μm~ The particles have a particle size distribution defined by d(0.5) of approximately 275 μm, approximately 275 μm to approximately 375 μm, approximately 275 μm to approximately 350 μm, approximately 275 μm to approximately 325 μm, approximately 275 μm to approximately 300 μm, approximately 300 μm to approximately 375 μm, approximately 300 μm to approximately 350 μm, approximately 300 μm to approximately 325 μm, approximately 325 μm to approximately 375 μm, approximately 325 μm to approximately 350 μm, or approximately 350 μm to approximately 375 μm. In one embodiment, the particles have a particle size distribution defined by d(0.5) of approximately 10 μm to approximately 400 μm.

[0093] In one embodiment, the particles are approximately 10 μm to 800 μm, 50 μm to 800 μm, 100 μm to 800 μm, 150 μm to 800 μm, 200 μm to 800 μm, 250 μm to 800 μm, 300 μm to 800 μm, 350 μm to 800 μm, 400 μm to 800 μm, 450 μm to 800 μm, 500 μm to 800 μm, 550 μm to 800 μm, 600 μm to 800 μm, 650 μm to 800 μm, 700 μm to 800 μm, 750 μm to 800 μm, and 150 μm to 7 50μm, about 150μm to about 700μm, about 150μm to about 650μm, about 150μm to about 600μm, about 150μm to about 550μm, about 150μm~about 500μm, about 150μm~about 450μm, about 150μm~about 400μm, about 150μm~about 350μm, about 150μm~ Approximately 300μm, approximately 150μm to approximately 250μm, approximately 150μm to approximately 200μm, approximately 200μm to approximately 750μm, approximately 200μm to approximately 700μm , about 200μm to about 650μm, about 200μm to about 600μm, about 200μm to about 550μm, about 200μm to about 500μm, about 200μm ~450μm, approx. 200μm ~ approx. 400μm, approx. 200μm ~ approx. 350μm, approx. 200μm ~ approx. 300μm, approx. 200μm ~ approx. 250μ m, about 250 μm to about 750 μm, about 250 μm to about 700 μm, about 250 μm to about 650 μm, about 250 μm to about 600 μm, about 250 μm ~ approx. 550 μm, approx. 250 μm ~ approx. 500 μm, approx. 250 μm ~ approx. 450 μm, approx. 250 μm ~ approx. 400 μm, approx. 250 μm ~ approx. 35 0μm, about 250μm to about 300μm, about 300μm to about 750μm, about 300μm to about 700μm, about 300μm to about 650μm, about 30 0μm~about 600μm, about 300μm~about 550μm, about 300μm~about 500μm, about 300μm~about 450μm, about 300μm~about 4 00μm, approximately 300μm to approximately 350μm, approximately 350μm to approximately 750μm, approximately 350μm to approximately 700μm, approximately 350μm to approximately 650μm, approximately 350μm~about 600μm, about 350μm~about 550μm, about 350μm~about 500μm, about 350μm~about 450μm, about 350μm~ Approximately 400μm, approximately 400μm to approximately 750μm, approximately 400μm to approximately 700μm, approximately 400μm to approximately 650μm, approximately 400μm to approximately 600μm,Approximately 400μm to approximately 550μm, approximately 400μm to approximately 500μm, approximately 400μm to approximately 450μm, approximately 450μm to approximately 750μm, approximately 450μm to approximately 700μm, approximately 450μm to approximately 650μm, approximately 450μm~ Approximately 600μm, approximately 450μm to approximately 550μm, approximately 450μm to approximately 500μm, approximately 500μm to approximately 750μm, approximately 500μm to approximately 700μm, approximately 500μm to approximately 650μm, approximately 500μm to approximately 600μm, The particles have a particle size distribution defined by d(0.9) of approximately 500 μm to approximately 550 μm, approximately 550 μm to approximately 750 μm, approximately 550 μm to approximately 700 μm, approximately 550 μm to approximately 650 μm, approximately 550 μm to approximately 600 μm, approximately 600 μm to approximately 750 μm, approximately 600 μm to approximately 700 μm, approximately 600 μm to approximately 650 μm, approximately 650 μm to approximately 750 μm, approximately 650 μm to approximately 700 μm, or approximately 700 μm to approximately 750 μm. In one embodiment, the particles have a particle size distribution defined by d(0.9) of approximately 10 μm to approximately 800 μm, preferably less than 500 μm.

[0094] In various embodiments, the present invention is expressed by formula (IA) [ka] (IA) The present invention provides a pharmaceutical substance comprising particles of a crystalline hydrochloride salt of a compound represented by [formula], wherein the particles have a particle size distribution defined by d(0.9) of about 10 μm to about 800 μm, preferably less than 500 μm.

[0095] In one embodiment, the particles in the pharmaceutical substance have a needle-like crystalline shape.

[0096] In one embodiment, the total deuterium abundance in the compound of formula (IA) is approximately 0.3 to 2, approximately 0.4 to 2, approximately 0.6 to 2, approximately 0.8 to 2, approximately 1 to 2, approximately 1.2 to 2, approximately 1.4 to 2, approximately 1.6 to 2, approximately 1.8 to 2, approximately 0.3 to 1.8, approximately 0.3 to 1.6, approximately 0.3 to 1.4, approximately 0.3 to 1.2, approximately 0.3 to 1, approximately 0.3 to 0.8, approximately 0.3 to 0.6, approximately 0.3 to 0.4, approximately 0.4 to 1.8, approximately 0.4 to 1.6, approximately 0.4 to 1.4, approximately 0.4 to 1.2, approximately 0.4 to 1.2 1. Approximately 0.4 to 0.8, approximately 0.4 to 0.6, approximately 0.6 to 1.8, approximately 0.6 to 1.6, approximately 0.6 to 1.4, approximately 0.6 to 1.2, approximately 0.6 to 1, approximately 0.6 to 0.8, approximately 0.8 to 1.8, approximately 0.8 to 1.6, approximately 0.8 to 1.4, approximately 0.8 to 1.2, approximately 0.8 to 1.0, approximately 1 to 1.8, approximately 1 to 1.6, approximately 1 to 1.4, approximately 1 to 1.2, approximately 1.2 to 1.8, approximately 1.2 to 1.6, approximately 1.2 to 1.4, approximately 1.4 to 1.8, approximately 1.4 to 1.6, or approximately 1.6 to 1.8.

[0097] Pharmaceutical composition In some embodiments, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable salt (containing any of the pharmaceutical substances) of a compound of formula I or formula IA as described herein and a pharmaceutically acceptable excipient for the treatment of diseases, disorders, or conditions described herein (e.g., neurological disorders, cancer, respiratory diseases, metabolic disorders, hepatitis, cardiovascular diseases, inflammatory or immune-mediated diseases, skin diseases, wounds, etc.). In some embodiments, the pharmaceutically acceptable salt form of a compound of formula I or formula IA is a deuterium chloride salt. In some embodiments, the pharmaceutically acceptable salt form of a compound of formula I or formula IA is a hydrochloride salt.

[0098] In various embodiments, the pharmaceutical composition comprises a deuterium chloride salt of the compound of formula I and a pharmaceutically acceptable excipient. In one embodiment, the deuterium chloride salt of the compound of formula I is a crystalline deuterium chloride salt.

[0099] In various embodiments, the pharmaceutical composition comprises a crystalline deuterium chloride salt of the compound of formula I and a pharmaceutically acceptable excipient.

[0100] In various embodiments, the pharmaceutical composition comprises a hydrochloride salt of the compound of formula IA and a pharmaceutically acceptable excipient. In one embodiment, the hydrochloride salt of the compound of formula IA is a crystalline hydrochloride salt.

[0101] In various embodiments, the pharmaceutical composition comprises a crystalline hydrochloride salt of the compound of formula IA and a pharmaceutically acceptable excipient.

[0102] In various embodiments, the present invention is (i) Equation (I) [ka] (I) Particles of crystalline deuterium chloride salts of deuterium-enriched compounds shown, and (ii) Medicinally acceptable excipients A pharmaceutical composition containing, In the formula, R 1 is H or D, however R 1 The present invention provides a pharmaceutical composition in which the proportion of deuterium is at least 80%, and the particles in the pharmaceutical composition have a crystal shape selected from hexagonal, rod-shaped, and combinations thereof.

[0103] In various embodiments, the present invention is (i) Equation (I) [ka] (I) Particles of crystalline deuterium chloride salts of deuterium-enriched compounds shown, and (ii) Medicinally acceptable excipients A pharmaceutical composition containing, In the formula, R 1 is H or D, however R 1The present invention provides a pharmaceutical composition in which the proportion of deuterium is at least 80%, and the particles have a particle size defined by d(0.9) of about 10 μm to about 800 μm, preferably less than 500 μm.

[0104] In various embodiments, the present invention is (i) Formula (IA) [ka] (IA) Particles of the crystalline hydrochloride salt of the compound shown, and (ii) Medicinally acceptable excipients A pharmaceutical composition containing, The present invention provides a pharmaceutical composition in which the particles in the pharmaceutical composition have a needle-like crystalline shape.

[0105] In various embodiments, the present invention is (i) Formula (IA) [ka] (IA) Particles of the crystalline hydrochloride salt of the compound shown, and (ii) Medicinally acceptable excipients A pharmaceutical composition containing, The present invention provides a pharmaceutical composition in which the particles have a particle size distribution defined by d(0.9), which is approximately 10 μm to 800 μm, preferably less than 500 μm.

[0106] In some embodiments, the pharmaceutical composition described herein comprises a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula I or formula IA. In some embodiments, the pharmaceutical composition described herein comprises a therapeutically effective amount of a deuterium chloride salt of a compound of formula I. In some embodiments, the pharmaceutical composition described herein comprises a therapeutically effective amount of a crystalline deuterium chloride salt of a compound of formula I. In some embodiments, the pharmaceutical composition described herein comprises a therapeutically effective amount of a hydrochloride salt of a compound of formula IA. In some embodiments, the pharmaceutical composition described herein comprises a therapeutically effective amount of a crystalline hydrochloride salt of a compound of formula IA.

[0107] In one embodiment, the crystalline deuterium chloride salt of the compound of formula I is the crystalline deuterium chloride salt described herein.

[0108] In one embodiment, the crystalline deuterium chloride salt of the compound of formula IA is a crystalline hydrochloride salt as described herein.

[0109] The pharmaceutical compositions provided herein can be administered by various routes, including, but are not limited to, oral (intestinal), parenteral (injection), rectal, transdermal, intradermal, subarachnoid, subcutaneous (SC), intravenous (IV), intramuscular (IM), and intranasal administration. In one embodiment, the pharmaceutical compositions described herein are administered orally.

[0110] The pharmaceutical compositions provided herein may also be administered chronically ("chronic administration"). Chronic administration means the administration of the compound or the pharmaceutical composition over a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue indefinitely (for example, for the remainder of the subject's life). In one embodiment, chronic administration is intended to provide a certain level of the compound in the blood, for example, a therapeutic concentration range over a long period of time.

[0111] The pharmaceutical compositions provided herein may be supplied in unit formulations to facilitate precise administration. The term “unit formulation” means a physically separate unit suitable as a single dose for human subjects and other mammals, where each unit contains a predetermined amount of active substance calculated to produce a desired therapeutic effect in combination with appropriate pharmaceutical excipients. Typical unit formulations include pre-filled and pre-measured ampoules or syringes of liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, etc.

[0112] The descriptions of pharmaceutical compositions provided herein are primarily for use in humans; however, it will be understood by those skilled in the art that such compositions are generally suitable for use in all types of animals. It is well understood that modifications of pharmaceutical compositions suitable for human use can be made suitable for use in various animals, and those skilled in the art of animal pharmacology can design and / or carry out general experimental modifications. General matters concerning the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21st ed., Lippincott Williams & Wilkins, 2005.

[0113] formulation The pharmaceutical compositions can be used to manufacture each individual unit formulation. The pharmaceutical compositions and formulations provided herein comprise the compounds provided herein, or their pharmaceutically acceptable salts, solvates, or enantiomers. The pharmaceutical compositions and formulations may further comprise one or more excipients.

[0114] The pharmaceutical compositions and formulations provided herein may contain one or more additional active ingredients. Examples of optional second or additional active ingredients are described above.

[0115] The single unit formulations provided herein are suitable for administration to patients orally, mucosally (e.g., nasally, sublingual, vaginally, buccal, or rectally), parenterally (e.g., subcutaneously, intravenously, bolus infusion, intramuscularly, or intra-arterially), topically (e.g., eye drops or other ophthalmic formulations), transdermally, or transdermally. Examples of formulations include, but are not limited to, tablets; caplets; capsules, e.g., soft gelatin capsules; cashews; lozenges; dispersants; suppositories; powders; aerosols (e.g., nasal sprays or inhalers); gels; liquid formulations suitable for oral or mucosal administration to patients (including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water liquid emulsions, or water-in-oil liquid emulsions), solutions, and elixirs); liquid formulations suitable for parenteral administration to patients; eye drops or other ophthalmic formulations suitable for topical administration; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid formulations suitable for parenteral administration to patients.

[0116] The composition, form, and type of a pharmaceutical formulation generally vary depending on its intended use. For example, a formulation used for the acute treatment of a disease may contain one or more active ingredients in greater quantities than a formulation used for the chronic treatment of the same disease. Similarly, a parenteral formulation may contain one or more active ingredients in greater quantities than an oral formulation used to treat the same disease. These other ways in which the specific formulations used vary from one another are apparent to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).

[0117] In another embodiment, the pharmaceutical compositions and formulations of the present invention comprise one or more excipients. Suitable excipients are well known to those skilled in the pharmaceutical art, and non-limiting examples of suitable excipients are provided herein. Whether it is appropriate to include a particular excipient in a pharmaceutical composition or formulation depends on a variety of factors well known in the art, including, but not limited to, how the formulation is administered to a patient. For example, oral formulations such as tablets may contain excipients that are not suitable for use in parenteral formulations. The suitability of a particular excipient may also depend on the specific active ingredient in the formulation. For example, the degradation of a certain active ingredient may be accelerated by a certain excipient or when exposed to water. Active ingredients containing primary or secondary amines are particularly susceptible to such accelerated degradation. Thus, pharmaceutical compositions and formulations are provided that contain, if any, lactose, other mono or disaccharides. As used herein, the term “lactose-free” means that the amount of lactose present is sufficient to substantially increase the rate of degradation of the active ingredient.

[0118] Lactose-free compositions are well known in the art and may contain, for example, excipients described in US Pharmacopeia (USP) 25-NF20 (2002). Generally, lactose-free compositions are pharmaceutically acceptable and contain an active ingredient, a binder / filler, and a lubricant in pharmaceutically acceptable amounts. In another embodiment, a lactose-free formulation contains an active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0119] Since water can accelerate the decomposition of certain compounds, anhydrous pharmaceutical compositions and formulations containing active ingredients are also provided. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical field as a method for assuming long-term storage in order to determine properties such as half-life or the long-term stability of a formulation. See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In fact, water and heat accelerate the decomposition of certain compounds. Therefore, the effect of water in a formulation is very important because moisture and / or humidity come into contact with the formulation during its manufacture, handling, packaging, storage, transport, and use.

[0120] Anhydrous pharmaceutical compositions and formulations can be prepared using anhydrous or low-moisture components and low-moisture or low-humidity conditions. Pharmaceutical compositions and formulations containing lactose and at least one active ingredient, including a primary or secondary amine, are preferably anhydrous if substantial contact with moisture and / or humidity is anticipated during manufacturing, packaging, and / or storage.

[0121] Anhydrous pharmaceutical compositions should be prepared and stored in such a way that their anhydrous properties are maintained. Therefore, in another embodiment, anhydrous compositions are packaged with a substance known to prevent exposure to water and included in a suitable formulation kit. Examples of suitable packaging include, but are not limited to, airtight foil, plastic, dosing containers (e.g., vials), blister packs, and strip packs.

[0122] Also provided are pharmaceutical compositions and formulations comprising one or more compounds that reduce the rate at which the active ingredient degrades. Such compounds are referred to herein as “stabilizers” and include, but are not limited to, oxidizing agents such as ascorbic acid, pH buffers, or salt buffers.

[0123] Similar to the amount and type of excipients, the amount and specific type of the active ingredient in the formulation may vary depending on factors such as the route of administration to the patient, but are not limited to the following. In another embodiment, the formulation contains the compound provided herein in an amount of about 0.10 to about 500 mg. Examples of doses 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.

[0124] In another embodiment, the formulation contains the second active ingredient in amounts 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. Naturally, the specific amount of the second active ingredient depends on the specific drug used, the disease or disorder being treated or controlled, the amount of the compound provided herein, and any optional additional active agents administered concurrently to the patient.

[0125] Pharmaceutical compositions suitable for oral administration may be provided as separate formulations such as tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups), but are not limited to the following. Such formulations may contain a predetermined amount of the active ingredient and may be prepared by methods of the pharmaceutical art well known to those skilled in the art. See, for general information, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).

[0126] The oral formulations provided herein are prepared in accordance with conventional pharmaceutical formulation techniques, combining the active ingredient with at least one excipient. The excipient can be in a wide range of forms depending on the desired formulation for administration. For example, excipients suitable for use in oral liquid or aerosol formulations include, but are not limited to, water, glycols, oils, alcohols, fragrances, preservatives, and colorants. Examples of excipients suitable for use in solid oral formulations (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulators, lubricants, binders, and disintegrants.

[0127] In another embodiment, the present invention provides an oral formulation in the form of a tablet or capsule, in which case a solid excipient is used. In another embodiment, the tablet is coated by standard aqueous or non-aqueous techniques. Such formulations can be prepared by any of the methods of pharmaceutical production. Generally, pharmaceutical compositions and formulations are prepared by uniformly and firmly mixing an active ingredient with a liquid carrier, a granulated solid carrier, or both, and then appropriately molding the product into the desired product.

[0128] For example, tablets can be prepared by compression or molding. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form such as powder or granules, along with excipients as appropriate, in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0129] Examples of excipients that may be used in oral formulations provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants. Suitable binders for use in pharmaceutical compositions and formulations include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums, e.g., acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, alpha starch, hydroxypropyl methylcellulose (e.g., 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

[0130] Suitable forms of microcrystalline cellulose include, but are not limited to, substances marketed as AVCEL-PH-101, AVCEL-PH-103, AVCEL RC-581, and AVCEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales (Marcus Hook, Pennsylvania)), and mixtures thereof. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose, marketed as AVCEL RC-581. Suitable anhydrous or low-moisture excipients or additives include AVCEL-PH-103® and 1500 LM starch.

[0131] Examples of fillers suitable for use in the pharmaceutical compositions and formulations provided herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextran, kaolin, mannitol, silicic acid, sorbitol, starch, alpha-starch, and mixtures thereof. In another embodiment, the binder or filler in the pharmaceutical composition may be present in about 50 to about 99 percent by weight of the pharmaceutical composition or formulation.

[0132] Disintegrants may be used in the composition to provide tablets that disintegrate when exposed to an aqueous environment. Tablets containing very large amounts of disintegrant may disintegrate during storage, while those containing very small amounts may not disintegrate at the desired rate or under the desired conditions. Therefore, a sufficient amount of disintegrant that does not adversely affect the release of the active ingredient, neither too much nor too little, can be used to form a solid oral formulation. The amount of disintegrant used varies depending on the formulation type and is readily apparent to those skilled in the art. In another embodiment, the pharmaceutical composition contains about 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant.

[0133] Disintegrants that can be used in pharmaceutical compositions and formulations include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polaritrin potassium, sodium starch glycolate, potato or tapioca starch, other starches, alpha starch, other starches, clay, other alginic acid, other celluloses, gums, and mixtures thereof.

[0134] Lubricants that can be used in pharmaceutical compositions and formulations include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, diesel fuel, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. Further lubricants include, for example, syloid® silica gel (AEROSIL200, manufactured by WRGrace Co., Ltd. in Baltimore, Maryland), synthetic silica solidification aerosol (sold by Degussa Co., Ltd. in Plano, Texas), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co., Ltd. in Boston, Massachusetts), and mixtures thereof. When used, lubricants may be used in amounts less than about 2 weight percent of the pharmaceutical composition or formulation containing them.

[0135] In another embodiment, the present invention provides a solid oral formulation comprising the compounds provided herein, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, and gelatin.

[0136] The active ingredients provided herein may also be administered by controlled release means or delivery devices well known to those skilled in the art. Examples include, but are not limited to, those described in 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 of which is incorporated in whole by reference). Such formulations can be used to provide delayed or controlled release of one or more active ingredients in various proportions, for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof, to provide a desired release profile. Suitable controlled-release formulations known to those skilled in the art, including those specified herein, can be readily selected for use with the active agents provided herein. In another embodiment, the present invention provides single unit formulations suitable for oral administration, such as tablets, capsules, gel capsules, and caplets, which are used for controlled release, for example, but are not limited to the following.

[0137] Controlled-release pharmaceutical products improve drug therapy beyond what is achieved by their uncontrolled equivalents. In another embodiment, the present invention provides the use of controlled-release preparations in a medical setting, characterized by the smallest amount of drug substance used to cure or control a disease in the shortest possible time. Advantages of controlled-release formulations include sustained drug activity, reduced dosing frequency, and increased patient compliance. Furthermore, controlled-release formulations can be used to influence the time of onset of action or other characteristics, such as the blood level of the drug, and therefore the occurrence of side effects (e.g., adverse effects).

[0138] In another embodiment, a controlled-release formulation is designed to initially release a rapid amount of the drug (active ingredient) that produces the desired therapeutic or prophylactic effect, and then gradually and continuously release other amounts of the drug to maintain this therapeutic or prophylactic level over a longer period. In another embodiment, in order to maintain a constant level of the drug in the body, the drug may be released from the formulation at a rate that replaces the amount of drug that is metabolized and excreted from the body. The controlled release of the active ingredient may be facilitated by a variety of conditions, including but not limited to pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0139] Parenteral formulations can be administered to patients by various routes, including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial. In these embodiments, parenteral formulations may be sterile or sterilized before administration to the patient, in order to avoid the patient's natural defenses against contaminants. Examples of parenteral formulations include, but not limited to, solutions for injection, dried products for dissolution or suspension in pharmaceutically acceptable vehicles for injection, suspensions for injection, and emulsions.

[0140] Suitable vehicles that can be used to provide parenteral formulations are well known to those skilled in the art. Examples include, but are not limited to, water for injection (USP); aqueous vehicles, such as, but are not limited to, sodium chloride injection, Ringer's injection, dextrose injection, dextrose chloride and sodium chloride injection, and Ringer's lactate injection; water-miscible vehicles, such as, but are not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, such as, but are not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0141] Compounds that increase the solubility of one or more of the active ingredients described herein may also be included in parenteral formulations. For example, cyclodextrins and their derivatives can be used to increase the solubility of the compounds provided herein. See, for example, U.S. Patent No. 5,134,127, which is incorporated in whole by reference.

[0142] Topical and mucosal formulations provided herein include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, eye drops or other ophthalmic formulations, or other forms known to those skilled in the art. See, for example, 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). Formulations suitable for treating oral mucosal tissues can be formulated as mouthwashes or oral gels.

[0143] Suitable excipients (e.g., carriers and diluents) and other substances that can be used to provide the topical and mucosal formulations contained herein are well known to those skilled in the pharmaceutical art and depend on the specific tissue to which the given pharmaceutical composition or formulation is applied. In another embodiment, excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to produce non-toxic and pharmaceutically acceptable solutions, emulsions, or gels. Humectants or wetting agents may also be added to pharmaceutical compositions and formulations. Examples of further components are well known in the art. See, for example, Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton PA (1980 & 1990).

[0144] The pH of a pharmaceutical composition or formulation may also be adjusted to improve the delivery of one or more active ingredients. Furthermore, the polarity, ionic strength, or osmotic pressure of the solvent carrier may be adjusted to improve delivery. Compounds such as stearic acid may also be added to a pharmaceutical composition or formulation to modify the hydrophilicity or hydrophobicity of one or more active ingredients to improve delivery. In other embodiments, stearic acid may be used as a lipid vehicle for the formulation, as an emulsifier or surfactant, or as a delivery accelerator or penetration enhancer. In other embodiments, salts, solvates, prodrugs, or enantiomers of the active ingredients may be used to further adjust the properties of the resulting composition.

[0145] In another embodiment, the active ingredients provided herein are not administered to a patient simultaneously or via the same route of administration. In another embodiment, a kit is provided that can simplify the administration of an appropriate amount of the active ingredient.

[0146] In another embodiment, the present invention provides a kit comprising formulations of the compounds provided herein. The kit may further contain additional active ingredients.

[0147] In other embodiments, the kit may further include devices used for administering the active ingredient. Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers.

[0148] The kit may further include cells or blood for transplantation, as well as pharmaceutically acceptable vehicles, which can be used to administer one or more active ingredients. For example, if the active ingredient is supplied in a solid form that needs to be reconstituted for parenteral administration, the kit may include a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particle-free sterile solution suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to, water for injection (USP); aqueous vehicles, such as, but are not limited to, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, and Ringer's lactate injection; water-miscible vehicles, such as, but are not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, such as, but are not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0149] In one embodiment, a pharmaceutical composition is provided comprising the hydrochloride or deuterium chloride salt of deuterium-concentrated pioglitazone described herein, lactose, carmellose, hyprolose (hyprolose), and stearate.

[0150] Instructions for use and treatment methods A method for treating a disease, disorder, or disability (e.g., neurological disorders, cancer, respiratory diseases, endocrine disorders, metabolic disorders, renal diseases, hepatitis, cardiovascular diseases, inflammatory or immune-mediated diseases, skin diseases, wounds, etc.) is provided, comprising administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula I or formula IA, for example, a deuterium chloride salt or hydrochloride salt of a compound of formula I or formula IA as described herein, to a patient in need to treat the disease, disorder, or disability. In various embodiments, the method comprises administering a therapeutically effective amount of a deuterium chloride salt of a compound of formula I, for example, a crystalline deuterium chloride salt form as described herein, to a patient in need to treat the disease, disorder, or disability. In various embodiments, the method comprises administering a therapeutically effective amount of a hydrochloride salt of a compound of formula IA, for example, a crystalline hydrochloride salt form as described herein, to a patient in need to treat the disease, disorder, or disability.

[0151] In one embodiment, the disease, disorder, or disorder is a neurological disorder. In one embodiment, the disease, disorder, or disorder is cancer. In one embodiment, the disease, disorder, or disorder is a respiratory disease. In one embodiment, the disease, disorder, or disorder is an endocrine or metabolic disorder. In one embodiment, the disease, disorder, or disorder is a metabolic disorder. In one embodiment, the disease, disorder, or disorder is hepatitis. In one embodiment, the disease, disorder, or disorder is a cardiovascular disease. In one embodiment, the disease, disorder, or disorder is a kidney disease. In one embodiment, the disease, disorder, or disorder is an inflammatory or immune-mediated disease. In one embodiment, the disease, disorder, or disorder is a skin disease. In one embodiment, the disease, disorder, or disorder is a wound. In one embodiment, the disease, disorder, or disorder is a skin disease.

[0152] Also provided herein are methods for regulating the quantity and / or function of endogenous biomolecules (e.g., triglycerides, fatty acids, carbohydrates or sugars, low-density lipoproteins, high-density lipoproteins, cytokines, etc.) for the prevention or treatment of diseases, disorders, or disabilities described herein, comprising regulating the endogenous biomolecules by administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula I or formula IA, for example, a deuterium chloride salt or hydrochloride salt of a compound of formula I or formula IA as described herein, to a patient in need. In various embodiments, the method includes regulating the endogenous biomolecules by administering a therapeutically effective amount of a deuterium chloride salt of a compound of formula I, for example, a crystalline deuterium chloride salt form as described herein, to a patient in need. In various embodiments, the method includes regulating the endogenous biomolecules by administering a therapeutically effective amount of a hydrochloride salt of a compound of formula IA, for example, a crystalline hydrochloride salt form as described herein, to a patient in need.

[0153] In one embodiment, the endogenous biomaterial is a triglyceride. In one embodiment, the endogenous biomaterial is a fatty acid. In one embodiment, the endogenous biomaterial is a carbohydrate or sugar. In one embodiment, the endogenous biomaterial is a low-density lipoprotein. In one embodiment, the endogenous biomaterial is a high-density lipoprotein. In one embodiment, the endogenous biomaterial is a cytokine.

[0154] (i) Treatment of metabolic disorders Another aspect of the present invention provides a method for treating metabolic disorders or liver disorders selected from the group consisting of non-alcoholic fatty liver disease, non-alcoholic fatty liver, viral hepatitis, cirrhosis, hepatic fibrosis, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, beta-cell deficiency insulin resistance in patients with congenital adrenal hyperplasia treated with glucocorticoids, polycystic ovary syndrome, leukodystrophy (including adrenoleukodystrophy) and adrenal spinal neuropathy, metabolic disorders in peritoneal dialysis patients, decreased insulin secretion, inadequate distribution of brown and white adipocytes, obesity, or inadequate regulation of leptin levels. The method comprises treating the metabolic disorder by administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula I or formula IA, for example, a deuterium chloride or hydrochloride salt of a compound of formula I or formula IA as described herein, to a patient in need. In one embodiment, the method comprises administering a therapeutically effective amount of a deuterium chloride salt of the compound of formula I, for example, the crystalline deuterium chloride salt form described herein, to a patient in need thereof to treat the metabolic disorder. In one embodiment, the method comprises administering a therapeutically effective amount of a hydrochloride salt of the compound of formula IA, for example, the crystalline hydrochloride salt form, to a patient in need thereof to treat the metabolic disorder. In one embodiment, the metabolic disorder is further selected from complications of diabetes. In one embodiment, the metabolic disorder is beta-cell deficiency insulin resistance in patients with non-alcoholic fatty liver disease, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, or congenital adrenal hyperplasia treated with glucocorticoids. In one embodiment, the metabolic disorder is beta-cell deficiency insulin resistance, inadequate distribution of brown and white adipocytes, obesity, or inadequate regulation of leptin levels in patients with non-alcoholic fatty liver disease, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, or congenital adrenal hyperplasia treated with glucocorticoids. In another embodiment, the metabolic disorder is non-alcoholic fatty liver disease. In yet another embodiment, the metabolic disorder is non-alcoholic fatty liver. In yet another embodiment, the metabolic disorder is type 2 diabetes mellitus.In another embodiment, the metabolic disorder is a beta cell deficiency treatable by B cell regeneration. In another embodiment, the metabolic disorder is central obesity, dyslipidemia, or prediabetes. In another embodiment, the metabolic disorder is polycystic ovary syndrome. In another embodiment, the metabolic disorder is leukodystrophy (including adrenoleukodystrophy) and adrenal spinal neuropathy.

[0155] Non-alcoholic fatty liver disease In one embodiment, a method for treating non-alcoholic fatty liver disease is provided, comprising administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula I or formula IA, for example, a deuterium chloride or hydrochloride salt of a compound of formula I or formula IA as described herein, to a patient in need thereof to treat the non-alcoholic fatty liver disease. The treatment method is intended to provide specific benefits to patients suffering from non-alcoholic fatty liver disease. Typical benefits include achieving improvement in the patient's non-alcoholic fatty liver disease with little to no PPAR-gamma side effects (e.g., weight gain, edema, and / or bone loss) (which may include reducing the amount of fatty liver caused by the treatment).

[0156] Non-alcoholic fatty liver disease In one embodiment, a method for treating non-alcoholic fatty liver disease is provided, comprising administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula I or formula IA, for example, a deuterium chloride or hydrochloride salt of a compound of formula I or formula IA as described herein, to a patient in need thereof to treat the non-alcoholic fatty liver disease. The treatment method is intended to provide specific benefits to patients suffering from non-alcoholic fatty liver disease. Typical benefits include achieving improvement in the patient's non-alcoholic fatty liver disease with little to no PPAR-gamma side effects (e.g., weight gain, edema, and / or bone loss) (which may include reducing the amount of fatty liver disease treated).

[0157] type 2 diabetes In one embodiment, a method for treating type 2 diabetes is provided, comprising administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula I or formula IA, for example, a deuterium chloride salt or hydrochloride salt of a compound of formula I or formula IA as described herein, to a patient in need thereof to treat the type 2 diabetes. The treatment method is intended to provide specific benefits to a patient suffering from type 2 diabetes. Typical benefits include achieving improvement in the patient's type 2 diabetes with little to no PPAR-gamma side effects (e.g., weight gain, edema, and / or bone loss) (which may include improvement in the patient's blood glucose control).

[0158] (ii) Cancer treatment Another aspect of the present invention provides a method for treating cancer. The method comprises treating the cancer by administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula I or formula IA, for example, a deuterium chloride salt or hydrochloride salt of a compound of formula I or formula IA as described herein, to a patient who needs it. In one embodiment, the method comprises treating the cancer by administering a therapeutically effective amount of a deuterium chloride salt of a compound of formula I, for example, a crystalline deuterium chloride salt form as described herein, to a patient who needs it. In another embodiment, the method comprises treating the cancer by administering a therapeutically effective amount of a hydrochloride salt of a compound of formula IA, for example, a crystalline hydrochloride salt form as described herein, to a patient who needs it.

[0159] In one embodiment, the cancer is lung cancer, hepatocellular carcinoma, astrocytoma, glioma, glioblastoma, meningioma, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, colorectal cancer, pituitary cancer, thyroid cancer, esophageal cancer, or prostate cancer. In another embodiment, the cancer is non-small cell lung cancer or hepatocellular carcinoma.

[0160] In another embodiment, the cancer is lung cancer, hepatocellular carcinoma, astrocytoma, glioma, glioblastoma, meningioma, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, colorectal cancer, pituitary cancer, thyroid cancer, esophageal cancer, prostate cancer, nasal cancer, throat cancer, kidney cancer, breast cancer, stomach cancer, or uterine cancer. In another embodiment, the cancer is brain cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, leukemia, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, kidney cancer, stomach cancer, testicular cancer, or uterine cancer. In further embodiments, the cancers include angioplastic tumors, squamous cell carcinoma, adenocarcinoma, squamous cell carcinoma, melanoma, glioma, neuroblastoma, sarcoma (e.g., angiosarcoma or chondrosarcoma), laryngeal cancer, parotid gland cancer, biliary tract cancer, thyroid cancer, acral lentiginous melanoma, actinic keratosis, acute lymphoblastic leukemia, acute myeloid leukemia, adenoid cystic carcinoma, adenoma, adenosarcoma, adenosquamous cell carcinoma, anal canal cancer, anal cancer, anorectal cancer, and star Cellular tumors, Bartholin's gland carcinoma, basal cell carcinoma, biliary tract cancer, bone cancer, bone marrow cancer, bronchial cancer, bronchial gland cancer, carcinoid, cholangiocarcinoma, choroid plexus papilloma / cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, clear cell carcinoma, connective tissue carcinoma, cystadenoma, gastrointestinal cancer, duodenal cancer, endocrine cancer, endoderm sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, endothelial cell carcinoma, ependymal cell carcinoma, epithelial cell carcinoma, Uygyo Ang's sarcoma, eye and orbital cancer, female genital cancer, focal nodular hyperplasia, bile bladder cancer, pyloric sinus cancer, fundus cancer, gastrinoma, glioblastoma, glucagonoma, cardiac cancer, hemangioblastoma, hemangioendothelioma, hemangioma, hepatic adenoma, hepatic adenomatous disease, hepatobiliary tract cancer, hepatocellular carcinoma, Hodgkin's disease, ileal cancer, insulinoma, intraepithelial neoplasia, intraepithelial squamous cell tumor, intrahepatic cholangiocarcinoma, invasive squamous cell carcinoma, jejunal cancer, joint cancer, Kaposi's sarcoma, pelvic cancer Cancer, large cell carcinoma, colorectal cancer, leiomyosarcoma, melanoma originating from lentigo malignant, lymphoma, male reproductive organ cancer, malignant mesothelioma, malignant mesothelioma, medulloblastoma, medullary epithelioma, meningeal cancer, mesothelial carcinoma, metastatic cancer, oral cancer, mucoepidermoid carcinoma, multiple myeloma, muscle cancer, nasal passage cancer, nervous system cancer, neuroepithelial adenocarcinoma, nodular melanoma, non-epithelial skin cancer, non-Hodgkin lymphoma, oat cell carcinoma, oligodendroglioma, oral cancer, osteosarcoma, papillary serous adenocarcinoma,Penile cancer, pharyngeal cancer, pituitary abscess, plasmacytoma, pseudosarcoma, pulmonary blastoma, rectal cancer, renal cell carcinoma, respiratory cancer, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, paranasal sinus cancer, skin cancer, small cell carcinoma, small intestine cancer, leiomyocyte carcinoma, parenchymal tissue carcinoma, somatostatin-secreting cell tumor, spinal cancer, squamous cell carcinoma, rhabdomyosarcoma, submesothelial carcinoma, superficial spreading melanoma, T-cell leukemia, tongue cancer, undifferentiated carcinoma, ureteral cancer, urethral cancer, bladder cancer, urinary tract cancer, cervical cancer, uterine body cancer, uveal melanoma, vaginal cancer, verrucous carcinoma, VIP-producing tumor, vulvar cancer, well-differentiated carcinoma, or Wilms' tumor.

[0161] In one other embodiment, the cancer is a non-Hodgkin lymphoma, such as a B-cell lymphoma or a T-cell lymphoma. In one embodiment, the non-Hodgkin lymphoma is a B-cell lymphoma, such as diffuse large B-cell lymphoma, mediastinal large 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 another embodiment, the non-Hodgkin lymphoma is a T-cell lymphoma, such as a precursor T-lymphoblastic lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, angioimmunoblastic T-cell lymphoma, extranodal natural killer / T-cell lymphoma, enteropathy-associated T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma, or peripheral T-cell lymphoma.

[0162] (iii) Treatment of respiratory diseases Another aspect of the present invention provides a method for treating a respiratory disease. The method comprises administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula I or formula IA, for example, a deuterium chloride salt or hydrochloride salt of a compound of formula I or formula IA as described herein, to a patient in need to treat the respiratory disease. In one embodiment, the method comprises administering a therapeutically effective amount of a deuterium chloride salt of a compound of formula I, for example, a crystalline deuterium chloride salt form as described herein, to a patient in need to treat the respiratory disease. In another embodiment, the method comprises administering a therapeutically effective amount of a hydrochloride salt of a compound of formula IA, for example, a crystalline hydrochloride salt form as described herein, to a patient in need to treat the respiratory disease.

[0163] In one embodiment, the respiratory disease is chronic obstructive pulmonary disease, asthma, bronchitis, cystic fibrosis, pulmonary edema, pulmonary embolism, pulmonary arterial hypertension, pneumonia, pulmonary sarcoidosis, silicosis, pulmonary fibrosis, respiratory failure, acute respiratory distress syndrome, emphysema, chronic bronchitis, tuberculosis, lung cancer, or a chronic respiratory disease. In one embodiment, the respiratory disease is chronic obstructive pulmonary disease, asthma, or a chronic respiratory disease. In another embodiment, the respiratory disease is chronic obstructive pulmonary disease. In yet another embodiment, the respiratory disease 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 one embodiment, asthma is mild asthma, moderate asthma, severe asthma, or steroid-resistant asthma.

[0164] (iv) Treatment of neurological disorders Accordingly, one aspect of the present invention provides a method for treating a neurological disorder selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, autism spectrum disorder, depression, mild cognitive impairment, Down syndrome, neurodegeneration, adrenoleukodystrophy, adrenal spinal neuropathy, Zellweger syndrome, Huntington's disease, stroke, traumatic brain injury, substance abuse, spinal cord injury, nerve injury, major depressive disorder or bipolar disorder complicated with metabolic syndrome, and neurological disorders caused by functional mitochondrial dysfunction. The method comprises treating the neurological disorder by administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula I or formula IA, for example, a deuterium chloride or hydrochloride of a compound of formula I or formula IA as described herein, to a patient in need. In one embodiment, the method comprises treating the neurological disorder by administering a therapeutically effective amount of a deuterium chloride of a compound of formula I, for example, a crystalline deuterium chloride form as described herein, to a patient in need. In one embodiment, the method comprises administering a therapeutically effective amount of the hydrochloride of the compound of formula IA, for example, the crystalline hydrochloride form described herein, to a patient in need thereof to treat the neurological disorder. In one embodiment, the neurological disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, autism spectrum disorder, depression, mild cognitive impairment, neurodegeneration, adrenoleukodystrophy, adrenospinal neuropathy, Huntington's disease, stroke, traumatic brain injury, substance abuse, spinal cord injury, nerve injury, and major depressive disorder or bipolar disorder complicated with metabolic syndrome. In one embodiment, the neurological disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, depression, mild cognitive impairment, neurodegeneration, adrenoleukodystrophy, adrenospinal neuropathy, and Huntington's disease. In another embodiment, the neurological disorder is Alzheimer's disease. In another embodiment, the neurological disorder is Down syndrome. In another embodiment, the neurological disorder is adrenoleukodystrophy. In another embodiment, the neurological disorder is adrenal spinoneuropathy.

[0165] In another embodiment, the neurological impairment is a cognitive impairment, such as agnosia and / or memory impairment. The agnosia may be, for example, agnosia associated with Alzheimer's disease.

[0166] In one embodiment, the substance abuse is one or more of the following: alcohol craving, heroin addiction, and nicotine addiction.

[0167] (v) Treatment of hepatitis symptoms Another aspect of the present invention provides a method for treating the symptoms of hepatitis. The method comprises treating the hepatitis by administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula I or formula IA, for example, a deuterium chloride salt or hydrochloride salt of a compound of formula I or formula IA as described herein, to a patient in need. In one embodiment, the method comprises treating the hepatitis by administering a therapeutically effective amount of a deuterium chloride salt of a compound of formula I, for example, a crystalline deuterium chloride salt form as described herein, to a patient in need. In one embodiment, the method comprises treating the hepatitis by administering a therapeutically effective amount of a hydrochloride salt of a compound of formula IA, for example, a crystalline hydrochloride salt form as described herein, to a patient in need.

[0168] (vi) Treatment of cardiovascular diseases Another aspect of the present invention provides a method for treating a cardiovascular disease. The method comprises administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula I or formula IA, for example, a deuterium chloride or hydrochloride salt of a compound of formula I or formula IA as described herein, to a patient in need to treat the cardiovascular disease. In one embodiment, the method comprises administering a therapeutically effective amount of a deuterium chloride salt of a compound of formula I, for example, a crystalline deuterium chloride form as described herein, to a patient in need to treat the cardiovascular disease. In one embodiment, the method comprises administering a therapeutically effective amount of a hydrochloride salt of a compound of formula IA, for example, a crystalline hydrochloride form as described herein, to a patient in need to treat the cardiovascular disease. In one embodiment, the cardiovascular disease is hypertension, hyperlipidemia, atherosclerosis, inadequate vascular function, dyslipidemia, stenosis, restenosis, myocardial infarction, stroke, intracerebral hemorrhage, acute coronary syndrome, stable angina, or unstable angina. In another embodiment, the cardiovascular disease is intracerebral hemorrhage, acute coronary syndrome, stable angina, or unstable angina.

[0169] In another embodiment, the present invention provides a method for preventing stroke in a patient. The method comprises administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula I or formula IA, for example, a deuterium chloride salt or hydrochloride salt of a compound of formula I or formula IA as described herein, to a patient in need to prevent stroke in the patient. In one embodiment, the method comprises administering a therapeutically effective amount of a deuterium chloride salt of a compound of formula I, for example, a crystalline deuterium chloride salt form as described herein, to a patient in need to prevent stroke in the patient. In one embodiment, the method comprises administering a therapeutically effective amount of a hydrochloride salt of a compound of formula IA, for example, a crystalline hydrochloride salt form as described herein, to a patient in need to prevent stroke in the patient.

[0170] The aforementioned treatment or preventive measures may be relevant to patients at risk of central nervous system ischemic stroke or to patients at risk of stroke due to cardiovascular disease.

[0171] (vii) Reduction in the amount of triglycerides or low-density lipoproteins Another aspect of the present invention provides a method for reducing the amount of triglycerides or low-density lipoprotein (LDL) in a patient. The method comprises administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula I or formula IA, for example, a deuterium chloride salt or hydrochloride salt of a compound of formula I or formula IA as described herein, to a patient in need to reduce the amount of triglycerides or low-density lipoprotein (LDL) in the patient. In one embodiment, the method comprises administering a therapeutically effective amount of a deuterium chloride salt of a compound of formula I, for example, a crystalline deuterium chloride salt form as described herein, to a patient in need to reduce the amount of triglycerides or low-density lipoprotein (LDL) in the patient. In one embodiment, the method comprises administering a therapeutically effective amount of a hydrochloride salt of a compound of formula IA, for example, a crystalline hydrochloride salt form as described herein, to a patient in need to reduce the amount of triglycerides or low-density lipoprotein (LDL) in the patient.

[0172] In one embodiment, the method provides a reduction of at least 1%, 5%, 10%, or 25% in the amount of triglycerides or low-density lipoprotein (LDL) in the patient.

[0173] (viii) Increase in the amount of high-density lipoprotein Another aspect of the present invention provides a method for increasing the amount of high-density lipoprotein (HDL) in a patient. The method comprises administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula I or formula IA, for example, a deuterium chloride salt or hydrochloride salt of a compound of formula I or formula IA as described herein, to a patient in need to increase the amount of high-density lipoprotein (HDL) in the patient. In one embodiment, the method comprises administering a therapeutically effective amount of a deuterium chloride salt of a compound of formula I, for example, a crystalline deuterium chloride salt form as described herein, to a patient in need to increase the amount of high-density lipoprotein (HDL) in the patient. In one embodiment, the method comprises administering a therapeutically effective amount of a hydrochloride salt of a compound of formula IA, for example, a crystalline hydrochloride salt form as described herein, to a patient in need to increase the amount of high-density lipoprotein (HDL) in the patient.

[0174] In one embodiment, the method provides an increase of at least 1%, 5%, 10%, or 25% in the amount of high-density lipoprotein (HDL) in the patient.

[0175] (ix) Treatment of inflammation or immune-mediated diseases Another aspect of the present invention provides a method for treating inflammatory or immune-mediated diseases selected from the group consisting of chronic kidney disease, arthritis, primary scarring 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 diseases, inflammatory skin diseases, rhinitis (e.g., allergic rhinitis), and skin lesions. The method comprises treating the inflammatory or immune-mediated disease by administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula I or formula IA, for example, a deuterium chloride or hydrochloride of a compound of formula I or formula IA as described herein, to a patient in need. In one embodiment, the method comprises treating the inflammatory or immune-mediated disease by administering a therapeutically effective amount of a deuterium chloride of a compound of formula I, for example, a crystalline deuterium chloride form as described herein, to a patient in need. In one embodiment, the method comprises administering a therapeutically effective amount of the hydrochloride of the compound of formula IA, for example, the crystalline hydrochloride form described herein, to a patient in need to treat the inflammatory or immune-mediated disease. In one embodiment, the inflammatory or immune-mediated disease is selected from the group consisting of chronic kidney disease, arthritis, primary scarring 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 diseases, inflammatory skin diseases, and skin lesions. In one embodiment, the inflammatory or immune-mediated disease is selected from the group consisting of chronic kidney disease, arthritis, primary scarring 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 diseases, inflammatory skin diseases, and skin lesions, and in one embodiment, the chronic kidney disease may be, for example, polycystic kidney disease (e.g., autosomal dominant or autosomal recessive).

[0176] (x) Treatment of skin diseases Another aspect of the present invention provides a method for treating a skin disease selected from the group consisting of psoriasis, atopic dermatitis, acne, vitiligo, scleroderma, and cutaneous malignancies. The method comprises treating the skin disease by administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula I or formula IA, for example, a deuterium chloride or hydrochloride salt of a compound of formula I or formula IA as described herein, to a patient in need. In one embodiment, the method comprises treating the skin disease by administering a therapeutically effective amount of a deuterium chloride salt of a compound of formula I, for example, a crystalline deuterium chloride salt form as described herein, to a patient in need. In one embodiment, the method comprises treating the skin disease by administering a therapeutically effective amount of a hydrochloride salt of a compound of formula IA, for example, a crystalline hydrochloride salt form as described herein, to a patient in need. In one embodiment, the administration is by topical administration.

[0177] (xi) Regulation of inflammatory cytokine expression Another aspect of the present invention provides a method for modulating the expression of inflammatory cytokines (e.g., TNFα, IL-1β, IL-6, IL-17, IL-23, or MCP-1) in a patient suffering from an inflammatory disease. The method comprises administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A, for example, a compound of Formula I or Formula I-A as a deuterium chloride salt or hydrochloride salt described herein, to a patient in need thereof to modulate the expression of inflammatory cytokines (e.g., TNFα, IL-1β, or IL-6) in a patient suffering from an inflammatory disease. In one embodiment, the method comprises administering a therapeutically effective amount of a deuterium chloride salt of a compound of Formula I, for example, a crystalline deuterium chloride salt form described herein, to a patient in need thereof to modulate the expression of inflammatory cytokines (e.g., TNFα, IL-1β, or IL-6) in a patient suffering from an inflammatory disease. In one embodiment, the method comprises administering a therapeutically effective amount of a hydrochloride salt of a compound of Formula I-A, for example, a crystalline hydrochloride salt form described herein, to a patient in need thereof to modulate the expression of inflammatory cytokines (e.g., TNFα, IL-1β, or IL-6) in a patient suffering from an inflammatory disease. In one embodiment, the inflammatory cytokine is TNFα.

[0178] Another aspect of the present invention provides a method of regulating the expression of anti-inflammatory cytokines in a patient suffering from an inflammatory disease. The method comprises administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A, for example, a compound of Formula I or Formula I-A as a deuterium chloride salt or a hydrochloride salt as described herein, to a patient in need thereof to regulate the expression of anti-inflammatory cytokines in a patient suffering from an inflammatory disease. In one embodiment, the method comprises administering a therapeutically effective amount of a deuterium chloride salt of a compound of Formula I, for example, a crystalline deuterium chloride salt form thereof as described herein, to a patient in need thereof to regulate the expression of anti-inflammatory cytokines in a patient suffering from an inflammatory disease. In one embodiment, the method comprises administering a therapeutically effective amount of a hydrochloride salt of a compound of Formula I-A, for example, a crystalline hydrochloride salt form thereof as described herein, to a patient in need thereof to regulate the expression of anti-inflammatory cytokines in a patient suffering from an inflammatory disease.

[0179] (xii) Regulation of macrophage function Another aspect of the present invention provides a method of regulating macrophage function in a patient suffering from an infectious disease, an inflammatory disease, or an autoimmune disease. The method comprises administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I or Formula I-A, for example, a compound of Formula I or Formula I-A as a deuterium chloride salt or a hydrochloride salt as described herein, to a patient in need thereof to regulate macrophage function in a patient suffering from an infectious disease. In one embodiment, the method comprises administering a therapeutically effective amount of a deuterium chloride salt of a compound of Formula I, for example, a crystalline deuterium chloride salt form thereof as described herein, to a patient in need thereof to regulate macrophage function in a patient suffering from an infectious disease, an inflammatory disease, or an autoimmune disease. In one embodiment, the method comprises administering a therapeutically effective amount of a hydrochloride salt of a compound of Formula I-A, for example, a crystalline hydrochloride salt form thereof as described herein, to a patient in need thereof to regulate macrophage function in a patient suffering from an infectious disease.

[0180] (xiii) A method for promoting wound healing Another aspect of the present invention provides a method for promoting wound healing. The method comprises administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula I or formula IA, for example, a deuterium chloride salt or hydrochloride salt of a compound of formula I or formula IA as described herein, to a patient in need to promote wound healing. In one embodiment, the method comprises administering a therapeutically effective amount of a deuterium chloride salt of a compound of formula I, for example, a crystalline deuterium chloride salt form as described herein, to a patient in need to promote wound healing. In one embodiment, the method comprises administering a therapeutically effective amount of a hydrochloride salt of a compound of formula IA, for example, a crystalline hydrochloride salt form as described herein, to a patient in need to promote wound healing. In one embodiment, the administration is by topical administration.

[0181] (xiv) Treatment of skin diseases Another aspect of the present invention provides a method for treating skin diseases caused by exposure to ultraviolet irradiation. The method comprises administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula I or formula IA, for example, a deuterium chloride salt or hydrochloride salt of a compound of formula I or formula IA as described herein, to a patient in need to treat a skin disease caused by exposure to ultraviolet irradiation. In one embodiment, the method comprises administering a therapeutically effective amount of a deuterium chloride salt of a compound of formula I, for example, a crystalline deuterium chloride salt form as described herein, to a patient in need to treat a skin disease caused by exposure to ultraviolet irradiation. In another embodiment, the method comprises administering a therapeutically effective amount of a hydrochloride salt of a compound of formula IA, for example, a crystalline hydrochloride salt form as described herein, to a patient in need to treat a skin disease caused by exposure to ultraviolet irradiation.

[0182] (xv) Methods to regulate stem cell differentiation Another aspect of the present invention provides a method for modulating stem cell differentiation (for example, in a patient). The method comprises administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula I or formula IA, for example, a deuterium chloride salt or hydrochloride salt of a compound of formula I or formula IA as described herein, to a patient who needs it to modulate stem cell differentiation (for example, in a patient). In one embodiment, the method comprises administering a therapeutically effective amount of a deuterium chloride salt of a compound of formula I, for example, a crystalline deuterium chloride salt form as described herein, to a patient who needs it to modulate stem cell differentiation (for example, in a patient). In one embodiment, the method comprises administering a therapeutically effective amount of a hydrochloride salt of a compound of formula IA, for example, a crystalline hydrochloride salt form as described herein, to a patient who needs it to modulate stem cell differentiation (for example, in a patient).

[0183] (xvi) Further medical complications Another aspect of the present invention provides a method for treating a disease selected from the group consisting of graft rejection, hepatic dysfunction, Rabson-Mendenhall syndrome, Donahue syndrome, Leber hereditary optic neuropathy, myotonic dystrophy, toxic hearing loss, Niemann-Pick disease, autosomal dominant optic atrophy, spinal and bulbar muscular atrophy, Mohr-Tranebjaerg syndrome, hereditary spastic paraplegia, MELAS syndrome, monoclonal immunoglobulinemia (MIDD), hearing loss, insulin resistance in patients receiving growth hormone, and chronic progressive extraocular ophthalmoplegia with mitochondrial myopathy. The method comprises treating the disorder by administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula I or formula IA, for example, a deuterium chloride or hydrochloride of a compound of formula I or formula IA as described herein, to a patient in need. In one embodiment, the method includes administering a therapeutically effective amount of a deuterium chloride salt of the compound of formula I, for example, the crystalline deuterium chloride salt form described herein, to a patient in need to treat the disorder. In another embodiment, the method includes administering a therapeutically effective amount of a hydrochloride salt of the compound of formula IA, for example, the crystalline hydrochloride salt form described herein, to a patient in need to treat the disorder.

[0184] (xvii) Prevention of medical disorders Methods for preventing medical ailments in patients are also provided. The method includes administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula I or formula IA, for example, a deuterium chloride or hydrochloride salt of a compound of formula I or formula IA as described herein, to a patient in need to prevent the medical ailment. In one embodiment, the method includes administering a therapeutically effective amount of a deuterium chloride salt of a compound of formula I, for example, a crystalline deuterium chloride salt form as described herein, to a patient in need to prevent the medical ailment. In another embodiment, the method includes administering a therapeutically effective amount of a hydrochloride salt of a compound of formula IA, for example, a crystalline hydrochloride salt form as described herein, to a patient in need to prevent the medical ailment. The aforementioned medical disorder may be one or more of the medical disorders described above, for example, neurological disorders (e.g., Alzheimer's disease or Parkinson's disease), cancer (e.g., non-small cell lung cancer or hepatocellular carcinoma), metabolic disorders, cardiovascular diseases (e.g., in-stent restenosis in diabetic patients, reinfarction in diabetic patients, or coronary artery lesions after heart transplantation), or respiratory diseases (e.g., chronic obstructive pulmonary disease).

[0185] (xviii) Further medical applications The present invention provides methods for using the compounds and solid forms described herein for therapeutic purposes, including regenerative medicine. Methods for treating veterinary disorders (e.g., laminitis) are also provided herein. The methods include treating the veterinary disorder by administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula I or formula IA, for example, a deuterium chloride salt or hydrochloride salt of a compound of formula I or formula IA as described herein, to a patient in need. In some embodiments, the methods include treating the veterinary disorder by administering a therapeutically effective amount of a deuterium chloride salt of a compound of formula I, for example, a crystalline deuterium chloride salt form as described herein, to a patient in need. In some embodiments, the methods include treating the veterinary disorder by administering a therapeutically effective amount of a hydrochloride salt of a compound of formula IA, for example, a crystalline hydrochloride salt form as described herein, to a patient in need.

[0186] In one embodiment, pharmaceutically acceptable salts of the compounds of formula I or formula IA provided herein may be administered as a single active agent, or they may be administered in combination with other therapeutically active agents (e.g., combination therapy).

[0187] The combination therapies of the present invention described herein are thought to be synergistic in treating the specific diseases, disorders, or conditions described herein, and / or one or more symptoms associated with such diseases, disorders, or conditions. pharmaceutically acceptable salts of the compounds of formula I or formula IA provided herein are also thought to be effective in reducing adverse effects associated with a second therapeutically active agent, or vice versa.

[0188] In various embodiments, one or more second therapeutically active agents can be used in the methods and compositions provided herein. In some embodiments, one or more second therapeutically active agents may be polymers (e.g., proteins) or small molecules (e.g., synthetic inorganic, organometallic, or organic molecules).

[0189] In one embodiment, the combination therapy includes a pharmaceutically acceptable salt of a compound of formula I or formula IA as described herein and a second therapeutically active agent for the treatment of a disease, disorder, or condition described herein (e.g., neurological disorders, cancer, respiratory diseases, metabolic disorders, hepatitis, cardiovascular diseases, inflammatory or immune-mediated diseases, skin diseases, wounds, etc.).

[0190] In one embodiment, the second therapeutically active agent may be an agent useful for treating metabolic disorders, and such therapeutically active agents may include, but are not limited to, metformin, imeglimin, dipeptidyl peptidase IV inhibitors (e.g., sitagliptin, vildagliptin), statins (e.g., HMG-CoA reductase inhibitors, e.g., atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, simvastatin, rosuvastatin, pravastatin, or combinations thereof), AMPK activators, thyroid β-agonists, GLP-1 agonists, GLP-2 agonists, or SGLT2 inhibitors.

[0191] In one embodiment, the second therapeutically active agent is a diuretic (e.g., hydrochlorothiazide).

[0192] In one embodiment, the second therapeutically active agent may be an agent useful for treating hypertension, diabetes, or inflammatory diseases. In one embodiment, the second therapeutically active agent may be an agent that restricts the activity of the renin-angiotensin system, such as an angiotensin-converting enzyme inhibitor (e.g., ACE inhibitors, e.g., ramipril, captopril, enalapril), angiotensin receptor blocker (e.g., candesartan, losartan, olmesartan), or a renin inhibitor. In one embodiment, the second therapeutic agent may restrict hypertension by another method, such as a beta-adrenergic receptor blocker or a calcium channel blocker (e.g., amlodipine).

[0193] In some embodiments, the second therapeutically active agent is a glucocorticoid agonist. In some embodiments, combination therapy comprising a pharmaceutically acceptable salt of a compound of formula I or formula IA described herein and a glucocorticoid agonist may be useful for the treatment of inflammatory diseases, e.g., to suppress immune responses, prevent graft rejection, and treat autoimmune diseases. Typical disorders may include, for example, rheumatoid arthritis, lupus, myasthenia gravis, muscular dystrophy, multiple sclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, treatment of acute allergic reactions, and graft rejection.

[0194] In one embodiment, a combination therapy comprising a pharmaceutically acceptable salt of a compound of formula I or formula IA described herein and a second therapeutically active agent that increases cAMP or a beta-adrenergic agonist may be useful in the treatment of renal disease. Typical beta-adrenergic agonists may include, but are not limited to, beta-1-adrenergic agonists, beta-2-adrenergic agonists, beta-3-adrenergic agonists, or combinations thereof. In one embodiment, the second therapeutically active agent is norepinephrine, isoprenaline, dobutamine, salbutamol, levosalbutamol, terbutaline, pirbuterol, procaterol, metaproterenol, fenoterol, bitolterol mesylate, salmeterol, formoterol, bambuterol, clenbuterol, indacaterol, L-796568, amibegron, solabegron, isoproterenol, albuterol, metaproterenol, albutamine, befnolol, bromo Acetylalprenololmenthane, broxaterol, simaterol, silazolin, denopamine, dopexamine, epinephrine, etilephrine, hexoprenaline, higenamine, isoetaline, isoxuprine, mabuterol, methoxyphenamine, nilidrine, oxyfedrine, prenalterol, ractopamine, reproterol, limiterol, ritodrine, tretokinol, tulobuterol, xamoterol, zilpaterol, zinterol, or any pharmaceutically acceptable salt thereof; or any combination thereof.

[0195] In one embodiment, the combination therapy includes a pharmaceutically acceptable salt of a compound of formula I or formula IA as described herein and a second therapeutically active agent useful for treating cancer. Representative second therapeutically active agents useful for treating cancer include, but are not limited to, alkylating agents, antimetabolites (e.g., molecules that inhibit DNA and / or RNA synthesis), microtubule inhibitors, topoisomerase inhibitors, cytotoxic antibiotics, tyrosine kinase inhibitors, tumor necrosis factor alpha inhibitors, anti-cancer radiotherapy, or programmed death protein-1 (PD-1) modifiers (e.g., inhibitors). In one embodiment, a second therapeutically active agent useful for treating cancer is azacitidine, azathioprine, bleomycin, carboplatin, capecitabine, carmustine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, eposilon, etoposide, fluorouracil, fulvestrant, gemcitabine, hydroxyure a, idarubicin, imatinib, lomustine, mechloretamine, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, procarbazine, raloxifene, teniposide, temozolomide, tamoxifen, toremifene, barrubicin, vinblastine, vincristine, vindesine, vinorelbine, or any pharmaceutically acceptable salt thereof; or any combination thereof.

[0196] In one embodiment, a second therapeutically active agent useful for treating cancer is Abraxane; Asibicin; Acralubicin; Acodazole hydrochloride; Acronin; Adzeresin; Aldesleukin; Altretamine; Ambomycin; Amethantrone acetate; Amrubicin; Amsacrin; Anastrozole; Anthramycin; Asparaginase; Asperin; Azacitidine; Azetepa; Azotomycin; Batymastam; Benzodepa; Bicalutamide; Bisanthren hydrochloride; Bisnafide mesylate; Biseresin; Bleomycin sulfate ;Breknal sodium;Bropyrimine;Busulfan;Cactinomycin;Carsterone;Calasemide;Carbetimer;Carboplatin;Carmustine;Carbicin hydrochloride;Carzelesin;Cedefmgol:Celecoxib;Chlorambucil;Siloremycin;Cisplatin;Cladoribine;Crisnator mesylate;Cyclophosphamide;Cytarabine;Dacarbazine;Dactinomycin;Daunorubicin hydrochloride;Decitabine;Dexormaplatin;Deaguanine;Dezag mesylate Anine; Diadiquan; Docetaxel; Doxorubicin; Doxorubicin hydrochloride; Raloxifene; Raloxifene citrate; Dromostanolone propionate; Suazomycin; Edatrexate; Eflornithine hydrochloride; Ersamitrusine; Enloplatin; Enpromate; Epipropidine; Epirubicin hydrochloride; Elbrozol; Esolubicin hydrochloride; Estramustine; Estramustine sodium phosphate; Etanidazole; Etoposide; Etoposide phosphate; Etoprine; Fadolone hydrochloride Zol; Fazarabine; Fenretinide; Floroxyuridine; Fludarabine phosphate; Fluorouracil; Flurocitabine; Fosquidone; Fostriesin sodium; Gemcitabine; Gemcitabine hydrochloride; Herceptin; Hydroxyurea; Idarubicin hydrochloride; Ifosfamide; Irumofosine; Iproplatin; Irinotecan; Irinotecan hydrochloride; Lanreotide acetate; Lapatinib; Letrozole; Leuprolide acetate; Rialozol hydrochloride; Lometrexol sodium; Lomustine; Soxanthrone hydrochloride; Masopropyl; Maytansine; Mechloretamine hydrochloride;Megestrol acetate; Melengestrol acetate; Melphalan; Menogalyl; Mercaptopurine; Methotrexate; Methotrexate sodium; Metoprin; Metsuredepa; Mitindomide; Mitocalcin; Mitochromin; Mitogiline; Mitomarcin; Mitomycin; Mitospel; Mitotan; Mitoxantrone hydrochloride; Mycophenolic acid; Nocodazole; Nogaramycin; Ormaplatin; Oxythran; Paclitaxel; Pegaspargase; Periomycy n; pentamustine; peplomycin sulfate; perphosphamide; pipobromane; piposulfan; piroxantrone hydrochloride; plicamycin; promestan; porfimer sodium; portiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofulin; ribopurine; romidepsin; safingol; safingol hydrochloride; semustine; simtrazene; sparphosate sodium; Sparsomycin; Spirogermanium hydrochloride; Spiromustin; Spiroplatin; Stem cell therapy; Streptonigrin; Streptozocin; Slofenull; Talisomycin; Tecogalan sodium; Taxotere; Tegafur; Teroxantrone hydrochloride; Temoporfin; Teniposide; Teroxylone; Testolactone; Thiamipurine; Thioguanine; Thiotepa; Thiazofulin; Tirapazamine; Toremifene citrate; Trestron acetate; Trisilibine phosphate; Tri Methrexate; Trimethrexate glucuronide; Triptorelin; Tubrozol hydrochloride; Uracil mustard; Uredepa; Bupreotide; Verteporfin; Vinblastine sulfate; Vincristine sulfate; Vindesine; Vindesine sulfate; Vinepidine sulfate; Vingricinate sulfate; Vinleulosine sulfate; Vinorelbine tartrate; Vinrosidine sulfate; Vinzolidine sulfate; Borozol; Zeniplatin; Dinostatin; Solbicine hydrochloride, or combinations thereof.

[0197] Administration of a pharmaceutically acceptable salt of the compound of Formula I or Formula I-A described herein and a second therapeutically active agent to a patient can be performed simultaneously or sequentially via the same or different administration routes. The suitability of a particular route of administration for a particular active agent depends on the active agent itself (e.g., whether it can be administered orally without decomposition before entering the bloodstream) and the disease being treated. One route of administration for the compounds provided herein is oral. Routes of administration for the second active ingredient or ingredients are known to those skilled in the art. See, for example, Physicians' Desk Reference (60th Ed., 2006).

Examples

[0198] In order that the disclosure provided herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described herein are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and should not be construed in any way as limiting to the scope thereof.

[0199] Example 1: Synthesis of Deuterium-enriched (R)-Pioglitazone L-Dibenzoyltartrate Reaction temperatures are recorded as internal temperatures. Chemical intermediates, reagents, and solvents were obtained from commercial sources.

[0200] Filtration: Unless otherwise specified, the solid product was isolated by filtration through a PTFE Buchner funnel using MN617G (rapid filtration, phosphate-free; catalog number: MN494024) and MN640m (catalog number: MN203015) filter paper, and washed by plug flow method with 1:1 MeOD:D₂O (v / v) (partial; 2× / 3×) unless otherwise indicated.

[0201] Drying: After filtration, the initial solid was air-dried in vacuo for several hours (3 to 4 hours), then dried at 50°C / 42°C (24 to 72 hours) in a drying oven equipped with a vacuum pump.

[0202] NMR:1 H spectra were recorded using a Bruker Avance 300 MHz or higher spectrometer. Chemical shifts were referenced as a residual solvent signal with δ 2.50 (DMSO-d6) compared to TMS as an internal standard, where applicable.

[0203] For HPLC de% / ee% measurement, all samples were dissolved in MeOH to prepare a 1 mg / mL solution.

[0204] HPLC for identification and chemical purity: The sample was flowed onto a 150 mm x 4.6 mm, 5 μm YMC triart C18 column. The mobile phase was an isocratic elution system of 1:1 0.1 M NH4OAc:CH3CN (containing 2% HOAc). The flow rate was 0.75 mL / min; the flow time was 35 minutes; and the detector wavelength was 269 nm.

[0205] Where the details of the flow of the embodiment are shown in the following embodiments, square brackets ([]) are used to indicate any changes that are not part of the embodiment's implementation but may be made or made in other embodiments.

[0206] Step 1: Preparation of racemic gravimetrically concentrated pioglitazone (compound B) [ka] Pioglitazone·HCl (HCl salt of compound A) was dissolved in D2O at high temperature. The mixture was stirred at 90°C–100°C for at least 5 hours, a small amount of DCl was added, and then it was cooled to ambient temperature. The suspension was allowed to stand at 15°C–25°C for several hours, and the product was filtered off as the DCl salt of compound B. After this first cycle, approximately 95% of the hydrogen atoms in the chiral center were replaced with deuterium.

[0207] If necessary, the crude product is subjected to a second cycle of the same process. 1 The deuteration rate in compound (B) was further increased to 98+%, as measured by 1H-NMR.

[0208] Implementation of the example: First deuteration cycle: 19.96 kg of pioglitazone (compound (A)) was placed in a 100 L glass-lined container. Subsequently, 79.54 kg (71.86 L; 4.0 w / w equivalent) of D2O was placed in the same container. The reaction mixture was heated to approximately 95°C and stirred, and stirred at that temperature for 5 hours. [The temperature can be approximately 90°C to approximately 100°C (preferably 95°C) for at least 5 hours. Temperatures of 95°C or lower resulted in a low deuteration level, but temperatures of approximately 95°C to approximately 100°C were favorable. Small amounts of D2O were tested, but the reaction mixture was difficult to stir at less than 4 w / w equivalents, and the increase in deuteration was at least 5 w / w equivalents. A significant increase in the deuteration level was observed up to 3-4 hours at high temperatures.] A pale white suspension was observed, and 35% DCl in 0.13 kg (0.10 L, 0.005 v / w equivalent) of D2O was added, and the flux was rinsed with approximately 0.25 L of D2O (0.0125 v / w equivalent). The reaction mixture was cooled to approximately 25°C over approximately 240 minutes [cooling time is at least 3 hours at a final temperature of approximately 15°C to approximately 25°C]. The reaction mixture was then stirred at 15°C for approximately 13 hours [holding time is at least 5 hours at approximately 15°C to approximately 25°C. The resulting solid is more agitable and filterable after cooling for just 1 hour rather than 3 hours or more]. The crude product was removed by filtration through a 140 L stainless steel Nutsche filter. The product was washed with 5.52 kg (4.99 L; 0.25 v / w equivalent) of D2O. The crude product was blow-dried under a nitrogen stream for approximately 3 hours [a drying time of at least 1 hour is required]. The wet crude product was isolated, and the sample to be monitored was... 1 The sample was subjected to 1H-NMR. Subsequently, the sample was subjected to a second deuteration to increase its deuterium content. [This was repeated three times, and deuteration percentages of 96.5%, 97.2%, and 96.9% on the chiral center were observed at this stage.]

[0209] Second deuteration cycle: The entire amount of wet crude product was placed in a container. Then 75.57 kg (68.26 L) of D2O was added. The reaction mixture was heated to about 95°C for about 5 hours [heating may be carried out at a temperature of about 90°C to about 100°C (preferably 95°C) for at least 5 hours]. A pale white suspension was observed. Subsequently, 35% DCl in 0.12 kg (0.09 L) of D2O was added, and the migration line was rinsed with about 0.25 L of D2O. The reaction mixture was cooled to 25°C over 4 hours [the cooling period should be at a temperature of about 15°C to about 25°C for at least 3 hours]. The reaction mixture was stirred at about 20°C for 9 hours [stirring may be carried out at 15°C to 25°C for at least 5 hours]. Next, the crude product was filtered through a 140 L stainless steel Nutsche filter and rinsed with 5.52 kg (4.99 L) of D2O. Deuterium NMR showed that there were at least two deuterium atoms per molecule. The compound (B)DCl salt product (or, optionally, a mixture of HCl and DCl salt) was dried in a 140 L stainless steel Nutsche filter under vacuum at a maximum of approximately 60°C to a LOD (loss on drying) of ≤2% (approximately 48 hours) [the drying temperature should not exceed 60°C].

[0210] Step 2: Preparation of deuterium-concentrated (R)-pioglitazone L-dibenzoyl tartrate (compound (C)) [ka] The synthesis was initiated by dissolving compound (B) or its salt and L-dibenzoyl tartrate in a mixture of MeOD (methanol-d1) and D2O at high temperature. The mixture was then cooled to approximately 55°C. Seed crystals (2 w / w% or less relative to compound B) were added as appropriate, and the mixture was then cooled very slowly over a long period of time. Finally, the resulting compound (C) was filtered off, washed with the mixture of MeOD and D2O, and dried under vacuum.

[0211] Implementation of the example: 28.10 kg of racemic gravimetrically concentrated pioglitazone (compound (B)) DCl salt was placed in a 1000 L glass container, followed by 25.49 kg of L,L-dibenzoyl tartaric acid (1 molar equivalent) and 187.3 kg of MeOD (230.4 L; 6.67 w / w equivalent) [using 0.6 molar equivalents of L,L-dibenzoyl tartaric acid can produce a high ee% although the yield is slightly lower]. The reaction mixture was heated to a temperature of approximately 60°C to 70°C (65°C was achieved), and 280.9 kg of D2O (253.7 L; 10.0 w / w equivalent) was added. The reaction mixture was heated to 70°C to 80°C (76°C was achieved), and the mixture was stirred at that temperature for at least 30 minutes. A nearly clear solution was obtained. Next, the mixture was cooled to 55°C for 66 minutes [cooling time is required at least 1 hour at approximately 52°C to approximately 58°C]. Then the mixture was stirred at 56°C for 2 hours [stirring can be done at a temperature of approximately 52°C to approximately 58°C for at least 2 hours]), during which time seed crystals (0.25 kg) of compound (C) were added [crystals of compound (C) or (C') can be used as seed crystals]. The suspension was cooled to 25°C for 7.5 hours [cooling time to a temperature of approximately 22°C to approximately 28°C is required at least 5 hours]. Subsequently, the suspension was stirred for 37 hours [stirring is required at a temperature of 22°C to 28°C for at least 15 hours].

[0212] The product was filtered using a stainless steel centrifuge and washed with a pre-mixed mixture of D2O (13.38 kg; 12.08 L; 0.48 w / w equivalent) and MeOD (9.82 kg; 12.08 L; 0.35 w / w equivalent). The product was air-dried with a nitrogen stream for at least 1 hour. Next, the resulting compound (C) was dried under vacuum at a maximum temperature of 60°C using a Hastray vacuum tray dryer. Deuterium NMR showed that there were approximately 2 deuterium atoms per molecule.

[0213] Step 3: Recrystallization of enantiomer-rich (R)-deuterium-enriched pioglitazone L-dibenzoyl tartrate (compound (C) relative to the recrystallized compound (C')) [ka] Implementation of the example: To prepare HCl salt derivatives 46.88 kg of enantiomer-rich (R)-deuterium-concentrated pioglitazone dibenzoyl tartrate (compound (C)) was placed in a 1000 L glass container, followed by 185.6 kg of MeOH (234.4 L; 4.0 w / w equivalent), 55.0 kg of D2O (49.7 L; 1.17 w / w equivalent), and 7.1 kg of 35% DCl (in D2O) (5.6 L; 0.15 w / w equivalent). The reaction mixture was heated to 60°C-70°C (reaching 63°C), and 218.0 kg of D2O (196.9 L; 4.65 w / w equivalent) was added. The reaction mixture was heated to 70°C-80°C, and the mixture was stirred at that temperature for at least 30 minutes. A nearly clear solution was obtained. The mixture was then cooled to 55°C for 85 minutes. [A cooling time of at least 1 hour is required.] The mixture was then stirred at 55°C for 120 minutes, and seed crystals of compound C' (0.14 kg) were added. [Stirring can be carried out at 52-58°C for at least 2 hours, during which seed crystals of compound (C) or (C') may be added as needed.] The suspension was cooled to 26°C over 10 hours and 50 minutes. [A cooling rate from 22°C to 28°C is required over at least 5 hours.] The suspension was then stirred at 25°C for 34 hours and 20 minutes. [The suspension needs to be stirred at 22°C to 28°C for at least 15 hours.]

[0214] The product was filtered using a stainless steel centrifuge and washed with a pre-mixed mixture of D2O (17.1 kg; 15.5 L; 0.36 w / w equivalent) and MeOD (12.3 kg; 15.5 L; 0.26 w / w equivalent). The resulting compound (C') was air-dried under a nitrogen stream for at least 1 hour. Subsequently, the product was subjected to HPLC for measurement of optical purity. If the optical purity was satisfactory (above 91%), the compound (C') was dried under vacuum at a maximum temperature of 60°C using a Hastray vacuum tray dryer. If unsatisfactory, a second recrystallization was performed (actual example: 93 ee%; no second recrystallization was performed). Deuterium NMR showed that there were approximately 2 deuterium atoms per molecule.

[0215] If a second or further recrystallization is required, the above procedure can be repeated. As described above, the recrystallized material was separated and dried under vacuum at a maximum temperature of 60°C using a Hastray vacuum tray dryer.

[0216] It should be noted that the details described below include the steps in steps b) and c).

[0217] To prepare the DCl salt derivative, it was necessary to use only the deuterated solvent.

[0218] Example 2: Preparation and Characterization of Crystalline DCl Salt of Deuterium-Concentrated (R)-Pioglitazone 278.5 g of deuterium-concentrated(R)-pioglitazone L-dibenzoyl tartrate (as prepared in Example 1), 450 mL of MeOD, and approximately 38% DCl (in D2O) (36 g, 2.9 equivalents) were heated to 50°C. The slightly turbid solution was filtered over a Buchner funnel (100 mL) equipped with a Porcelain-1 filter, and the filtrate was reheated to 50°C. Then, ethyl acetate (1500 mL) was added in seven portions (reducing the temperature to 30°C), and the mixture was brought to 20°C. The mixture was stirred at this temperature for 2 hours, and the crystalline DCl salt of deuterium-concentrated(R)-pioglitazone was isolated by filtration over a Buchner funnel (250 mL) equipped with a Porcelain-4 filter. The mixture was thoroughly washed with ethyl acetate (in divided portions) (5 x 250 mL), and the isolated moist cake was dried overnight at 50°C under vacuum to obtain 44.6 g (Y=89.9%) of deuterium chloride as a white crystalline substance. The enantiomeric excess was found to be 97.1% (HPLC), and the D content in the chiral center was 99.0%. 1 (H-NMR) Note: Other samples synthesized using the exact same method were... 2 The analysis was performed using 1H-NMR. 2 1H-NMR analysis revealed approximately three deuterium atoms per molecule (one at the chiral center and one at the interchangeable NH position with DCl).

[0219] Chiral HPLC method: The sample was flowed onto a 250 mm x 4.6 mm, 3 μm Chiralpak IC or equivalent. The mobile phase was an isocratic elution system containing 70:30 (v / v) hexane / IPA. The flow rate was 1.0 mL / min; the flow time was 30 minutes; and the detector wavelength was 225 nm.

[0220] 1 1H-NMR method: Approximately 5-10 mg of sample, 1 For H-NMR analysis, it was dissolved in DMSO D6. 1 1H-NMR analysis was performed using a Bruker Avance 300 MHz or higher spectrometer.

[0221] Characterization by X-ray powder diffraction Figure 1A provides an X-ray powder diffractogram of the crystalline DCl salt of deuterium-enriched (R)-pioglitazone. The X-ray powder diffraction data was obtained at room temperature (e.g., approximately 21°C to 23°C) for Cu K a1 The data was collected using a D8 Advance diffractometer with radiation (1.54056 Å) in conjunction with a germanium monochromator. Detector scanning on the solid-state LynxEye detector was performed at a scan speed of 5 seconds / step with a step size of 0.016°. The sample was analyzed using an 8 mm long glass capillary tube with an outer diameter of 0.3 mm. The characteristics of the X-ray powder diffractogram shown in Figure 1A are presented in Table 4 below, where the diffraction angle 2θ, interplanar spacing d, and relative intensity (expressed as a percentage of the strongest peak) are listed. Table 4 - X-ray powder diffractogram data of crystalline deuterium chloride of deuterium-enriched (R)-pioglitazone [Table 4]

[0222] As shown in Figure 1B, (R)- 2It should be noted that the X-ray powder diffraction (XRPD) pattern of H-pioglitazone HCl salt (upper trace) is not identical to the XRPD pattern of pioglitazone HCl salt (lower trace), and in particular, several peaks are twice as pronounced.

[0223] Characterization by single-crystal X-ray diffraction Single crystals of the crystalline DCl salt of deuterium-enriched (R)-pioglitazone were analyzed by single-crystal X-ray diffraction. Data were collected at 296 K using a Nonius kappa-CCD system.

[0224] Data processing was performed using HKL Scalepack (Otwinowski & Minor, 1997), and grid parameters were obtained using Denzo and Scalepak (Otwinowski & Minor, 1997).

[0225] The crystal structure of the crystalline DCl salt of deuterium-enriched (R)-pioglitazone was analyzed using the direct method with SHELXL-2014 / 7 (Sheldrick, GM, 2015a). The structure was refined using the complete matrix least squares method with SHELXL-2014 / 7 (Sheldrick, GM, 2015b). All H-atoms bonded to C were included from the geometry and maintained under fixed temperature parameters. H-atoms related to the hydrogen bond network were identified using a difference Fourier map and refined using the isotropic method.

[0226] Table 5 shows the unit cell parameters, data acquisition methods, and structural refinement methods for the crystalline DCl salt of deuterium-enriched (R)-pioglitazone. Table 5 - Unit cell parameters and data acquisition and structural refinement methods for crystalline DCl salts of deuterium-enriched (R)-pioglitazone [Table 5]

[0227] Characterization by optical microscopy Figure 2 shows an optical microscope image of the crystalline DCl salt of deuterium-enriched (R)-pioglitazone. The optical microscope image was acquired using a Leica DM2500M optical microscope. The crystals exhibited both hexagonal and rod-shaped crystal forms.

[0228] Characterization by differential scanning calorimetry Figure 3 shows the differential scanning calorimetry (DSC) curve of the crystalline DCl salt of deuterium-enriched(R)-pioglitazone. DSC data were collected using a heat flux DSC3+STARe system. The sample (~2 mg) was placed in a standard 40 μL aluminum pan with a lid, a small hole was made in the lid, and the pan was heated by 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 showed an endothermic phenomenon with starting and peak values ​​at approximately 191 °C and 202 °C, corresponding to the melting point of the crystalline DCl salt form of deuterium-enriched(R)-pioglitazone.

[0229] Characterization by thermogravimetric analysis and thermogravimetric mass spectrometry Thermogravimetric analysis (TGA) and thermogravimetric mass spectrometry (TGMS) data for the crystalline DCl salt form of deuterium-enriched (R)-pioglitazone are shown in Figures 4A and 4B, respectively. TGA data were collected using a TGA / DSC3+STARe system (Mettler-Toledo GmbH, Switzerland) calibrated for temperature using indium and aluminum samples. The sample was weighed in a 100 μL aluminum crucible and sealed. A small hole was made in the lid, and the crucible was heated from 25°C to 300°C at a heating rate of 10°C. The crucible was purged with dry N2 gas during the measurement. Volatile substances produced in the TGA sample upon heating were analyzed using an Omnistar GSD301T2 (Pfeiffer Vacuum GmbH, Germany) mass spectrometer. TGA and TGMS data showed that the crystalline DCl salt form of deuterium-enriched (R)-pioglitazone was anhydrous, exhibited a mass loss of 0.07% at 40°C to 170°C, and thermal decomposition occurred above 190°C.

[0230] Characterization by NMR spectroscopy Deuterium-enriched (R)-pioglitazone in crystalline DCl salt form 1 ¹H-NMR spectra were collected at room temperature using a 500 MHz Bruker instrument with a standard pulse sequence. A sample of deuterium-enriched (R)-pioglitazone in crystalline DCl form was dissolved in DMSO-d6. 1 The 1H-NMR chemical shifts (ppm) were 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). This represents a typical crystalline DCl salt. 1 The 1H-NMR spectrum is shown in Figure 5.

[0231] Example 3: Preparation and Characterization of the Crystalline HCl Salt Form of Deuterium-Concentrated (R)-Pioglitazone 2.2 g of deuterium-concentrated(R)-pioglitazone L-dibenzoyl tartrate (prepared in Example 1), 11 mL of MeOH, and 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. The mixture was stirred at this temperature for 2 hours, and the HCl salt form of deuterium-concentrated(R)-pioglitazone was isolated by filtration (using a P-4 Buchner funnel with filter paper) and thoroughly washed with ethyl acetate (5 x 20 mL). It was dried overnight under vacuum at 50°C to obtain 1.1 g (Y = 90.9%) of white crystalline material. The enantiomeric excess was 97.2% (HPLC), and the D content was > 98%. 1 It was found to be (H-NMR). Note: 2 The deuterium content determined by H-NMR shows that there is approximately one deuterium atom per molecule. 1 It was confirmed to be located at the chiral center by 1H-NMR.

[0232] Chiral HPLC method: The sample was flowed onto a 250 mm x 4.6 mm, 3 μm Chiralpak IC or equivalent. The mobile phase was an isocratic elution system containing 70:30 (v / v) hexane / IPA. The flow rate was 1.0 mL / min; the flow time was 30 minutes; and the detector wavelength was 225 nm.

[0233] 1H-NMR method: Approximately 5-10 mg of sample, 1 For H-NMR analysis, it was dissolved in DMSO D6. 1 1H-NMR analysis was performed using a Bruker Avance 300 MHz or higher spectrometer.

[0234] Characterization by powder X-ray diffraction Figure 6 shows the X-ray powder diffractogram of the crystalline HCl salt form of deuterium-enriched (R)-pioglitazone. X-ray powder diffraction data was collected as described in Example 2. The characteristics of the X-ray powder diffractogram in Figure 6 are shown in Table 6 below, where the diffraction angle 2θ, interplanar spacing d, and relative intensity (expressed as a percentage of the strongest peak) are listed. Table 6 - X-ray powder diffractogram data of the crystalline HCl salt form of deuterium-enriched(R)-pioglitazone [Table 6]

[0235] Characterization by optical microscopy Figure 7 shows an optical microscope image of the crystalline HCl salt of deuterium-enriched (R)-pioglitazone. The optical microscope image was acquired using a Leica DM2500M optical microscope. The crystals exhibited hexagonal and rod-shaped crystal forms.

[0236] Characterization by differential scanning calorimetry Figure 8 shows the differential scanning calorimetry (DSC) curve of the crystalline HCl salt form of deuterium-enriched(R)-pioglitazone. The DSC data was collected using the method described in Example 2. The DSC curve shows an endothermic phenomenon with starting and peak values ​​at approximately 190°C and 200°C, corresponding to the melting point of the crystalline HCl salt form of deuterium-enriched(R)-pioglitazone.

[0237] Characterization by thermogravimetric analysis / simultaneous thermal analysis and thermogravimetric mass spectrometry Thermogravimetric analysis (TGA) and thermogravimetric mass spectrometry (TGMS) data for the crystalline HCl salt form of deuterium-enriched(R)-pioglitazone are shown in Figures 9A and 9B, respectively. The TGA and TGMS data were collected using the method described in Example 2. The TGA and TGMS data indicated that the crystalline HCl salt form of deuterium-enriched(R)-pioglitazone was anhydrous, showed a mass loss of 0.2% at 40°C to 180°C, and that thermal decomposition occurred above 220°C.

[0238] Characterization by NMR spectroscopy Deuterium-enriched (R)-pioglitazone in crystalline HCl form 1 The 1H-NMR spectrum was collected as described in Example 2. A sample of the crystalline HCl salt form of deuterium-enriched(R)-pioglitazone was dissolved in DMSO-d6. 1 The 1H-NMR chemical shifts (ppm) were 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). This is representative of crystalline HCl salts. 1 The 1H-NMR spectrum is shown in Figure 10.

[0239] Example 4: Preparation and characterization of the crystalline free base form of deuterium-enriched (R)-pioglitazone The free base form of deuterium-enriched R-pioglitazone was prepared by incubating the crystalline DCl salt of deuterium-enriched R-pioglitazone from Example 2 in water at 50°C for 2 weeks.

[0240] The enantiomeric excess was found to be 43%, as measured by HPLC. The HPLC method used is described in Examples 2 and 3.

[0241] The D content at the chiral center is 1 As measured by H-NMR, it was found to be approximately 66%. 1 The 1H-NMR method is described in Examples 2 and 3.

[0242] Characterization by powder X-ray diffraction Figure 11 shows the X-ray powder diffractogram of the crystalline free base form of deuterium-enriched R-pioglitazone. X-ray powder diffraction data was collected as described in Example 2. Table 7 below shows representative diffraction peaks from the X-ray powder diffractogram in Figure 11, with the diffraction angle (2θ) described. Table 7 - X-ray powder diffractogram data of the crystalline free base form of deuterium-enriched R-pioglitazone [Table 7]

[0243] Characterization by differential scanning calorimetry Figure 12 shows the differential scanning calorimetry (DSC) curve of the crystalline free base form of deuterium-enriched R-pioglitazone. The DSC data was collected using the method described in Example 2. The DSC curve shows an endothermic phenomenon with starting and peak values ​​at approximately 174°C and 178°C, respectively, corresponding to the melting point of the crystalline free base form of deuterium-enriched (R)-pioglitazone.

[0244] Characterization by thermogravimetric analysis / simultaneous thermal analysis and thermogravimetric mass spectrometry Thermogravimetric analysis (TGA) and thermogravimetric mass spectrometry (TGMS) data of the crystalline free base form of deuterium-enriched R-pioglitazone are shown in Figures 13A and 13B, respectively. The TGA and TGMS data were collected using the method described in Example 2. The TGA and TGMS data indicated that the crystalline free base form of deuterium-enriched R-pioglitazone was anhydrous and that thermal decomposition occurred above 160°C.

[0245] Characterization by NMR spectroscopy Deuterium-enriched (R)-pioglitazone in crystalline free base form 1 The 1H-NMR spectrum was collected as described in Example 2. A sample of deuterium-enriched (R)-pioglitazone in crystalline free base form was dissolved in DMSO-d6. 1 The 1H-NMR chemical shifts (ppm) were 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).

[0246] Example 5: Solubility of crystalline DCl and HCl salts of deuterium-concentrated (R)-pioglitazone in various organic solvents Crystalline DCl salt of deuterium-concentrated(R)-pioglitazone: Suspensions of the crystalline substance were prepared in ethanol, methanol, 3-pentanone, 2-propanol, DMSO, tert-butyl methyl ether, N,N-dimethylformamide, ethyl acetate, acetone, water, tetrahydrofuran, and chloroform, and incubated at room temperature (approximately 21°C to 23°C) for 24 hours. A certain amount of the mother liquor was then taken from each suspension and analyzed by HPLC to determine the concentration of deuterium-concentrated(R)-pioglitazone in different solvents. The HPLC methods are shown in Table 8. Table 8: HPLC method [Table 8]

[0247] Crystalline HCl salt of deuterium-concentrated (R)-pioglitazone: Qualitative test: (i) Approximately 5 mg of crystalline HCl 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 (approximately 21°C to 23°C) for 5 to 10 minutes; (iii) The mixture was then visually inspected to determine whether the crystalline HCl salt was completely dissolved; (iv) If the crystalline HCl salt was not completely dissolved, additional solvent was added until it was completely dissolved. Quantitative test: (i) 100 mg of crystalline HCl salt was added to 4 volume percent (0.4 mL) of each solvent (dimethylformamide, methanol, and DMSO); (ii) the resulting mixture was then stirred at ambient temperature (approximately 20°C to 25°C) for 5 to 10 minutes; (iii) the mixture was then visually inspected to determine if the crystalline HCl salt was completely dissolved; (iv) if the crystalline HCl salt was not completely dissolved, additional solvent was added until it was completely dissolved.

[0248] Next, the solubility was calculated using the total amount of crystalline HCl salt and solvent used in each solvent.

[0249] The solubility data for crystalline DCl and HCl salts of deuterium-enriched (R)-pioglitazone in various organic solvents are shown in Tables 9 and 10, respectively. Table 9. Solubility of deuterium-enriched (R)-pioglitazone in crystalline DCl salt form in various organic solvents. [Table 9] Table 10. Solubility of deuterium-enriched (R)-pioglitazone in crystalline HCl form in various organic solvents. [Table 10]

[0250] Example 6: Effect of pH on the solubility of crystalline DCl and HCl salts of deuterium-concentrated (R)-pioglitazone, and crystalline pioglitazone HCl. The pH-dependent solubility profiles of the crystalline DCl salt form of deuterium-enriched(R)-pioglitazone and crystalline pioglitazone HCl were investigated at room temperature (approximately 21°C to 23°C) in the pH range of 0.3 to 7.6. For the crystalline HCl salt form of deuterium-enriched(R)-pioglitazone, the pH-dependent solubility profile was measured at room temperature (approximately 21°C to 23°C) in the pH range of 0.3 to 3.5.

[0251] The pH-dependent solubility profile of the crystalline DCl salt form of deuterium-enriched pioglitazone was measured at room temperature (approximately 21°C to 23°C) in the pH range of 0.7 to 3.5.

[0252] Suspensions of the three crystalline forms were prepared in water or USP buffer solution. The pH of the suspensions was adjusted by adding 0.1 M HCl or 0.1 M NaOH. For suspensions with a pH of 0.5 or lower, the pH was adjusted with 1 M HCl.

[0253] Next, the suspension was allowed to equilibrate at room temperature (approximately 21°C to 23°C) for 48 hours. After equilibration, the solid phase was separated from the liquid phase by centrifugation, dried, and subsequently analyzed by XRPD. The concentration of deuterium-concentrated (R)-pioglitazone or pioglitazone in the liquid phase (mother liquor) was determined by HPLC (see the HPLC method described in Example 5).

[0254] Table 11 shows the solubility data collected for the four crystalline forms mentioned above, and Figure 14 shows a superposition of the pH-dependent solubility profiles of the crystalline DCl and HCl salt forms of deuterium-enriched (R)-pioglitazone, the crystalline DCl salt form of deuterium-enriched pioglitazone, and crystalline pioglitazone HCl.

[0255] The crystalline DCl and HCl salts of deuterium-concentrated(R)-pioglitazone showed similar pH-dependent solubility profiles: solubility was higher at very low pH values ​​(0.4–1.4), with maximum solubility reached at pH 1.4 (4.54 mg / mL and 5.25 mg / mL for DCl and HCl salts, respectively). A decrease in solubility was observed as the pH increased thereafter. At pH 1.6, solubility decreased to 2.58 mg / mL for the crystalline DCl salt of deuterium-concentrated(R)-pioglitazone and to 3.47 mg / mL for the crystalline HCl salt of deuterium-concentrated(R)-pioglitazone. A more pronounced decrease in solubility was observed at pH values ​​of 2.4 and 3.0 (0.39 mg / mL and 0.20 mg / mL for DCl and HCl salts, respectively). Both salts were observed to be insoluble above pH 4.

[0256] In contrast, the maximum solubility of pioglitazone HCl was determined to be 4.00 mg / mL at pH 0.7. The solubility of pioglitazone HCl was found to decrease as the pH of the solution increased: pH 0.6–2.88 mg / mL and pH 1.2–0.67 mg / mL. Further decreases in solubility were observed at higher pH values. Pioglitazone HCl was observed to be insoluble at pH values ​​above 3. The crystalline DCl salt form of deuterium-enriched pioglitazone exhibits similar behavior to the form of pioglitazone HCl.

[0257] For all four solid forms, no changes were observed in the equilibrium-resolved solid form within the pH range of 0.3 to 0.8. Within the pH range of 1.2 to 1.4, partial or complete conversion to the respective free base forms was observed for all three solid forms. Table 11. Crystalline DCl and HCl salt forms of deuterium-enriched (R)-pioglitazone, and pH-dependent solubility data of crystalline pioglitazone HCl. [Table 11] [Table 12] a Average solubility value.

[0258] Example 7: Measurement of particle size distribution of crystalline DCl and HCl salts of deuterium-enriched (R)-pioglitazone The particle size distributions of crystalline DCl and HCl salts of deuterium-enriched (R)-pioglitazone, prepared using the methods described in Examples 2 and 3, were measured using laser diffraction. Samples of crystalline DCl and HCl salts (100 mg to 200 mg) were moistened and dispersed in 30 mL of heptane. Details of the experiment are shown in Table 12.

[0259] Table 13 shows the typical particle size distributions of HCl (before and after milling) and DCl salt.

[0260] Crystalline HCl salts were pulverized using a fluid air jet milling system or equivalent. Table 12. Particle size distribution analysis - Laser diffraction method [Table 13] Table 13. Typical particle size distributions of crystalline DCl and HCl salts of deuterium-enriched (R)-pioglitazone. [Table 14]

[0261] Example 8: Test to evaluate the effect of processability on the particle size distribution of deuterium-enriched (R)-pioglitazone crystalline HCl salt (API). The study was conducted using 15 mg PXL065 tablets. Table 14. Particle size distribution of three pulverized batches of PXL065 used in the test: [Table 15]

[0262] The tablets contain 15 mg of PXL065, as well as lactose, carmellose calcium, hyprolose, and magnesium stearate. The manufacturing process includes mixing, gliding, and compression steps. The particle size distribution of three batches is shown in Table 14.

[0263] liquidity Mixtures prepared with APIs with a D90 < 10 μm exhibit higher viscosity.

[0264] Mixing uniformity Table 15: Mixing uniformity [Table 16]

[0265] Conclusion: Mixing uniformity (shown in Table 15) is satisfactory for all three batches (acceptable threshold = 90-110%). However, mixtures prepared with APIs with D90 < 10 μm show lower uniformity values. Some may be lost during preparation due to the tackiness of the APIs.

[0266] The average content uniformity was <97% for batch LF21026, while it was >97% for batches LF21027 and LF21028, which is consistent with the results for mixing uniformity.

[0267] Elasticity test Objective: To evaluate the improvement of tablet hardness (CQA) due to compressive force and speed. Tablet hardness is shown in Table 16.

[0268] conclusion As shown in Table 15, the lower the PSD of the API, the lower the maximum hardness. Tablet hardness was not specified, and the analysis focuses on information at the time of release.

[0269] As shown in Table 16, tablets produced from mixtures with APIs having a D90 < 10 μm are more affected by changes in compression rate. Table 16 - Tablet Hardness (Newtons) [Table 17]

[0270] Example 9. Canine pharmacokinetic (PK) study The objective of this study was to evaluate the pharmacokinetic profiles of deuterium-enriched (R)- and (S)-enantiomers of pioglitazone (PXL064 and PXL065) after single oral administration (capsule) and to compare them with deuterium-enriched pioglitazone (PXL061). Three male beagle dogs were fasted prior to administration. All test drugs were then administered orally using APIs in capsules. The administration schedule is shown in Table 17. Table 17. Administration of test drugs in canine PK studies. [Table 18]

[0271] Food was administered within one hour after administration on the day of treatment. Each administration was separated by a washout period of at least two days. Blood samples were taken before administration (immediately before administration), and at T0.25h, T0.5h, T1h, T2h, T4h, T8h, T12h, and T24h after administration for analysis of plasma concentrations and area under the curve (AUC) for quantification of dR-pioglitazone, dS-pioglitazone, hR-pioglitazone, and hS-pioglitazone. Table 18. Mean plasma PK parameters of total pioglitazone and pioglitazone enantiomers after single oral administration of PXL065, PXL064, PXL061, or pioglitazone in dogs. [Table 19] AUC 0-24 = Area under the plasma concentration-time curve from 0 to 24 hours; C max =Maximum plasma concentration; pio=Pioglitazone; SD=Standard deviation; t 1 / 2 z = terminal phase disappearance half-life; t max = time to reach maximum plasma concentration Note: The table shows total exposure to pioglitazone (the sum of deuterated and hydrogenated (R)- and (S)-enantiomers of pioglitazone). Note: Unless otherwise specified, the data is t max Except for the median [minimum, maximum] value, the values ​​are shown as mean ± SD. Note: Unless otherwise specified, data is shown for n=3. In (a), the data is shown for n=2 instead of n=3. The data is shown as the mean (value for each animal).

[0272] Mean plasma PK parameters are shown in Table 18, and plasma exposure and relative bioavailability are shown in Table 19.

[0273] The plasma PK profiles over time are shown in Figures 17-19. Table 19. Total pioglitazone plasma exposure (AUC) in dogs 0-24 Relative bioavailability of deuterium-enriched (R)-pioglitazone (PXL065) and deuterium-enriched (S)-pioglitazone (PXL064) compared to deuterium-enriched pioglitazone (PXL061) [Table 20] AUC 0-24 = Area under the plasma concentration-time curve from 0 to 24 hours; Frel = Relative oral bioavailability; geo = Geometric; Total pioglitazone (sum of deuterated and hydrogenated (R)- and (S)-enantiomers of pioglitazone)

[0274] These test results, showing an increase in total pioglitazone (total of hydrogenated and deuterated (R)- and (S)-enantiomers) observed with PXL065 compared to deuterium-enriched pioglitazone (PXL061) but not with deuterium-enriched (S)-enantiomer (PXL064), support the conclusion that the increased bioavailability of PXL065 is not due to the presence of deuterium.

[0275] Example 10. 13-week toxicity test in dogs The objective of this study was to evaluate the potential toxicity and toxicological effects of deuterium-concentrated (R)-pioglitazone (PXL065) after 13 weeks of daily oral administration (capsules) to beagle dogs compared with pioglitazone. Four groups of beagle dogs, each containing 3 or 5 animals / sex, were orally administered PXL065 at 0 (empty capsule), 1.5, 5, or 15 mg / kg / day (1 capsule of API / day) for 13 weeks; another group was given pioglitazone at 10 mg / kg / day (1 capsule of API / day). Blood was collected for toxicological assessment at various time points during the administration period (before administration, and 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after administration) to examine plasma concentrations of dR-pioglitazone, dS-pioglitazone, hR-pioglitazone, and hS-pioglitazone.

[0276] Although not all toxicological assessments are presented herein, relative bioavailability data based on total pioglitazone plasma concentration on day 91 are shown in Table 20 and Figure 20. Table 20: Mean total pioglitazone exposure in dogs on day 91 [Table 21] AUC 0-24,SS = Area under the plasma concentration-time curve from 0 to 24 hours in steady state; total pioglitazone (sum of deuterated and hydrogenated (R)- and (S)-enantiomers of pioglitazone)

[0277] These test results indicate that PXL065 increases the bioavailability of total pioglitazone (the sum of hydrogenated and deuterated (R)- and (S)-enantiomers) compared to pioglitazone.

[0278] Example 11: Phase Ia study to evaluate the safety, tolerability, and pharmacokinetics of repeated administration of deuterium-enriched (R)-pioglitazone (PXL065) crystalline HCl salt in healthy human subjects compared to pioglitazone HCl (ACTOS®).

[0279] the purpose The primary objective of this study was to evaluate the safety and tolerability of single oral doses of PXL-065 (7.5 mg, 22.5 mg, and 30 mg as capsules) in healthy subjects.

[0280] The second objective of this study was to evaluate the pharmacokinetics of PXL065 in healthy subjects after a single dose compared to 45 mg of ACTOS®, and to specifically focus on assessing exposure to both deuterated and hydrogenated(R)- and (S)-pioglitazone, and to investigate, if any, the degree of interconversion of PXL065 to hydrogenated(R)- and (S)-enantiomers.

[0281] Test method This trial was conducted in two parts. Part 1 used an open-label, parallel-group design. Eligible subjects were authorized to the clinical trial unit within 21 days of screening. On day 1 of the trial, subjects were randomly assigned to receive either a single dose of 22.5 mg of PXL065 (6 subjects) or a single dose of 45 mg of ACTOS® (6 subjects). The investigational dose was administered in a fasted state at approximately 8 AM on day 1. Subjects remained in the clinical unit for 36 hours after administration. Subjects were returned to the hospital as outpatients on days 4 and 7 for follow-up evaluation. Following a review of the safety and tolerability of PXL065 in Part 1 by a Data Review Committee (DRC) and measurements of comparative PK exposure to enantiomers, six healthy subjects were added to Part 2.

[0282] Part 2 used an open-label design in which a single dose of 7.5 mg of PXL065 was administered to fasted patients on the morning of day 1. Participants remained in the clinical unit for at least 36 hours after administration and returned to the hospital as outpatients on days 4 and 7 for follow-up evaluation. Following a review of safety, tolerability, and PK data from the 7.5 mg PXL065 dose group, a further treatment group (30 mg of PXL065) was evaluated for six healthy subjects. Prior to administration to the further group, a safety and tolerability review from the preceding group was performed by the DRC.

[0283] Diagnostic and Criteria for Inclusion The target is ≥17 to ≤32 kg / m 2 The study included healthy adult men or women aged 18-40 years with a Body Mass Index (BMI). Female participants were neither pregnant nor breastfeeding.

[0284] Test formulation, dosage, and mode of administration PXL065 was administered orally. Dosage = 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, as well as lactose.

[0285] Control formulation, dosage, and mode of administration ACTOS® was administered orally. Dosage = 1 x 45 mg tablet. I purchased ACTOS® as a commercially available product. The 45mg tablets contain 45mg of pioglitazone HCl, lactose, carmellose calcium, hyprolose, and magnesium stearate.

[0286] Treatment period In Part 1, each subject received a single dose of either 22.5 mg of PXL065 or 45 mg of ACTOS®, and was evaluated for 7 days after administration. In Part 2, each subject received a single dose of either 7.5 mg or 30 mg of PXL065, and was evaluated for 7 days after administration. The total study period, from the confinement period (-1 day) to the end of the study visit, was 8 days.

[0287] Evaluation Criteria Safety: Researchers assessed safety using the following criteria: physical examination, electrocardiogram (ECG), vital signs measurement, laboratory assessment, and reported or observed adverse events (AEs). Participants were monitored for all AEs from the start of the confinement study to the end of the study. Pharmacokinetics: 1 / 2 t max , C max AUC 0-last , and AUC 0-inf Plasma PK parameters, including but not limited to those listed above, were calculated for the deuterated and hydrogenated forms of (R)- and (S)-pioglitazone.

[0288] statistical methods Generally, all data were presented as descriptive statistics for continuous endpoints (number of subjects, mean, standard deviation, minimum, median, and maximum), as well as frequency and proportion for categorical endpoints. Within each part of the clinical trial, data were presented separately for each cohort and by treatment group within each cohort.

[0289] Safety and Tolerability: All safety and tolerability data were recorded. For continuous variables, descriptive statistics were used to summarize outcomes and changes from baseline at treatment and time points. Category evaluation values ​​were listed. Adverse events (AEs) were coded according to MedDRA.

[0290] result As shown in Table 21 and Figure 21, PXL065 showed improved bioavailability after a single dose in healthy human subjects compared to ACTOS®. Table 21: Total pioglitazone exposure in human Phase Ia trials [Table 22] AUC inf = Area under the plasma concentration-time curve from 0 to infinity; total pioglitazone (sum of deuterated and hydrogenated (R)- and (S)-enantiomers of pioglitazone)

[0291] Example 12. Phase Ib study to evaluate the safety, tolerability, and pharmacokinetics of repeated administration of deuterium-enriched (R)-pioglitazone (PXL065) crystalline HCl salt in healthy human subjects compared to pioglitazone HCl (ACTOS®).

[0292] the purpose The primary objective of this study was to evaluate the safety and tolerability of repeated administration of different doses of PXL-065 compared to 45 mg of pioglitazone HCl (ACTOS®) in healthy subjects.

[0293] The second objective of this study was to evaluate the pharmacokinetics (PK) of PXL065 in healthy subjects after single and multiple doses compared to 45 mg of ACTOS®, to assess exposure to both deuterated and hydrogenated(R)- and (S)-enantiomers of pioglitazone, and, if any, to investigate the degree of interconversion of PXL065 to its hydrogenated(R)- and (S)-enantiomers.

[0294] Test method Participants were screened within 28 days prior to the first dose of the study drug. They were kept in the hospital from 1 day before administration (-1 day) until at least 48 hours after the final dose of the study drug (day 11). Participants returned to the hospital for outpatient evaluation and / or PK sample collection on day 12 (approximately 72 hours after administration), day 13 (approximately 96 hours after administration), day 14 (approximately 120 hours after administration), and day 15 (approximately 144 hours after administration), and for a follow-up visit 10 days (±2 days) after the final dose.

[0295] Up to 30 healthy subjects were included in this study: • Three types (3) of PXL065 treatment groups: Eight subjects in each treatment group (6 in the active drug and 2 in the placebo). Each treatment group consisted of 4 men and 4 women in an active drug / placebo ratio of 3:1. • One type (1) of ACTOS®: Six subjects (3 men and 3 women) were given ACTOS®. A placebo was not given to the subjects in this group.

[0296] The dose levels for groups 1-4 were as follows (Table 22): Table 22. Dose levels for groups 1-4 [Table 23]

[0297] Participants received a single oral dose of the study drug (7.5, 15, or 30 mg tablets of PXL065 or the corresponding placebo tablet, or a 45 mg tablet of ACTOS®) on day 1 while fasting. They then received repeated doses of each study drug for 7 days, from day 3 to day 9. All study drugs were administered under fasting conditions.

[0298] The PK parameters of PXL065 after single oral administration of three different drugs on day 1 and after seven daily administrations on day 9 were compared with the PK parameters of ACTOS® after seven daily administrations on day 1 and day 9.

[0299] Diagnostic and Criteria for Inclusion The target range is ≥18.5 to ≤32 kg / m 2 The study included healthy adult men or women aged 18-45 years with a Body Mass Index (BMI). Female participants were neither pregnant nor breastfeeding.

[0300] Test formulation, dosage, and mode of administration PXL065 was administered orally. Dosage = 1 x 7.5 mg tablet, 1 x 15 mg tablet, or 1 x 30 mg tablet.

[0301] PXL065 tablets contain 7.5 mg, 15 mg, or 30 mg of PXL065, as well as lactose, carmellose calcium, hyprolose, and magnesium stearate.

[0302] Control formulation, dosage, and mode of administration ACTOS® was administered orally. Dosage = 1 x 45 mg tablet.

[0303] I purchased ACTOS® as a commercially available product. The 45mg tablets contain 45mg of pioglitazone HCl, lactose, carmellose calcium, hyprolose, and magnesium stearate.

[0304] Treatment period A single oral dose of PXL065, the corresponding placebo, or ACTOS® was administered on day 1 in a fasted state, followed by multiple oral doses of PXL065, the corresponding placebo, or ACTOS® once daily from day 3 to day 9 (7 days) in a fasted state.

[0305] Evaluation Criteria Pharmacokinetics: Plasma samples were analyzed using valid assays. Samples were analyzed from all evaluable subjects. Samples from subjects who experienced vomiting within 4 hours of administration were not analyzed.

[0306] Plasma PK parameters included, but were not limited to, the following: • Single administration described below on Day 1 and Day 3 (for the PXL065 group): 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, AUC 0-last / dose, AUC 0-inf / dose, and MRT (calculated using compartmental or non-compartmental analysis as appropriate for deuterated or non-deuterated (R)- and (S)-enantiomers of pioglitazone, respectively). • Days 4 to 9: C for deuterated and non-deuterated (R)- and (S)-enantiomers of pioglitazone trough ; and • Repeated administration described below on Day 9: t max , C max , C avg , t lag , AUC 0-last , AUC 0-24 , AUC 0-inf , λ z , t 1 / 2 , %AUC ext , CLss / F, Vz ss / F, MRT, PTF, R ac (AUC 0-24 ), Rac(C max )SR(AUC), C max / dose, AUC 0-last / dose, AUC 0-inf / dose, AUC 0-24 / dose.

[0307] Safety Investigators assessed safety using the following assessments: physical measurements, vital sign measurements, clinical laboratory evaluations, electrocardiography, and adverse events (AEs) reported or observed. Subjects were monitored for any AEs from informed consent through the end of the study.

[0308] Statistical Methods Generally, all data were presented as descriptive statistics for continuous endpoints (number of subjects, mean, standard deviation, minimum, median, and maximum), as well as frequency and proportion for categorical endpoints. Within each part of the clinical trial, data were presented separately for each cohort and by treatment group within each cohort.

[0309] Safety and Tolerability: All safety and tolerability data were recorded. For continuous variables, descriptive statistics were used to summarize outcomes and changes from baseline at treatment and time points. Category evaluation values ​​were listed. Adverse events (AEs) were coded according to MedDRA.

[0310] result Pharmacokinetic study results: The relative bioavailability of PXL065 in humans increased by 55% to 65% compared to ACTOS® (see Table 23 and Figure 18). Table 23. Pharmacokinetic parameters of PXL065 and ACTOS® in humans [Table 24] As shown in Table 23 and Figure 22, PXL065 shows improved bioavailability after repeated dose administration in healthy human subjects compared to ACTOS®.

[0311] The combined results from the two canine PK studies and two human PK studies described above in Examples 9-12 demonstrate that, compared to pioglitazone, the bioavailability of total pioglitazone (total of hydrogenated and deuterated (R)- and (S)-enantiomers) by PXL065 is independent of the formulation (capsule or tablet).

[0312] Import by reference This application references various published patents, published patent applications, articles, and other publications, all of which are incorporated herein by reference. In the event of any conflict between any of the incorporated references and this specification, this specification shall prevail. Furthermore, any specific embodiment of this disclosure that falls within the scope of prior art may be expressly excluded from any one or more claims. Such embodiments are known to those skilled in the art and may be excluded even if the exclusion is not expressly described herein. Any specific embodiment of this disclosure may be excluded from any claim for any reason, whether relating to the existence of prior art or otherwise.

[0313] equivalent The present invention may be embodied in other specific forms without departing from its spirit or essential features. Therefore, the embodiments described herein are considered to be all illustrative rather than limiting. Thus, the scope of the present invention is indicated by the claims rather than the specification, and all modifications within the meaning of the claims and equivalent scope are included in the present invention.

Claims

1. Equation (I-A): 【Chemistry 1】 (I-A) A crystalline hydrochloride salt of the compound shown, A crystalline hydrochloride salt characterized by an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 15.8°±0.2°, 22.8°±0.2°, and 26.0°±0.2°.

2. The crystalline hydrochloride salt according to claim 1, characterized by an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 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 according to claim 1 or 2, characterized by an X-ray powder diffraction pattern including peaks at the following diffraction angles (2θ): 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 according to any one of claims 1 to 3, wherein the crystalline hydrochloride salt is characterized by an X-ray powder diffraction pattern identical to the X-ray powder diffraction pattern shown in Figure 6.

5. The crystalline hydrochloride salt according to any one of claims 1 to 4, wherein the crystalline hydrochloride salt exhibits a melting point at approximately 190°C to approximately 210°C, as determined by differential scanning calorimetry.

6. The crystalline hydrochloride salt according to any one of claims 1 to 5, wherein the crystalline hydrochloride salt is an anhydrous crystalline hydrochloride salt.

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

8. A therapeutic agent for metabolic disorders, comprising a crystalline hydrochloride salt according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7.

9. The therapeutic agent according to claim 8, wherein the metabolic disorder is polycystic ovary syndrome.

10. A therapeutic agent for type 2 diabetes, comprising a crystalline hydrochloride salt according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7.

11. A therapeutic agent for non-alcoholic fatty liver disease, comprising a crystalline hydrochloride salt according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7.

12. A therapeutic agent for non-alcoholic fatty liver disease, comprising a crystalline hydrochloride salt according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7.

13. A therapeutic agent for neurological disorders, comprising a crystalline hydrochloride salt according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7.

14. The therapeutic agent according to claim 13, wherein the nerve disorder is adrenoleukodystrophy or adrenal spinal neuropathy.

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