Solid forms of malaxibat, intermediates and processes for producing same

Abstract

The present invention relates to a highly pure crystalline compound as a starting material and intermediate for the preparation of maralixibat, as well as a process for preparing highly pure maralixibat. The present invention also relates to an amorphous form of malalixibat.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and claims priority to U.S. Provisional Patent Application No. 63 / 406,556, filed September 14, 2022, which is incorporated herein by reference in its entirety. [Technical Field]

[0002] The present invention relates to a highly pure crystalline compound as a starting material and intermediate for the preparation of maralixibat, and to a process for the preparation of highly pure maralixibat. [Background technology]

[0003] Hypercholic acidemia and cholestatic liver disease are liver diseases associated with impaired bile secretion (i.e., cholestasis) and are often secondary to the intracellular accumulation of bile acids / bile salts in hepatocytes. Hypercholic acidemia is characterized by elevated serum concentrations of bile acids or bile salts. Clinicopathologically, cholestasis can be divided into two major categories: biliary obstructive, often extrahepatic, cholestasis, and non-biliary obstructive or intrahepatic cholestasis. Non-biliary obstructive intrahepatic cholestasis can be further divided into two major subgroups: primary intrahepatic cholestasis, which is caused by a constitutive defect in bile secretion, and secondary intrahepatic cholestasis, which is caused by hepatocellular damage. Primary intrahepatic cholestasis includes diseases such as benign recurrent intrahepatic cholestasis, an adult form with primarily similar clinical symptoms, and progressive familial intrahepatic cholestasis (PFIC) types 1, 2, and 3, which are diseases that affect children.

[0004] Alagille syndrome (ALA) is a hereditary condition in which bile accumulates in the liver. One of the primary features of Alagille syndrome is liver damage caused by abnormalities in the bile ducts. Alagille syndrome is associated with liver, cardiac, skeletal, eye, and kidney abnormalities, as well as a characteristic facial appearance.

[0005] Maralixibat (as maralixibat chloride) is currently the only approved medication for treating pruritus in patients with Alagille syndrome. Maralixibat chloride is known to inhibit apical sodium-codependent bile acid transport (Patent Document 1). The synthesis of maralixibat chloride was previously disclosed in Patent Document 2. Previous methods for synthesizing maralixibat chloride resulted in the presence of undesirable structurally related impurities and other solid forms.

[0006] Therefore, there is a need for novel processes for producing high purity malalixibat from high purity crystalline compounds with starting materials or intermediates that minimize the formation of impurities. Embodiments of the present disclosure are directed to this and other considerations. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] U.S. Patent No. 5,994,391 [Patent Document 2] US Patent Application Publication No. 2003 / 0199515 Summary of the Invention [Means for solving the problem]

[0008] Various non-limiting aspects and embodiments of the present invention are described below.

[0009] As used herein, (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (Formula 1): [ka] The crystalline form of the compound represented by the formula (I) is Form A.

[0010] Also provided herein is a crystalline form of Formula I, which is Form B.

[0011] Also provided herein is a highly purified compound of Formula I, wherein the purity of the compound of Formula I is at least about 95%.

[0012] As used herein, (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-hydroxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (Formula II): [ka] Also provided is a crystalline form of the formula: which is Form X.

[0013] Also provided is a highly purified compound of Formula II, wherein the purity of the compound of Formula II is at least about 95%.

[0014] Provided herein is 1-(4-((4-((4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b]thiepin-5-yl)phenoxy)methyl)benzyl)-1,4-diazabicyclo[2.2.2]octan-1-ium chloride (Formula III): [ka] Also provided is an amorphous form of the compound characterized by an amorphous content of at least about 80%, which amorphous form is characterized by an XRPD pattern substantially similar to the XRPD pattern of FIG.

[0015] Also provided herein is a process for producing a highly pure compound of formula III, which process comprises converting a highly pure compound of formula I to a highly pure compound of formula II.

[0016] Also provided herein are highly pure crystalline Form I, Form II, and / or amorphous forms of Formula III, which are prepared by a process comprising converting highly pure crystalline Form A of Formula I to highly pure crystalline Form X of Formula II.

[0017] These and other aspects of the present invention will become apparent to those skilled in the art after reading the following detailed description of the invention, including the appended claims.

[0018] Reference will now be made to the accompanying drawings, which are not necessarily drawn to scale, that illustrate various implementations, aspects and principles of the disclosed technology. [Brief explanation of the drawings]

[0019] [Figure 1] 1 is an XRPD plot of crystalline form A of the compound of formula I. [Figure 2] 1 is a TGA / DSC plot of crystalline form A of the compound of formula I. [Figure 3] 1 is a PLM image of crystalline form A of the compound of formula I. [Figure 4] 1 is an XRPD plot of crystalline form B of the compound of formula I. [Figure 5] 1 is a TGA plot of crystalline form B of the compound of formula I. [Figure 6] 1 is an XRPD plot of crystalline form X of the compound of formula II. [Figure 7] 1 is a TGA / DSC plot of crystalline form X of the compound of formula II. [Figure 8] 1 is a PLM image of crystalline form X of the compound of formula II. [Figure 9] 1 is an XRPD plot of the amorphous form of the compound of formula III. [Figure 10] 1 is a DSC plot of the amorphous form of the compound of formula III. [Figure 11] 1 is an XRPD plot of crystalline Form II of compound of formula III compared to a reference. [Figure 12] 1 is a TGA / DSC plot of crystalline Form II of the compound of formula III. [Figure 13] 1 is a PLM image of crystalline Form II of the compound of formula III. [Figure 14] 1 is an XRPD plot of crystalline Form I of the compound of formula III. [Figure 15] 1 is a TGA / DSC plot of crystalline Form I of the compound of formula III. DETAILED DESCRIPTION OF THE INVENTION

[0020] Detailed embodiments of the present invention are disclosed herein; however, it should be understood that the disclosed embodiments are merely exemplary of the invention, which may be embodied in various forms. Furthermore, each of the examples given in connection with various embodiments of the present invention is intended to be illustrative, not limiting. Therefore, the specific structural and functional details disclosed herein should not be construed as limiting, but merely as a representative basis for teaching those skilled in the art to variously use the present invention.

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0022] In some embodiments, when aspects of the disclosure are described as "comprising" a feature or versions thereof (e.g., "comprise"), it is also contemplated that the embodiment "consisting of" or "consisting essentially of" that feature.

[0023] The term "treat" a state, disorder, or condition, or the term "treatment," includes: (1) preventing, delaying, or reducing the occurrence and / or likelihood of at least one clinical or subclinical symptom of the condition, disorder, or condition occurring in a subject who may be afflicted with or predisposed to the condition, disorder, or condition, but who has not yet experienced or displayed clinical or subclinical symptoms of the condition, disorder, or condition; or (2) inhibiting the condition, disorder, or condition, i.e., arresting, reducing, or delaying the progression of the disease or its recurrence, or at least one clinical or subclinical symptom thereof; or (3) palliating the disease, i.e., causing regression of the condition, disorder, or condition, or at least one clinical or subclinical symptom thereof. The benefit to the treated subject is statistically significant or at least perceptible to the patient or physician.

[0024] As used herein, "subject" or "patient" or "individual" or "animal" refers to humans, veterinary animals (e.g., cats, dogs, cows, horses, sheep, pigs, etc.) and experimental animal models of disease (e.g., mice, rats). In a preferred embodiment, the subject is a human.

[0025] As used herein, the term "effective" as applied to a dose or amount refers to an amount of a compound or pharmaceutical composition sufficient to produce the desired activity when administered to a subject in need thereof. It should be noted that when a combination of active ingredients is administered, the effective amount of the combination may or may not include the amount of each ingredient that would be effective when administered individually. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition being treated, the particular drug(s) used, the mode of administration, etc.

[0026] The phrase "pharmaceutically acceptable" as used in connection with the compositions of the present invention refers to molecular entities and other components of such compositions that are physiologically tolerable and typically do not produce adverse reactions when administered to a mammal (e.g., a human). Preferably, as used herein, the term "pharmaceutically acceptable" means approved by a federal or state regulatory agency or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeias for use in mammals, more specifically, humans.

[0027] Ranges can be expressed herein as from "about" or "approximately" one particular value and / or to "about" or "approximately" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value.

[0028] "Comprising" or "containing" or "including" means that at least the specified compounds, elements, particles or method steps are present in a composition or article or method, but does not exclude the presence of other such compounds, materials, particles or method steps, even if they have the same function as the one specified.

[0029] The compounds of the present invention include those generally described herein and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Furthermore, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0030] The term "alkyl," as used herein, alone or in combination, refers to a straight-chain or branched-chain alkyl group. The alkyl group may be optionally substituted as defined herein. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl, nonyl, and the like.

[0031] The term "alkylene," as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight- or branched-chain saturated hydrocarbon bonded at two or more positions, such as methylene (-CH-). Unless otherwise specified, the term "alkyl" can include an "alkylene" group.

[0032] The term "amorphous" refers to a solid form of molecules and / or ions that is not crystalline. Amorphous solids do not exhibit distinct X-ray diffraction patterns with sharp maxima.

[0033] The term "anhydrous" or "anhydrous" when referring to a crystalline form means that solvent molecules, including water solvent molecules, do not form part of the unit cell of the crystalline form. Nevertheless, a sample of an anhydrous crystalline form may contain solvent molecules that do not form part of the unit cell of the anhydrous crystalline form, for example, residual solvent molecules left over from the preparation of the crystalline form. In preferred embodiments, the solvent can constitute up to 0.5% by weight of the total composition of the anhydrous form sample. In more preferred embodiments, the solvent can constitute up to 0.2% by weight of the total composition of the anhydrous form sample. In some embodiments, a sample of an anhydrous crystalline form does not contain solvent molecules, for example, does not contain detectable amounts of solvent. The term "solvate," when referring to a crystalline form, means that solvent molecules, for example, organic solvent and water, form part of the unit cell of the crystalline form. A solvate containing water as the solvent is also referred to herein as a "hydrate." The term "isomorphic," when referring to a crystalline form, means that the form may contain different chemical components, for example, different solvent molecules in the unit cell, but have the same XRPD pattern. Isomorphic crystalline forms are sometimes referred to herein as "isomorphs."

[0034] As used herein, "crystalline" refers to a solid having a highly ordered chemical structure, i.e., long-range structural order in a crystal lattice. The molecules are regularly and periodically arranged in the three-dimensional space of the lattice. In particular, a crystalline form can be produced as one or more single crystal forms. A crystalline form of a compound refers to a substantially crystalline form having at least a specified weight percent of crystals. The specified weight percent can be 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 70% and 100%. In certain embodiments, the specified weight percent of crystallinity is at least 90%. In certain other embodiments, the specified weight percent of crystallinity is at least 95%. In some embodiments, the compound of Formula I is a substantially crystalline sample of any of the crystalline solid forms described herein (e.g., crystalline forms A and B). In some embodiments, the compound of Formula II is a substantially crystalline sample of any of the crystalline solid forms described herein (e.g., crystalline forms X and Y). In some embodiments, the compound of Formula III is a substantially crystalline sample of any of the crystalline solid forms described herein (e.g., crystalline forms I and II).

[0035] For the purposes of this application, the terms "crystalline form," "single crystalline form," "crystalline solid form," "solid form," and "polymorph" are synonymous and are used interchangeably; these terms distinguish between crystals with different properties (e.g., different XRPD patterns and / or different DSC scan results).

[0036] As used herein, "Form A" and "Form B" refer to specific crystalline solid state forms of (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (Formula I) in which the molecules are arranged to form distinct crystal lattices that (i) contain distinct unit cells and (ii) give rise to distinct diffraction peaks when exposed to X-rays.

[0037] As used herein, "Form X" and "Form Y" refer to specific crystalline solid state forms of (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-hydroxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (Formula II) in which the molecules are arranged to form distinct crystal lattices that (i) contain distinct unit cells and (ii) give rise to distinct diffraction peaks when exposed to X-rays.

[0038] As used herein, "Form I" and "Form II" refer to specific crystalline solid state crystal forms of 1-(4-((4-((4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b]thiepin-5-yl)phenoxy)methyl)benzyl)-1,4-diazabicyclo[2.2.2]octan-1-ium chloride (Formula III) in which the molecules are arranged to form distinct crystal lattices that (i) contain distinct unit cells and (ii) give rise to distinct diffraction peaks when exposed to X-rays.

[0039] The term "high purity" refers to a composition of a compound containing at least about 90% by weight of such crystalline form. The term "at least about 90%" is not intended to limit the applicability of the doctrine of equivalents to the claims, but includes, for example, but is not limited to, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, and about 100% by weight of the referenced crystalline form. The remainder of the composition may contain, for example, other crystalline forms of the compound and / or reaction and / or processing impurities that arise when the crystalline form is prepared. The presence of reaction and / or processing impurities can be determined by analytical techniques known in the art, such as, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectroscopy, and / or infrared spectroscopy.

[0040] "Maralixibat chloride" refers to 1-(4-((4-((4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b]thiepin-5-yl)phenoxy)methyl)benzyl)-1,4-diazabicyclo[2.2.2]octan-1-ium chloride, the structure of which is represented by formula III. [ka]

[0041] "Maralixibat" refers to 1-(4-((4-((4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b]thiepin-5-yl)phenoxy)methyl)benzyl)-1,4-diazabicyclo[2.2.2]octan-1-ium, which is the free form of maralixibat chloride. The structure of maralixibat is shown below. [ka]

[0042] Unless otherwise specified, percentages (%) refer to percentages by weight.

[0043] The compounds of the present disclosure, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomers, which may be defined in terms of absolute stereochemistry as (R)- or (S)-. The present disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms, whether or not specifically depicted herein. Optically active (+) and (-), or (R)- and (S)-isomers, can be prepared using chiral synthetic groups or chiral reagents, or resolved using conventional techniques, such as, for example, chromatography and fractional crystallization.

[0044] "Stereoisomer" refers to a compound composed of the same atoms connected by the same bonds but with different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof, including "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another. In one embodiment, the compounds disclosed herein include racemic mixtures, enantiomers, diastereomers, or enantiomerically or diastereomerically enriched mixtures.

[0045] "XRPD" refers to X-ray powder diffraction or X-ray powder diffractogram. As used herein, "VT-XRPD" refers to variable temperature X-ray powder diffraction or variable temperature X-ray powder diffractogram. As used herein, "TGA" refers to thermogravimetric analysis. As used herein, "DSC" refers to differential scanning calorimetry. As used herein, "NMR" refers to nuclear magnetic resonance. As used herein, "DVS" refers to dynamic vapor sorption. As used herein, "DCM" refers to dichloromethane. As used herein, "EtOAc" refers to ethyl acetate. As used herein, "MeOH" refers to methanol. As used herein, "MBTE" refers to methyl tert-butyl ether. As used herein, "RH" refers to relative humidity. As used herein, "RT" refers to room temperature.

[0046] As used herein, (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (Formula I): [ka] wherein the crystalline form is crystalline form A.

[0047] In some embodiments, crystalline Form A of the compound of Formula (I) is characterized by an X-ray powder diffractogram (XRPD) having at least three peak signals at 2θ values ​​selected from 4.7±0.2, 6.6±0.2, 9.3±0.2, 10.4±0.2, 13.3±0.2, 16.8±0.2, 19.3±0.2, and 23.4±0.2.

[0048] In some embodiments, crystalline Form A of the compound of formula I is characterized by an XRPD pattern substantially similar to the XRPD pattern of FIG.

[0049] In some embodiments, crystalline form A of the compound of formula I is characterized by a melting point of about 133°C to about 135°C.

[0050] In some embodiments, crystalline form A of the compound of formula I is characterized by a melting point of about 134.7°C.

[0051] In some embodiments, crystalline form A of the compound of formula I is characterized by a DSC thermogram with an onset of about 130.8°C, an endotherm with a peak at about 134.7°C, and an exotherm at about 145°C.

[0052] In some embodiments, crystalline Form A of the compound of Formula I is characterized by a thermogravimetric analysis / differential scanning calorimetry (TGA / DSC) thermogram substantially similar to that of FIG.

[0053] In some embodiments, crystalline Form A of the compound of Formula I has no weight loss between about 25° C. and about 225° C. as measured by thermogravimetric analysis (TGA).

[0054] In some embodiments, crystalline Form A of the compound of Formula I is anhydrous.

[0055] In some embodiments, crystalline form A of the compound of formula I is a hydrate.

[0056] In some embodiments, crystalline Form A of the compound of Formula I comprises rod-shaped crystals when observed under a polarized light microscope.

[0057] In some embodiments, at least about 95% of the crystalline form A of the compound of formula I is the R,R stereoisomer.

[0058] In some embodiments, at least about 96% of the crystalline form A of the compound of formula I is the R,R stereoisomer.

[0059] In some embodiments, at least about 97% of the crystalline form A of the compound of formula I is the R,R stereoisomer.

[0060] In some embodiments, at least about 98% of the crystalline form A of the compound of formula I is the R,R stereoisomer.

[0061] In some embodiments, at least about 99% of the crystalline form A of the compound of formula I is the R,R stereoisomer.

[0062] In some embodiments, about 100% of the crystalline form A of the compound of formula I is the R,R stereoisomer.

[0063] In some embodiments, about 99% to about 100% of the crystalline form A of the compound of formula I is the R,R stereoisomer.

[0064] (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (Formula I): [ka] Also provided herein is a crystalline form of the formula: which is crystalline form B.

[0065] Crystalline Form B of the compound of Formula I is characterized by an X-ray powder diffractogram (XRPD) having at least five peak signals at 2θ values ​​selected from 4.4±0.2, 6.3±0.2, 7.2±0.2, 8.9±0.2, 9.9±10.8±0.2, 11.2±0.2, 11.6±0.2, 17.5±0.2, 18.4±0.2, 21.9±0.2, and at least two peak signals at 2θ values ​​selected from 4.7±0.2, 6.6±0.2, 9.3±0.2, 13.3±0.2, 19.3±0.2, and 23.4±0.2.

[0066] In some embodiments, crystalline form B of the compound of formula I is characterized by an XRPD pattern substantially similar to the XRPD pattern of FIG.

[0067] In some embodiments, crystalline form B of the compound of formula I is characterized by a TGA thermogram substantially similar to the TGA thermogram of FIG.

[0068] In some embodiments, crystalline form B of the compound of formula I has a weight loss of about 45% between about 21.5° C. and about 100° C. as measured by thermogravimetric analysis (TGA).

[0069] In some embodiments, crystalline form B of the compound of formula I is a hydrate.

[0070] In some embodiments, at least about 95% of the crystalline form B of the compound of formula I is the R,R stereoisomer.

[0071] In some embodiments, at least about 96% of crystalline form B of the compound of formula I is the R,R stereoisomer.

[0072] In some embodiments, at least about 97% of crystalline form B of the compound of formula I is the R,R stereoisomer.

[0073] In some embodiments, at least about 98% of crystalline form B of the compound of formula I is the R,R stereoisomer.

[0074] In some embodiments, at least about 99% of the crystalline form B of the compound of formula I is the R,R stereoisomer.

[0075] In some embodiments, about 100% of the crystalline form B of the compound of formula I is the R,R stereoisomer.

[0076] In some embodiments, about 99% to about 100% of the crystalline form B of the compound of formula I is the R,R stereoisomer.

[0077] Provided herein is a highly purified compound having the structure of Formula I, (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide: [ka] Also provided is a compound having a purity of at least about 95%.

[0078] In some embodiments, the compound of formula I has a purity of at least about 96%.

[0079] In some embodiments, the compound of formula I is at least about 97% pure.

[0080] In some embodiments, the compound of formula I is at least about 98% pure.

[0081] In some embodiments, the compound of formula I is at least about 99% pure.

[0082] In some embodiments, the purity of the compound of formula I is about 100%.

[0083] In some embodiments, the purity of the compound of Formula I is about 99% to about 100%.

[0084] In some embodiments, the highly pure compound of formula I is in crystalline form.

[0085] In some embodiments, the highly pure compound of formula I is in amorphous form.

[0086] In some embodiments, the highly pure compound of formula I is crystalline form A.

[0087] In some embodiments, the highly pure compound of formula I is crystalline form B.

[0088] In some embodiments, the highly pure compound of formula I comprises crystalline form A and crystalline form B.

[0089] Also provided herein is a process for preparing crystalline Form A, comprising the step of: (a) combining a compound of formula I with a solvent.

[0090] In some embodiments, the process for preparing crystalline form A further comprises the step of (b) stirring the mixture in the slurry at about 25° C. In some embodiments, the process for preparing crystalline form A further comprises the step of (b) stirring the mixture in the slurry at about 65° C. In some embodiments, step (b) further comprises stirring the mixture in the slurry for about 3 days.

[0091] In some embodiments, the process for preparing crystalline form A has step (a) further comprising obtaining a clear solution of the mixture, the process further comprising the step of (b) adding an antisolvent. In some embodiments, step (b) further comprises stirring the mixture at about 25° C. In some embodiments, the solvent in step (a) is a volatile solvent, and step (a) further comprises contacting the solid form of the compound of formula I with vapors of the volatile solvent. In some embodiments, the contacting with vapors of the volatile solvent occurs at about 25° C. In some embodiments, the contacting continues for about 7 days.

[0092] In some embodiments, the process for preparing crystalline form A has step (a) further comprising obtaining a clear solution of the mixture, the process further comprising step (b) contacting the mixture with vapor of a volatile anti-solvent. In some embodiments, the contacting with vapor of a volatile anti-solvent occurs at about 25° C. In some embodiments, the contacting continues for about 7 days.

[0093] In some embodiments, the process for preparing crystalline form A has step (a) further comprising obtaining a clear solution of the mixture, the process further comprising step (b) evaporating the solvent. In some embodiments, the evaporation is carried out at about 25° C. In some embodiments, the evaporation continues for about 7 days.

[0094] In some embodiments, the process for preparing crystalline form A has step (a) further comprising obtaining a clear solution of the mixture, and the process further comprises step (b) adding an ionic liquid. In some embodiments, the ionic liquid is 1-butyl-3-methylimidazolium chloride.

[0095] In some embodiments, the process for preparing crystalline form A further comprises the step of (c) evaporating the solvent. In some embodiments, the evaporation occurs at about 25° C. In some embodiments, the evaporation continues for about 7 days.

[0096] In some embodiments, the process for preparing crystalline form A further comprises the step of (d) storing the mixture at about 5° C. In some embodiments, step (d) comprises storing the mixture at about 5° C. for about 3 days.

[0097] In some embodiments, the process for preparing crystalline form A includes step (a) further comprising forming a saturated solution, the process further comprising step (b) cooling the solution to form a clear solution. In some embodiments, the cooling is from about 50° C. to about 5° C. In some embodiments, the cooling time ranges from about 6 hours to about 9 hours.

[0098] In some embodiments, the process for preparing crystalline form A further comprises the step of (c) evaporating the solvent. In some embodiments, the evaporation occurs at about 25° C. In some embodiments, the evaporation continues for about 5 days.

[0099] In some embodiments, the process for preparing crystalline form A further comprises the step of (d) storing the mixture at about −14° C. In some embodiments, step (d) comprises storing the mixture at about −14° C. for about 3 days.

[0100] In some embodiments, the process for preparing crystalline form A comprises a solvent in step (a) comprising one or more selected from the group consisting of acetone, acetonitrile (ACN), n-butyl acetate, cyclohexane, dichloromethane (DCM), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl acetate (EtOAc), ethanol (EtOH), water, n-heptane, isopropyl alcohol (IPA), isopropyl acetate (IPAc), methanol (MeOH), methyl tetrahydrofuran (MeTHF), methyl isobutyl ketone (MIBK), methyl tert-butyl ether (MTBE), NMP, pentane, and toluene.

[0101] In some embodiments, the process for preparing crystalline form A comprises a solvent in step (a) selected from the group consisting of cyclohexane, water, n-heptane, IPA, MTBE, pentane, cyclohexane / acetone (3:2, vol:vol), cyclohexane / DCM (3:2, vol:vol), water / DMSO (3:2, vol:vol), water / EtOH (3:2, vol:vol), n-heptane / toluene (3:2, vol:vol), IPA / toluene (3:2, vol:vol), MTBE / DMSO (3:2, vol:vol), pentane / DCM (3:2, vol:vol), and pentane / acetone (3:2, vol:vol).

[0102] In some embodiments, the process for preparing crystalline form A comprises a solvent in step (a) selected from the group consisting of cyclohexane, water, n-heptane, IPA, MTBE, pentane, cyclohexane / toluene (3:2, vol:vol), cyclohexane / DCM (3:2, vol:vol), n-heptane / butyl acetate (3:2, vol:vol), n-heptane / toluene (3:2, vol:vol), IPA / acetone (2:1, vol:vol), IPA / DMF (2:1, vol:vol), MTBE / ACN (2:1, vol:vol), MTBE / DMSO (2:1, vol:vol), and MTBE / n-butyl acetate (2:1, vol:vol).

[0103] In some embodiments, the process for preparing crystalline form A comprises an anti-solvent in step (b) selected from the group consisting of cyclohexane, water, n-heptane, IPA, MTBE, and pentane.

[0104] In some embodiments, the process for preparing crystalline form A comprises a volatile solvent selected from the group consisting of acetone, ACN, n-butyl acetate, DCM, DMF, DMSO, EtOAc, MeOH, NMP, and MIBK.

[0105] In some embodiments, the process for preparing crystalline form A includes a solvent in step (a) that is n-butyl acetate, EtOAc, or toluene.

[0106] In some embodiments, the process for preparing crystalline form A comprises an anti-solvent in step (b) selected from the group consisting of cyclohexane, water, n-heptane, IPA, MTBE, and pentane.

[0107] In some embodiments, the process for preparing crystalline form A comprises a solvent in step (a) selected from the group consisting of DMF, MeTHF, MIBK, NMP, toluene, DCM, acetone, ACN, n-butyl acetate, and DMSO.

[0108] In some embodiments, the process for preparing crystalline form A comprises a solvent in step (a) selected from the group consisting of EtOH, IPAc, MeOH, MTBE, MIBK, CAN, acetone, NMP, toluene, and MeTHF.

[0109] Also provided herein is a process for preparing crystalline form B, the process comprising the steps of: (a) mixing the compound of formula I with a solvent; and (b) adding an anti-solvent, wherein the anti-solvent is a mixture of acetonitrile (ACN) and water.

[0110] (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-hydroxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (Formula II): [ka] Also provided herein is a crystalline form of the formula: which is Form X.

[0111] In one embodiment, crystalline form X of the compound of formula II is characterized by an X-ray powder diffractogram (XRPD) having at least nine peak signals at 2-theta (θ) values ​​selected from 5.0±0.2, 8.7±0.2, 10.0±0.2, 12.5±0.2, 13.3±0.2, 14.9±0.2, 15.8±0.2, 17.0±0.2, 17.8±0.2, 19.3±0.2, 19.9±0.2, 21.7±0.2, 22.6±0.2, 23.2±0.2, 24.5±0.2, 24.9±0.2, 25.8±0.2, 26.4±0.2, 28.0±0.2, and 29.4±0.2.

[0112] In some embodiments, crystalline form X of the compound of formula II is characterized by an XRPD pattern substantially similar to the XRPD pattern of FIG.

[0113] In some embodiments, crystalline form X of the compound of formula II is characterized by a melting point of about 216.7°C to about 217.7°C.

[0114] In some embodiments, crystalline form X of the compound of formula II is characterized by a melting point of about 217.2°C.

[0115] In some embodiments, crystalline form X of the compound of formula II is characterized by a DSC thermogram with an onset of about 216.1°C, an endotherm with a peak at about 217.2°C, and an exotherm at about 218.3°C.

[0116] In some embodiments, crystalline form X of the compound of formula II is characterized by a TGA / DSC thermogram substantially similar to that of FIG.

[0117] In some embodiments, crystalline form X of the compound of formula II has a weight loss of less than about 0.1% between about 95.1° C. and about 200.0° C. as measured by thermogravimetric analysis (TGA).

[0118] In some embodiments, crystalline form X of the compound of formula II has a weight loss of about 0.07% between about 95.1° C. and about 200.0° C. as measured by thermogravimetric analysis (TGA).

[0119] In some embodiments, crystalline form X of the compound of formula II is anhydrous.

[0120] In some embodiments, crystalline form X of the compound of formula II is a hydrate.

[0121] In some embodiments, crystalline form X of the compound of formula II comprises rod-shaped crystals when observed under a polarized light microscope.

[0122] In some embodiments, at least about 95% of the crystalline form X of the compound of formula II is the R,R stereoisomer.

[0123] In some embodiments, at least about 96% of the crystalline form X of the compound of formula II is the R,R stereoisomer.

[0124] In some embodiments, at least about 97% of the crystalline form X of the compound of formula II is the R,R stereoisomer.

[0125] In some embodiments, at least about 98% of the crystalline form X of the compound of formula II is the R,R stereoisomer.

[0126] In some embodiments, at least about 99% of the crystalline form X of the compound of formula II is the R,R stereoisomer.

[0127] In some embodiments, about 100% of the crystalline form X of the compound of formula II is the R,R stereoisomer.

[0128] In some embodiments, about 99% to about 100% of the crystalline form X of the compound of formula II is the R,R stereoisomer.

[0129] Provided herein is the highly pure compound (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-hydroxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (Formula II): [ka] Also provided is a compound having a purity of at least about 95%.

[0130] In some embodiments, the purity of the compound of formula II is at least about 96%.

[0131] In some embodiments, the purity of the compound of formula II is at least about 97%.

[0132] In some embodiments, the purity of the compound of formula II is at least about 98%.

[0133] In some embodiments, the purity of the compound of formula II is at least about 99%.

[0134] In some embodiments, the purity of the compound of formula II is about 100%.

[0135] In some embodiments, the purity of the compound of formula II is about 99% to about 100%.

[0136] In some embodiments, the highly pure compound of formula II is in crystalline form.

[0137] In some embodiments, the highly pure compound of formula II is in amorphous form.

[0138] In some embodiments, the highly pure compound of formula II is in crystalline form X.

[0139] In some embodiments, the highly pure compound of formula II is in crystalline form Y.

[0140] In some embodiments, the highly pure compound of formula II comprises crystalline form X and crystalline form Y.

[0141] Also provided herein is a process for preparing a highly pure compound of formula II, the process comprising contacting a highly pure compound (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (formula I) with DL-methionine to form a mixture, wherein the highly pure compound of formula I has a purity of at least 95%.

[0142] In some embodiments, the process for preparing a highly pure compound of formula II further comprises contacting the mixture with CH3SO3H at about 85°C.

[0143] In some embodiments, the process for preparing a highly pure compound of formula II comprises contacting a compound of formula I that is at least about 96% pure.

[0144] In some embodiments, the process for preparing a highly pure compound of formula II comprises contacting a compound of formula I that is at least about 97% pure.

[0145] In some embodiments, the process for preparing a highly pure compound of formula II comprises contacting a compound of formula I that is at least about 98% pure.

[0146] In some embodiments, the process for preparing a highly pure compound of formula II comprises contacting a compound of formula I that is at least about 99% pure.

[0147] In some embodiments, the process for preparing a highly pure compound of formula II comprises contacting a compound of formula I that is about 100% pure.

[0148] In some embodiments, the process for preparing a highly pure compound of formula II comprises contacting a compound of formula I that is about 99% to about 100% pure.

[0149] In some embodiments, the process for preparing a highly pure compound of formula II comprises contacting a compound of formula I in crystalline form. In some embodiments, the crystalline form of the compound of formula I is crystalline form A. In some embodiments, the crystalline form of the compound of formula I is crystalline form B.

[0150] Also provided herein is a process for preparing crystalline form X, comprising the step of: (a) combining a compound of formula II with a solvent.

[0151] In some embodiments, the process for preparing crystalline form X further comprises (b) stirring the mixture in the slurry at about 25° C. In some embodiments, the process for preparing crystalline form X further comprises (b) stirring the mixture in the slurry at about 65° C. In some embodiments, step (b) further comprises stirring the mixture in the slurry for about 3 days.

[0152] In some embodiments, the process for preparing crystalline form X comprises step (a), which further comprises obtaining a clear solution of the mixture, and the process further comprises the step of (b) adding an anti-solvent. In some embodiments, step (b) further comprises stirring the mixture at about 25° C. In some embodiments, the solvent in step (a) is a volatile solvent, and step (a) further comprises contacting the solid form of the compound of formula II with vapors of the volatile solvent. In some embodiments, the contact with vapors of the volatile solvent occurs at about 25° C. In some embodiments, the contact continues for about 7 days.

[0153] In some embodiments, the process for preparing crystalline form X comprises step (a), further comprising obtaining a clear solution of the mixture, the process further comprising step (b) contacting the mixture with vapors of a volatile antisolvent. In some embodiments, the contacting with vapors of a volatile antisolvent occurs at about 25° C. In some embodiments, the contacting continues for about 7 days.

[0154] In some embodiments, the process for preparing crystalline form X comprises step (a), which further comprises obtaining a clear solution of the mixture, and the process further comprises step (b) evaporating the solvent. In some embodiments, the evaporation occurs at about 25° C. In some embodiments, the evaporation continues for about 7 days.

[0155] In some embodiments, the process for preparing crystalline form X comprises step (a), further comprising obtaining a clear solution of the mixture, and the process further comprises step (b) adding an ionic liquid. In some embodiments, the ionic liquid is 1-butyl-3-methylimidazolium chloride.

[0156] In some embodiments, the process for preparing crystalline form X further comprises (c) evaporating the solvent. In some embodiments, the evaporation occurs at about 25° C. In some embodiments, the evaporation continues for about 7 days.

[0157] In some embodiments, the process for preparing crystalline form X further comprises the step of (d) storing the mixture at about 5° C. In some embodiments, step (d) comprises storing the mixture at about 5° C. for about 3 days.

[0158] In some embodiments, the process for preparing crystalline form X includes step (a) further comprising forming a saturated solution, the process further comprising step (b) cooling the solution to form a clear solution. In some embodiments, the cooling is from about 50° C. to about 5° C. In some embodiments, the cooling time ranges from about 6 hours to about 9 hours.

[0159] In some embodiments, the process for preparing crystalline form X further comprises (c) evaporating the solvent. In some embodiments, the evaporation occurs at about 25° C. In some embodiments, the evaporation continues for about 5 days.

[0160] In some embodiments, the process for preparing crystalline form X further comprises the step of (d) storing the mixture at about −14° C. In some embodiments, step (d) comprises storing the mixture at about −14° C. for about 3 days.

[0161] In some embodiments, the process for preparing crystalline form X comprises a solvent in step (a) comprising one or more selected from the group consisting of acetone, acetonitrile (ACN), n-butyl acetate, cyclohexane, dichloromethane (DCM), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl acetate (EtOAc), ethanol (EtOH), water, n-heptane, isopropyl alcohol (IPA), isopropyl acetate (IPAc), methanol (MeOH), methyl tetrahydrofuran (MeTHF), methyl isobutyl ketone (MIBK), methyl tert-butyl ether (MTBE), NMP, pentane, and toluene.

[0162] In some embodiments, the process for preparing crystalline form X comprises a solvent in step (a) selected from the group consisting of cyclohexane, water, n-heptane, IPA, MTBE, EtOH, pentane, toluene, cyclohexane / acetone (3:2, vol:vol), water / DMF (2:1, vol:vol), n-heptane / ethyl acetate (3:2, vol:vol), pentane / acetone (3:2, vol:vol), toluene / DMSO (3:2, vol:vol), toluene / DMF (3:2, vol:vol), and butyl acetate / ACN (1:1, vol:vol).

[0163] In some embodiments, the process for preparing crystalline form X comprises a solvent in step (a) selected from the group consisting of cyclohexane, water, n-heptane, IPA, MTBE, EtOH, pentane, toluene, butyl acetate / DCM (1:1, vol:vol), cyclohexane / butyl acetate (1:1, vol:vol), EtOH / DMF (3:2, vol:vol), EtOH / DMSO (3:2, vol:vol), n-heptane / acetone (3:2, vol:vol), water / DMF (3:2, vol:vol), and water / DMSO (3:3, vol:vol).

[0164] In some embodiments, the process for preparing crystalline form X includes an anti-solvent in step (b) selected from the group consisting of cyclohexane, water, n-heptane, IPA, MTBE, and pentane.

[0165] In some embodiments, the process for preparing crystalline form X includes an anti-solvent in step (b) selected from the group consisting of water, n-heptane, toluene, and pentane.

[0166] In some embodiments, the process for preparing crystalline form X includes a volatile solvent selected from the group consisting of acetone, DMF, DMSO, EtOAc, MeTHF, NMP, MIBK, DMF / ethyl acetate (3:2, vol:vol), DMSO / ethyl acetate (3:2, vol:vol), and acetone / DMF (2:3 vol:vol).

[0167] In some embodiments, the process for preparing crystalline form X includes the solvent in step (a) being DMF, DMSO, acetone, and EtOAc.

[0168] In some embodiments, the process for preparing crystalline form X includes an anti-solvent in step (b) selected from the group consisting of toluene, water, n-heptane, and pentane.

[0169] In some embodiments, the process for preparing crystalline form X comprises a solvent in step (a) selected from the group consisting of NMP, acetone, DMF, DMSO, EtOAc, MeTHF, MIBK, DMF / ethyl acetate (3:2, vol:vol), and DMSO / ethyl acetate (3:2, vol:vol).

[0170] In some embodiments, the process for preparing crystalline form X comprises a solvent in step (a) selected from the group consisting of EtOH, IPAc, MeOH, MTBE, MIBK, CAN, acetone, NMP, toluene, and MeTHF.

[0171] In some embodiments, the process for preparing crystalline form X comprises a solvent in step (a) selected from the group consisting of NMP, acetone, DMF, DMSO, EtOAc, MeTHF, MIBK, acetone / DMF (2:3, vol:vol), acetone / DMSO (2:3, vol:vol), and DMF / ethyl acetate (3:2, vol:vol).

[0172] In some embodiments, the process for preparing crystalline form X comprises a solvent in step (a) selected from the group consisting of DMSO, EtOAc, MeTHF, MIBK, NMP, DMF, DMF / EtOAc (3:2, vol:vol), DMSO / EtOAc (3:2, vol:vol), acetone / DMF (2:3, vol:vol), and acetone / DMSO (2:3, vol:vol).

[0173] Also provided herein is an amorphous form of 1-(4-((4-((4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b]thiepin-5-yl)phenoxy)methyl)benzyl)-1,4-diazabicyclo[2.2.2]octan-1-ium chloride (Formula III) characterized by an amorphous content of at least about 80%. In some embodiments, the amorphous form of the compound of Formula III is characterized by an XRPD pattern substantially similar to the XRPD pattern of FIG. 9.

[0174] In some embodiments, the amorphous form of the compound of Formula III is characterized by a DSC thermogram substantially similar to the DSC thermogram of FIG.

[0175] In some embodiments, the amorphous form of the compound of formula III is characterized by an amorphous content of at least about 85%.

[0176] In some embodiments, the amorphous form of the compound of formula III is characterized by an amorphous content of at least about 90%.

[0177] In some embodiments, the amorphous form of the compound of formula III is characterized by an amorphous content of at least about 95%.

[0178] In some embodiments, the amorphous form of the compound of formula III is characterized by an amorphous content of at least about 96%.

[0179] In some embodiments, the amorphous form of the compound of formula III is characterized by an amorphous content of at least about 97%.

[0180] In some embodiments, the amorphous form of the compound of formula III is characterized by an amorphous content of at least about 98%.

[0181] In some embodiments, the amorphous form of the compound of formula III is characterized by an amorphous content of at least about 99%.

[0182] In some embodiments, the amorphous form of the compound of Formula III is characterized by an amorphous content of about 100%.

[0183] Also provided herein is a process for preparing the amorphous form, which process comprises (a) mixing the compound of formula III with methanol, and (b) evaporating the solvent by rotary evaporation.

[0184] Provided herein is a highly pure compound 1-(4-((4-((4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b]thiepin-5-yl)phenoxy)methyl)benzyl)-1,4-diazabicyclo[2.2.2]octan-1-ium chloride (Formula III): [ka] Also provided is a process for producing the highly pure compound (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (Formula I): [ka] to the highly pure compound (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-hydroxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (Formula II): [ka] The step of converting the

[0185] In some embodiments, the process for producing a highly pure compound of formula III comprises converting a highly pure compound of formula I to a purity of at least about 90%.

[0186] In some embodiments, the process for producing a highly pure compound of formula III comprises converting a highly pure compound of formula I to a purity of at least about 95%.

[0187] In some embodiments, the process for producing a highly pure compound of formula III comprises converting a highly pure compound of formula I to a purity of at least about 96%.

[0188] In some embodiments, the process for producing a highly pure compound of formula III comprises converting a highly pure compound of formula I to a purity of at least about 97%.

[0189] In some embodiments, the process for producing a highly pure compound of formula III comprises converting a highly pure compound of formula I to a purity of at least about 98%.

[0190] In some embodiments, the process for producing a highly pure compound of formula III comprises converting a highly pure compound of formula I to a purity of at least about 98.5%.

[0191] In some embodiments, the process for producing a highly pure compound of formula III comprises converting a highly pure compound of formula I to a purity of at least about 99%.

[0192] In some embodiments, the process for producing a highly pure compound of formula III comprises converting a highly pure compound of formula I to about 100% purity.

[0193] In some embodiments, the process for producing a highly pure compound of formula III comprises converting a highly pure compound of formula I to a highly pure compound of formula II that is at least about 90% pure.

[0194] In some embodiments, the process for producing a highly pure compound of formula III comprises converting a highly pure compound of formula I to a highly pure compound of formula II that is at least about 95% pure.

[0195] In some embodiments, the process for producing a highly pure compound of formula III comprises converting a highly pure compound of formula I to a highly pure compound of formula II that is at least about 96% pure.

[0196] In some embodiments, the process for producing a highly pure compound of formula III comprises converting a highly pure compound of formula I to a highly pure compound of formula II that is at least about 97% pure.

[0197] In some embodiments, the process for producing a highly pure compound of formula III comprises converting a highly pure compound of formula I to a highly pure compound of formula II that is at least about 98% pure.

[0198] In some embodiments, the process for producing a highly pure compound of formula III comprises converting a highly pure compound of formula I to a highly pure compound of formula II that is at least about 98.5% pure.

[0199] In some embodiments, the process for producing a highly pure compound of formula III comprises converting a highly pure compound of formula I to a highly pure compound of formula II that is at least about 99% pure.

[0200] In some embodiments, the process for producing a highly pure compound of formula III comprises converting a highly pure compound of formula I to a highly pure compound of formula II that is about 100% pure.

[0201] In some embodiments, the process produces a highly pure compound of formula III, at least about 90% pure.

[0202] In some embodiments, the process produces a highly pure compound of formula III, at least about 95% pure.

[0203] In some embodiments, the process produces a highly pure compound of formula III, at least about 96% pure.

[0204] In some embodiments, the process produces a highly pure compound of formula III, at least about 97% pure.

[0205] In some embodiments, the process produces a highly pure compound of formula III having a purity of at least about 98%.

[0206] In some embodiments, the process produces a highly pure compound of formula III, at least about 98.5% pure.

[0207] In some embodiments, the process produces a highly pure compound of formula III, at least about 99% pure.

[0208] In some embodiments, the process produces a highly pure compound of formula III, about 100% pure.

[0209] In some embodiments, the process for producing a highly pure compound of formula III comprises converting a highly pure compound of formula I, wherein the compound of formula I is in a crystalline form.

[0210] In some embodiments, the process for producing a highly pure compound of formula III comprises converting a highly pure compound of formula I, wherein the compound of formula I is crystalline form A.

[0211] In some embodiments, the process for producing a high-purity compound of formula III comprises converting a high-purity compound of formula I to a high-purity compound of formula II, wherein the compound of formula II is in a crystalline form.

[0212] In some embodiments, the process for producing a high-purity compound of formula III comprises converting a high-purity compound of formula I to a high-purity compound of formula II, wherein the compound of formula II is crystalline form X.

[0213] In some embodiments, the process for producing a high purity compound of formula III comprises converting a high purity compound of formula I to a high purity compound of formula II, wherein the compound of formula III is in a crystalline form.

[0214] In some embodiments, the process for producing a high-purity compound of formula III comprises converting a high-purity compound of formula I to a high-purity compound of formula II, wherein the compound of formula III is in crystalline form I.

[0215] In some embodiments, the process for producing a high-purity compound of formula III comprises converting a high-purity compound of formula I to a high-purity compound of formula II, wherein the compound of formula III is crystalline form II.

[0216] Provided herein is a highly pure compound 1-(4-((4-((4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b]thiepin-5-yl)phenoxy)methyl)benzyl)-1,4-diazabicyclo[2.2.2]octan-1-ium chloride (Formula III): [ka] A process for producing the compound (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (Formula I): [ka] Crystalline Form A of the compound (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-hydroxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (Formula II): [ka] The method comprises converting the compound into crystalline form X of the formula (I).

[0217] In some embodiments, the process produces a highly pure compound of formula III, at least about 90% pure.

[0218] In some embodiments, the process produces a highly pure compound of formula III, at least about 95% pure.

[0219] In some embodiments, the process produces a highly pure compound of formula III, at least about 96% pure.

[0220] In some embodiments, the process produces a highly pure compound of formula III, at least about 97% pure.

[0221] In some embodiments, the process produces a highly pure compound of formula III, at least about 98% pure.

[0222] In some embodiments, the process produces a highly pure compound of formula III, at least about 98.5% pure.

[0223] In some embodiments, the process produces a highly pure compound of formula III, at least about 99% pure.

[0224] In some embodiments, the process produces a highly pure compound of formula III, about 100% pure.

[0225] In some embodiments, a process for producing a highly pure crystalline form of a compound of formula III. In some embodiments, a process for producing a highly pure crystalline form I of a compound of formula III. In some embodiments, a process for producing a highly pure crystalline form II of a compound of formula III.

[0226] How to use Also provided herein is a method for treating a cholestatic liver disease or condition in a subject in need thereof, comprising administering a therapeutically effective amount of highly pure crystalline Form II of compound of Formula III prepared by the above process.

[0227] Also provided herein is a method for treating a cholestatic liver disease or condition in a subject in need thereof, comprising administering a therapeutically effective amount of highly pure crystalline Form II of compound of Formula III prepared by the above process.

[0228] Also provided herein is a method of treating a cholestatic liver disease or condition in a subject in need thereof, comprising administering a therapeutically effective amount of an amorphous form of the compound of Formula III.

[0229] In some embodiments, the cholestatic liver disease is progressive familial intrahepatic cholestasis (PFIC), biliary atresia, Alagille syndrome (ALGS), intrahepatic cholestasis of pregnancy (ICP), or any pediatric cholestatic condition that results in less than normal growth, height, or weight. In some embodiments, the cholestatic liver disease is biliary atresia. In various embodiments, the cholestatic liver disease is PFIC. In various embodiments, PFIC is selected from PFIC type 1, PFIC type 2, PFIC type 3, PFIC type 4, PFIC type 5, and PFIC type 6. In some embodiments, PFIC is selected from PFIC type 1, PFIC type 2, and PFIC type 3. In some embodiments, PFIC is PFIC type 2. In some embodiments, the subject has an ABCB11 gene that has a missense mutation and does not have a truncating mutation. In some embodiments, the cholestatic liver disease is ALGS. In some embodiments, the cholestatic liver disease is PFIC. In various embodiments, the cholestatic liver disease is ICP.

[0230] In some embodiments, the cholestatic liver disease or condition to be treated is obstructive cholestasis, non-obstructive cholestasis, extrahepatic cholestasis, intrahepatic cholestasis, primary intrahepatic cholestasis, secondary intrahepatic cholestasis, progressive familial intrahepatic cholestasis (PFIC), PFIC type 1, PFIC type 2, PFIC type 3, benign recurrent intrahepatic cholestasis (BRIC), BRIC type 1, BRIC type 2, BRIC type 3, total parenteral nutrition associated cholestasis, paraneoplastic cholestasis, Stauffer syndrome, intrahepatic cholestasis of pregnancy, contraceptive-associated cholestasis, drug-associated cholestasis, cholestasis, infection-associated cholestasis, Dubin-Johnson syndrome, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), gallstone disease, Alagille syndrome, Dubin-Johnson syndrome, biliary atresia, post-Kasai operation biliary atresia, post-liver transplant biliary atresia, post-liver transplant cholestasis, post-liver transplant associated liver disease, intestinal failure associated liver disease, bile acid mediated liver injury, MRP2 deficiency syndrome, and neonatal sclerosing cholangitis.

[0231] In some embodiments, the cholestatic liver disease or condition is Alagille syndrome (ALGS).

[0232] Alagille Syndrome Alagille syndrome is a genetic disorder affecting the liver and other organs. It often manifests during infancy (e.g., 6–18 months of age) or early childhood (e.g., 3–5 years of age) and may stabilize after age 10. Symptoms may include chronic progressive cholestasis, bile duct cystopenia, jaundice, pruritus, xanthomas, congenital heart defects, paucity of intrahepatic bile ducts, poor linear growth, hormone resistance, posterior embryotoxon, Axenfeld anomaly, retinitis pigmentosa, pupillary abnormalities, heart murmurs, atrial septal defect, ventricular septal defect, patent ductus arteriosus, and tetralogy of Fallot. Individuals diagnosed with Alagille syndrome have been treated with ursodiol, hydroxyzine, cholestyramine, rifampicin, and phenobarbitol. Due to a reduced ability to absorb fat-soluble vitamins, individuals with Alagille syndrome are additionally administered high-dose multivitamins.

[0233] In some embodiments, the cholestatic liver disease is associated with progressive familial intrahepatic cholestasis (PFIC).

[0234] Progressive familial intrahepatic cholestasis (PFIC) PFIC is a rare genetic disorder that causes progressive liver disease, typically resulting in liver failure. In individuals with PFIC, liver cells have a reduced ability to secrete bile. The resulting accumulation of bile leads to liver disease in affected individuals. Signs and symptoms of PFIC typically begin in infancy. Patients experience severe itching, jaundice, failure to grow at the expected rate (failure to thrive), and increasing liver dysfunction (liver failure). The disease is estimated to affect 1 in 50,000 to 100,000 live births in the United States and Europe. Six types of PFIC have been genetically identified, all of which are similarly characterized by impaired bile flow and progressive liver disease.

[0235] PFIC1 PFIC1 (also known as Byler disease or FIC1 deficiency) is associated with mutations in the ATP8B1 gene (also called FIC1). This gene, encoding a P-type ATPase, is located on human chromosome 18 and is also mutated in milder phenotypes, benign recurrent intrahepatic cholestasis type 1 (BRIO) and Greenland familial cholestasis. The FIC1 protein is located in the canalicular membrane of hepatocytes, but is primarily expressed in cholangiocytes within the liver. The P-type ATPase appears to be an aminophospholipid transporter responsible for maintaining the enrichment of phosphatidylserine and phosphatidylethanolamine in the inner leaflet of the plasma membrane compared with the outer leaflet. The asymmetric distribution of lipids in the membrane bilayer plays a protective role against high bile salt concentrations in the canalicular lumen. Abnormal protein function may indirectly interfere with biliary secretion of bile acids. Abnormal secretion of bile acids / salts leads to hepatocellular bile acid overload.

[0236] PFIC1 typically presents in infants (e.g., 6–18 months of age). Infants may exhibit signs of pruritus, jaundice, abdominal distension, diarrhea, malnutrition, and short stature. Biochemically, individuals with PFIC1 have elevated serum transaminases, elevated bilirubin, elevated serum bile acid levels, and low γGT levels. They may also have liver fibrosis. Individuals with PFIC1 typically lack bile duct proliferation. Most individuals with PFIC1 develop end-stage liver disease by age 10. No medical treatment has proven beneficial for the long-term treatment of PFIC1. Children are often given medium-chain triglycerides and fat-soluble vitamins to alleviate extrahepatic symptoms (e.g., malnutrition and growth failure). Ursodiol has not been proven effective in individuals with PFIC1.

[0237] PFIC2 PFIC2 (also known as Byler syndrome or BSEP deficiency) is associated with mutations in the ABCB11 gene (also called BSEP). The ABCB11 gene encodes the ATP-dependent canalicular bile salt export pump (BSEP) in the human liver and is located on human chromosome 2. The BSEP protein, expressed in the hepatocyte canalicular membrane, is the major exporter of primary bile acids / salts against extreme concentration gradients. Mutations in this protein are responsible for the reduced bile salt secretion described in affected patients, resulting in reduced bile flow and intrahepatic bile salt accumulation, accompanied by ongoing severe hepatocellular damage.

[0238] PFIC2 typically presents in infants (e.g., 6–18 months of age). Infants may exhibit signs of pruritus. Biochemically, individuals with PFIC2 have elevated serum transaminases, elevated bilirubin, elevated serum bile acid levels, and low γGT levels. They may also have portal vein inflammation and giant cell hepatitis. Additionally, individuals often develop hepatocellular carcinoma. No treatment has proven beneficial for the long-term treatment of PFIC2. To alleviate extrahepatic symptoms (e.g., malnutrition and growth failure), children are often given medium-chain triglycerides and fat-soluble vitamins. PFIC2 patients account for approximately 60% of the PFIC population.

[0239] PFIC3 PFIC3 (also known as MDR3 deficiency) is caused by a genetic defect in the ABCB4 gene (also known as MDR3) located on chromosome 7. Class III multidrug resistance (MDR3) P-glycoprotein (P-gp) is a phospholipid translocator involved in the export of bile phospholipids (phosphatidylcholine) across the canalicular membrane of hepatocytes. PFIC3 results from bile toxicity, in which surfactant bile salts are not inactivated by phospholipids, causing damage to the bile canaliculi and bile duct epithelium.

[0240] PFIC3 also develops in early childhood. In contrast to PFIC1 and PFIC2, individuals have elevated γGT levels. Individuals also have portal vein inflammation, fibrosis, cirrhosis, and massive bile duct proliferation. Individuals may also develop intrahepatic cholelithiasis. Ursodiol is effective in treating or improving PFIC3.

[0241] PFIC4 PFIC4 (also known as beta-hydroxy-delta-5-C27-steroid oxidoreductase deficiency or TJP2 deficiency) is caused by homozygous or compound heterozygous mutations in the TJP2 gene (607709) on chromosome 9q21. The TJP2 protein (also known as tight junction protein 2, ZO2) plays a role in "tight junctions," which are regions where the membranes of two adjacent cells join to form a barrier. The barrier controls which molecules can pass between cells. Such junctions are important throughout the body, and TJP2 is not specific to the liver. A mild form of liver disease associated with mutations in the TPJ2 gene was previously called familial hypercholanemia (meaning high bile salts in the blood). Because only a small number of patients with PFIC caused by TJP2 mutations have been studied to date, it is not yet known what symptoms TJP2-deficient patients may have beyond liver disease and its consequences.

[0242] Children with TJP2-related cholestasis (PFIC-4) have a heterogeneous presentation spectrum. Some have self-limited disease, while others have progressive liver disease with a high risk of hepatocellular carcinoma. Therefore, frequent surveillance for hepatocellular carcinoma is recommended, beginning in infancy.

[0243] PFIC5 PFIC5 (also known as FXR deficiency) is caused by mutations in the NR1H4 gene, which encodes the FXR (farnesoid X receptor) protein. This protein is important in regulating bile acid metabolism in the liver and intestine as well as other aspects of metabolism. Patients with PFIC due to FXR deficiency (PFIC5) appear to develop rapidly progressive liver disease, potentially very early in infancy. Because this cause of PFIC has only recently been described, it is expected that more patients will be identified in the future, but only a small number of patients have been reported to date.

[0244] Patients with PFIC-5 typically suffer from rapidly progressive liver disease, early development of blood clotting disorders, elevated alpha-fetoprotein, and ultimately the need for liver transplantation.

[0245] PFIC6 PFIC6, also known as MYO5B deficiency, is the most recently identified type of PFIC. MYO5B is involved in maintaining the proper function of cell membranes and helps proteins such as BSEP move to where they are needed. MYO5B has been associated with intestinal damage, cholestasis, or both. Some patients with cholestasis due to MYO5B deficiency have progressive liver disease, while others experience only intermittent disease. Subjects with MYO5B-related disorders may present with isolated cholestasis or cholestasis with refractory diarrhea (MVID). Because these children are at risk for worsening cholestasis after small intestinal transplantation (IT) for MVID, a combination of small intestinal transplantation and liver transplantation or IT combined with biliary diversion is preferred.

[0246] Immunohistochemistry can distinguish most PFIC variants, but genetic analysis is required for confirmation.

[0247] Benign recurrent intrahepatic cholestasis (BRIC) BRIC1 BRIC1 is caused by a genetic defect in the FIC1 protein in the bile canalicular membrane of hepatocytes. BRIC1 is typically associated with normal serum cholesterol and gamma-glutamyl transpeptidase levels but elevated serum bile salts. Residual FIC1 expression and function are associated with BRIC1. Despite repeated attacks of cholestasis or cholestatic liver disease, the majority of patients do not progress to chronic liver disease. During attacks, patients develop severe jaundice and experience pruritus, steatorrhea, and weight loss. Some patients also have kidney stones, pancreatitis, and diabetes.

[0248] BRIC2 BRIC2 is caused by mutations in ABCB11, resulting in defective BSEP expression and / or function in the bile canalicular membrane of hepatocytes.

[0249] BRIC3 BRIC3 is associated with defective MDR3 expression and / or function in the canalicular membrane of hepatocytes. Patients with MDR3 deficiency typically exhibit elevated serum gamma-glutamyl transpeptidase levels in the presence of normal or slightly elevated bile acid levels.

[0250] biliary atresia Biliary atresia is a life-threatening condition in infants whose bile ducts, either inside or outside the liver, lack normal openings. In biliary atresia, bile becomes trapped, builds up, and damages the liver. The damage leads to scarring, loss of liver tissue, and cirrhosis. Without treatment, the liver eventually fails, and the infant requires a liver transplant to survive. The two types of biliary atresia are fetal and perinatal. Fetal biliary atresia manifests while the baby is in the womb. Perinatal biliary atresia is more common and does not become apparent until 2 to 4 weeks after birth.

[0251] Biliary atresia after Kasai operation Biliary atresia is treated with a surgical procedure called the Kasai procedure or a liver transplant. The Kasai procedure is usually the first treatment for biliary atresia. During the Kasai procedure, a pediatric surgeon removes the infant's damaged bile ducts and replaces them with a loop of intestine. While the Kasai procedure can restore biliary flow and correct many problems caused by biliary atresia, the surgery does not cure the disease. If the Kasai procedure is unsuccessful, the infant usually requires a liver transplant within one to two years. Even after successful surgery, most infants with biliary atresia slowly develop cirrhosis over the years and require a liver transplant by adulthood. Possible complications after the Kasai procedure include ascites, bacterial cholangitis, portal hypertension, and pruritus.

[0252] Biliary atresia after liver transplantation Once complete atresia occurs, liver transplantation is the only option. Although liver transplantation is generally successful in treating biliary atresia, liver transplantation can lead to complications, such as organ rejection. Also, donor livers may become unavailable. Furthermore, in some patients, liver transplantation may not be successful in curing biliary atresia.

[0253] xanthomas Xanthomas are a skin condition associated with cholestatic liver disease, in which certain fats accumulate beneath the skin's surface. Cholestasis causes several disturbances in lipid metabolism, leading to the formation of abnormal lipid particles in the blood called lipoprotein X. Lipoprotein X is formed by the reflux of bile lipids from the liver into the blood and does not bind to LDL receptors to deliver cholesterol to cells throughout the body like normal LDL. Lipoprotein X increases hepatic cholesterol production fivefold and blocks the liver's normal removal of lipoprotein particles from the blood.

[0254] Acquired cholestatic disorders Pediatric primary sclerosing cholangitis (PSC) Pediatric PSC is a chronic inflammatory liver disorder that slowly progresses to end-stage liver failure in most affected individuals. The inflammation in pediatric PSC is marked by fibrosis and obstruction of large and medium-sized intrahepatic and extrahepatic bile ducts.

[0255] cholelithiasis Cholelithiasis is one of the most common and costly gastrointestinal diseases, with a prevalence of up to 17% among white women. Cholesterol-containing gallstones are the predominant form of gallstones, and therefore supersaturation of bile with cholesterol is a prerequisite for gallstone formation. Mutations in ABCB4 may be involved in the pathogenesis of cholesterol cholelithiasis.

[0256] Drug-induced cholestasis Drug-induced inhibition of BSEP function is an important mechanism of drug-induced cholestasis, leading to hepatic accumulation of bile salts and subsequent hepatocellular injury. Several drugs have been implicated in BSEP inhibition. Most of these drugs, such as rifampicin, cyclosporine, glibenclamide, or troglitazone, directly inhibit ATP-dependent taurocholate transport in a competitive manner through cis-inhibition, whereas estrogen and progesterone metabolites indirectly inhibit BSEP through trans-inhibition after secretion into the bile canaliculi by Mrp2. Alternatively, drug-mediated stimulation of MRP2 may promote cholestasis or cholestatic liver disease by altering bile composition.

[0257] Total Parenteral Nutrition Associated Cholestasis (TPNAC ) TPNAC represents one of the most serious clinical scenarios, characterized by the rapid development of cholestasis or cholestatic liver disease and a high risk of early death. Infants, usually premature and those who have undergone intestinal resection, rely on TPN for growth and frequently develop cholestasis or cholestatic liver disease, which rapidly progresses to fibrosis, cirrhosis, and portal hypertension, usually before 6 months of age. The extent of cholestasis or cholestatic liver disease and the likelihood of survival in these infants are related to the number of sepsis episodes, likely initiated by repeated bacterial translocation across the intestinal mucosa. While cholestatic effects from intravenous preparations may also play a role in these infants, sepsis mediators likely contribute most to altered liver function.

[0258] In some embodiments, the compound of formula III reduces serum or liver bile acid levels in a patient by at least about 20%, at least about 30%, or at least about 40%.

[0259] In some embodiments, less than 10% of the compound of formula III is systemically absorbed upon oral administration.

[0260] In some embodiments, the compound of formula III is administered at a dosage of about 10 μg / kg / day to about 10 mg / kg / day.

[0261] In some embodiments, the compound of formula III is administered at a dosage of about 140 μg / kg / day to about 1 mg / kg / day.

[0262] In some embodiments, the compound of formula III is administered at a dosage of about 280 μg / kg / day to about 800 μg / kg / day.

[0263] In some embodiments, the compound of formula III is administered in a dosage comprising from about 0.1 mg to about 40 mg.

[0264] In some embodiments, the compound of formula III reduces serum or liver bile acid levels, reduces bilirubin, reduces liver enzymes, reduces intestinal bile acids / salts, or reduces necrosis of and / or damage to hepatocellular structures.

[0265] In some embodiments, the compound of formula III reduces pruritus.

[0266] In some embodiments, the compound of Formula III is administered with a second agent selected from a bile acid sequestrant or bile acid binding agent.

[0267] In some embodiments, the compound of formula III is administered before ingestion of food.

[0268] In some embodiments, the compound of formula III is administered less than about 60 minutes or less than about 30 minutes before ingestion of food.

[0269] In some embodiments, the compound of formula III is administered orally.

[0270] In some embodiments, the compound of formula III is administered in an ileal-pH sensitive release formulation or an enteric-coated formulation.

[0271] In some embodiments, the compound of Formula III is administered with a vitamin supplement.

[0272] In some embodiments, the vitamin supplement comprises a fat-soluble vitamin.

[0273] In some embodiments, the fat-soluble vitamin is selected from the group consisting of vitamins A, D, E, or K.

[0274] Also provided herein are crystalline Form I, crystalline Form II, and / or amorphous forms of highly pure 1-(4-((4-((4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b]thiepin-5-yl)phenoxy)methyl)benzyl)-1,4-diazabicyclo[2.2.2]octan-1-ium chloride (Formula III), which forms of Formula III are highly pure (4R,5R)-3,3- It is prepared by a process comprising converting crystalline form A of dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (Formula I) into crystalline form X of highly pure (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-hydroxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (Formula II).

[0275] Also provided herein are methods for treating a cholestatic liver disease or condition in a subject in need thereof, comprising administering a therapeutically effective amount of highly pure crystalline Form I, crystalline Form II, and / or amorphous form of the compound of Formula III.

[0276] Provided herein is 1-(4-((4-((4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b]thiepin-5-yl)phenoxy)methyl)benzyl)-1,4-diazabicyclo[2.2.2]octan-1-ium chloride (Formula III): [ka] Also provided is a composition comprising one or more of the following: (a) about 1.0% or less to 0.30% or less, or about 0.01% or less, of 1-(4-((4-((4S,5S)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b]thiepin-5-yl)phenoxy)methyl)benzyl)-1,4-diazabicyclo[2.2.2]octan-1-ium (Compound VI-Cl-A); [ka] (b) about 0.50% or less to about 0.30% or less, or about 0.01% or less, of 1-(4-(((4-((4-((4-((4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b]thiepin-5-yl)phenoxy)methyl)benzyl)oxy)methyl)benzyl)-1,4-diazabicyclo[2.2.2]octan-1-ium (Compound VI-Cl-B): [ka] (c) about 0.50% or less to about 0.30% or less, or about 0.01% or less, of 1-(4-((4-((4R,5R)-3,3-dibutyl-4-hydroxy-7-(methylamino)-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b]thiepin-5-yl)phenoxy)methyl)benzyl)-1,4-diazabicyclo[2.2.2]octan-1-ium (Compound VI-Cl-C): [ka] (d) about 0.50% or less to about 0.30% or less, or about 0.01% or less, of 1-(4-((4-((4R,5R)-3,3-dibutyl-4-hydroxy-7-(N-methylformamido)-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b]thiepin-5-yl)phenoxy)methyl)benzyl)-1,4-diazabicyclo[2.2.2]octan-1-ium (Compound VI-Cl-D): [ka] (e) about 0.50% or less to about 0.30% or less, or about 0.01% or less, of (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-hydroxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (Formula II): [ka] (f) about 0.50% or less to about 0.30% or less, or about 0.01% or less, of (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-((4-(hydroxymethyl)benzyl)oxy)phenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (Formula VIII): [ka] (g) about 0.50% or less to about 0.30% or less of 1,1'-(1,4-phenylenebis(methylene))bis(1,4-diazabicyclo[2.2.2]octan-1-ium) (Formula IV): [ka]

[0277] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. Any and all examples provided herein, or the use of exemplary language (e.g., "etc.") are intended merely to better illustrate the disclosure and do not limit the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

[0278] Preferred embodiments of the present disclosure are described herein, including the best mode known to the inventors for carrying out the disclosure. Variations of these preferred embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors anticipate that skilled artisans will employ such variations as appropriate, and the inventors intend for the present disclosure to be practiced otherwise than as specifically described herein. Accordingly, this disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Furthermore, this disclosure encompasses any combination of the above-described elements in all possible variations thereof unless otherwise indicated herein or clearly contradicted by context.

[0279] All references, including publications, patent applications, and patents, referred to in this specification are herein incorporated by reference to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein. [Example]

[0280] Example 1 Apparatus and Method 1.1 XRPD XRPD was performed using a Panalytical X'Pert Powder XRPD on a Si zero background holder. 20 positions were calibrated against a Panalytical Si reference standard disk. The instrument parameters used are listed in Table 1-1. [Table 1-1]

[0281] 1.2TGA / DSC TGA data were collected using a TA Instrument TA Discovery 550 TGA. DSC was performed using a TA Instrument TA Q2000 DSC. The DSC was calibrated with an indium reference standard and the TGA was calibrated with a nickel reference standard. The detailed parameters used are listed in Table 1-2. [Table 1-2]

[0282] 1.3 PLM Polarized light microscopy (PLM) photographs were taken at room temperature with a Nikon DS-Fi2 upright microscope. Low-viscosity microscope immersion oil (Resolve®) was used to disperse the powder crystals. The following examples use the equipment and methods described in Example 1.

[0283] Example 2. Synthesis and Characterization of Compounds of Formula I 2.1 Synthesis of Compounds of Formula I The synthesis process is outlined in the flow diagram below. [ka]

[0284] As shown in Scheme 1, the compound of Formula I is synthesized by (a) cyclizing the acyclic precursor 2-butyl-2-(((4-(dimethylamino)-2-(4-methoxybenzyl)phenyl)sulfonyl)methyl)heptanal with potassium tert-butoxide (KOtBu) in tetrahydrofuran (THF) to produce a 1:1 racemic mixture of R,R and S,S stereoisomers; and separating the R,R and S,S stereoisomers by simulated moving bed (SMB) chromatography to obtain the isolated R,R stereoisomer of Formula I.

[0285] In another embodiment, recycling and racemization of the undesired S,S stereoisomer with KOtBu in THF in Scheme 1 produces a 1:1 racemic mixture of R,R and S,S isomers.

[0286] In some embodiments, the mobile phase used in SMB conditions is an inert solvent such as acetone, methyltetrahydrofuran (MeTHF), dichloromethane (DCM), pyridine, chlorobenzene (PhCl), methyl acetate (MeOAc), ethyl acetate (EtOAc), benzene, toluene, methyl tert-butyl ether (MtBE), and n-heptane.

[0287] In another embodiment, the mobile phases used in SMB conditions were 70 / 30 n-heptane:DCM, 70 / 30 PhCl:n-heptane, and 90 / 10 toluene:n-heptane.

[0288] In some embodiments, the immobilized chiral stationary phases (CSPs) were Chiralpak IA, Chiralpak OD-I(IB), Chiralpak IC, Chiralpak ID, Chiralpak IE, Chiralpak IF, Regis Whelk, O-2, Regis ULMO, Regis DACH-DMB, Regis Burke, Shiseido Ceramospher RU-1, and Shiseido Ceramospher RU-2.

[0289] In some embodiments, crystalline form A of the compound of Formula I was prepared from a solvent such as isopropanol, ethanol (EtOH), methanol (MeOH), ACN, acetone, methyltetrahydrofuran (MeTHF), dichloromethane (DCM), pyridine, chlorobenzene (PhCl), methyl acetate (MeOAc), ethyl acetate (EtOAc), benzene, toluene, methyl tert-butyl ether (MtBE), n-heptane, 70 / 30 n-heptane:DCM, 70 / 30 PhCl:n-heptane, and 90 / 10 toluene:n-heptane. In a preferred embodiment, crystalline form A of the compound of Formula I was prepared from an aprotic solvent.

[0290] In some embodiments, the purified crystalline compound of formula I contains no more than about 0.30% to no more than about 0.50% of the S,S stereoisomer.

[0291] The preparation of the compound of Formula I utilized simulated moving bed (SMB) chromatography to separate the desired enantiomer from a racemic mixture. SMB is known for separating racemic mixtures into enantiomers. SMB separation cycles were typically performed two to four times to obtain a sufficient amount of the compound of Formula I for subsequent process steps. This process produced a highly pure compound of Formula I. Other known chiral separation techniques can also be implemented. A sample of the compound of Formula I with 99.5% chiral purity and 100% achiral purity was obtained and characterized using various analytical techniques, and the results are listed in Table 2-1. The polymorphs were characterized by powder X-ray diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and polarized light microscopy (PLM). The XRPD data showed that the compound of Formula I prepared according to Example 2.1 was crystalline and was assigned crystalline form A. [Table 2-1]

[0292] 2.2 Stability Testing of Compounds of Formula I Long-term and accelerated stability studies were carried out using the compound of formula I prepared as described in Example 2.1 as follows. [Table 2-2]

[0293] Twelve-month stability data available under long-term storage conditions are shown in Table 2-3. Additionally, stressed stability in 95 / 5 (v / v) acetonitrile / isopropanol solution was also evaluated (e.g., during SMB separation and subsequent workup). Samples were stored under two different conditions over a 10-day period: at room temperature and in a 60°C oven exposed to light. Stability data are shown in Table 2-4. The purity (in terms of chemical and chiral purity) of the compound of Formula I indicates adequate stability for both the SMB procedure and subsequent workup. [Table 2-3] [Table 2-4]

[0294] 2.3 Crystalline Form A of the Compound of Formula I The compound of Formula I, prepared as described in Example 2.1, was characterized by XRPD, TGA / DSC, and PLM using the same parameters as above. Crystals of Form A of the compound of Formula I were identified based on the XRPD pattern shown in Figure 1. As shown by the TGA and DSC data in Figure 2, there was no weight loss before decomposition, which began at approximately 200 °C. A melting endotherm was observed with an onset temperature of 130.8 °C (onset) and an enthalpy of 47 J / g. Additionally, an endotherm-like event was observed at 255 °C, likely due to a pressure increase due to sample decomposition. Polarized light microscopy (PLM) revealed that the material consisted of rod-shaped crystals (Figure 3).

[0295] 2.4 Crystalline Form B of the Compound of Formula I Form B was obtained from Form A through an anti-solvent addition experiment using ACN / water. Form B was observed only as a wet cake and reverted to Form A upon air drying. XRPD, TGA / DSC, and PLM characterization were performed using the same parameters as above. Figure 4 shows the XRPD of the wet cake. A TGA of Form B was also obtained, showing a weight loss of 45.09% up to 100 °C (Figure 5). Weight loss began immediately upon application of heat and stopped at 75 °C. The wet cake sample was air-dried overnight, and the XRPD of the air-dried cake showed reversion to Form A.

[0296] Example 3. Polymorph Screening of Compounds of Formula I The estimated solubility of the compound of Formula I (starting material, prepared as described above) was measured in 20 different solvents at room temperature. Approximately 2 mg of starting material was added to a 3 mL glass vial. Solvent was then added stepwise to the vial until the solid dissolved or a total volume of 1 mL was reached. (Note: This is not an estimate of thermodynamic solubility; vortexing and sonication were applied between each solvent to accelerate dissolution.) The results, summarized in Table 3-1, were used to guide solvent selection for polymorph screening. Starting with the starting material, polymorph screening experiments were set up using methods such as slurry at different temperatures, slow cooling, liquid and solid vapor diffusion, slow evaporation, anti-solvent addition, and ionic liquids. The methods utilized and the crystalline forms identified are summarized in Table 3-2 (Type A and Form A are used interchangeably, and Type B and Form B are used interchangeably). [Table 3-1] [Table 3-2]

[0297] 3.1 Slurry method at room temperature (RT) A total of 15 room-temperature slurry experiments were performed. For each experiment, approximately 20 mg of starting material was weighed into a 2 mL glass vial, and 0.2 mL of the corresponding solvent was added to form a suspension. The suspension was magnetically stirred at room temperature (25 °C) for 3 days. After 3 days, the suspension was removed from the vial, and a 4-minute XRPD analysis of the wet cake was performed.

[0298] The experimental summary in Table 3-3 below indicates the solvent used in each experiment, its corresponding volume, and indicates that crystalline form A (i.e., Type A) was the only solid form obtained in these experiments. [Table 3-3]

[0299] 3.2 Slurry method at 65°C A total of 15 slurry experiments were performed at 65 °C. For each experiment, approximately 20 mg of starting material was weighed into a 2 mL glass vial and 0.2 mL of the corresponding solvent was added to form a suspension. This suspension was magnetically stirred at 65 °C for 3 days.

[0300] After 3 days, the suspension was skimmed from the vial for 4 min XRPD analysis of the wet cake. The experimental summary in Table 3-4 below indicates the solvent used in each experiment, its corresponding volume, and indicates that crystalline form A (i.e., Type A) was the only solid form obtained in these experiments. [Table 3-4]

[0301] 3.3 Anti-solvent Addition A total of 11 anti-solvent addition experiments were performed. For each experiment, approximately 20 mg of starting material was weighed into a 20 ml glass vial and dissolved in 0.2 mL of the corresponding solvent to obtain a clear solution. These solutions were magnetically stirred at room temperature (25°C), and the corresponding anti-solvent was added dropwise continuously (every 1 second) until crystallization was observed. The resulting precipitate was skimmed from the vial for 4-min XRPD analysis of the wet cake. For samples in which no crystallization was observed, the anti-solvent addition was stopped at 10 mL, and these samples were transferred to 5°C for 3 days. The resulting solid was skimmed from the vial for 4-min XRPD analysis of the wet cake. The experimental summary in Tables 3-5 below shows the solvent used in each experiment and its corresponding volume, indicating that crystalline form A (i.e., Type A), crystalline form B (i.e., Type B), gel, and amorphous were obtained in these experiments. [Table 3-5]

[0302] 3.4 Solid Vapor Diffusion A total of 10 solid vapor diffusion experiments were performed. For each experiment, approximately 20 mg of starting material was weighed into an uncapped 4 mL glass vial and placed in a 20 mL vial filled with approximately 3 mL of volatile solvent. The 20 mL vial was then sealed with a cap and kept at room temperature for 7 days to allow the solvent vapor to interact with the starting material in the 4 mL vial. After 7 days, the solid was removed from the vial and a 4-minute XRPD analysis of the wet cake was performed.

[0303] The vials in which the starting material was completely converted to a liquid after interaction with the solvent vapor were set aside for evaporation for 5 days. After this period, the resulting solid was removed from the vial for 4 min XRPD analysis of the wet cake.

[0304] The experimental summaries in Tables 3-6 below indicate the solvent used in each experiment, its corresponding volume, and indicate that the solid forms obtained in these experiments were crystalline form A (i.e., Type A), gel, and amorphous. [Table 3-6]

[0305] 3.5 Liquid Vapor Diffusion A total of 12 liquid vapor diffusion experiments were performed. For each experiment, approximately 20 mg of starting material was weighed into a 4 mL glass vial and dissolved in the corresponding solvent to obtain a clear solution. This vial was then placed, unsealed, into a 20 mL vial filled with approximately 3 mL of a volatile antisolvent. The 20 mL vial was then sealed with a cap and kept at room temperature (RT) for 7 days to allow the antisolvent vapor to interact with the solution in the 4 mL vial. After 7 days, solids were removed from the vial for 4-min XRPD analysis of the wet cake. Vials in which no solids were observed were set aside for 5 days of evaporation. After this period, the resulting solids were removed from the vial for 4-min XRPD analysis of the wet cake.

[0306] The experimental summaries in Tables 3-7 below indicate the solvent and antisolvent used in each experiment, along with their corresponding volumes, and indicate that crystalline form A (i.e., Type A) was the only solid form obtained in these experiments. [Table 3-7]

[0307] 3.6 Slow Evaporation A total of 10 slow evaporation experiments were performed. For each experiment, approximately 20 mg of starting material was weighed into a 2 mL vial and then dissolved in 0.2 mL of the corresponding solvent to obtain a clear solution. The vial was then covered with Parafilm® with three pinholes and allowed to evaporate at room temperature for 7 days. If no solids were observed after this period, the sample was transferred to 5 °C for 3 days to induce precipitation.

[0308] The resulting solid was removed from the vial for 4 min XRPD analysis of the wet cake.

[0309] The experimental summaries in Tables 3-8 below indicate the solvent used in each experiment, its corresponding volume, and indicate that crystalline form A (i.e., Type A), gel, and amorphous were obtained in these experiments. [Table 3-8]

[0310] 3.7 Ionic Liquids A total of 10 ionic liquid experiments were performed. For each experiment, approximately 20 mg of starting material was weighed into a 2 mL glass vial and then dissolved in 0.1 mL of the corresponding solvent to obtain a clear solution. Approximately 5 mg (25 wt % of the starting material) of the ionic liquid 1-butyl-3-methylimidazolium chloride was added to each glass vial. All samples were allowed to evaporate at room temperature for 7 days to induce precipitation. After this period, no solids were observed, so all samples were transferred to 5 °C for 3 days.

[0311] The resulting solid was removed from the vial for 4 min XRPD analysis of the dried cake. The experimental summary in Tables 3-9 below indicates the solvent used in each experiment, its corresponding volume, and indicates that crystalline form A (i.e., Type A), gel, and amorphous were obtained. [Table 3-9]

[0312] 3.8 Slow Cooling A total of 10 slow-cooling experiments were performed. For each experiment, approximately 20 mg of starting material was weighed into a 2 mL glass vial, and then 0.1 mL of the corresponding solvent was added to form a saturated solution. These solutions were then cooled from 50 °C to 5 °C over 7.5 hours in an incubator. After this period, all solutions were clear (no solids). They were then allowed to slowly evaporate at room temperature for 5 days. Since no solids were observed after 5 days, the samples were transferred to -14 °C for 3 days. After this period, the resulting solids were removed from the vials for 4-min XRPD analysis of the dried cakes.

[0313] The experimental summaries in Tables 3-10 below indicate the solvent used in each experiment, its corresponding volume, and indicate that crystalline form A (i.e., Type A), gel, and amorphous were obtained in these experiments. [Table 3-10]

[0314] As described above, polymorph screening experiments were conducted using the slurry method at different temperatures, slow cooling, liquid and solid vapor diffusion, slow evaporation, antisolvent addition, and ionic liquid methods. Two types of crystalline forms, Form A (anhydrous) and Form B (weak solvate), were obtained from the experiments. Form B was obtained from the wet cake of the antisolvent addition experiment using ACN / water; however, the dried cake reverted to Form A.

[0315] Further investigations were conducted on crystalline form B to better understand the origin of the phase. Form B was successfully regenerated using the same method (antisolvent addition with ACN / water), and the centrifuged wet cake was rapidly tested by TGA, resulting in a 45% weight loss. The air-dried cake again reverted to crystalline form A. Since none of the other experiments involving water or acetonitrile produced form B, form B is either a mixed, highly unstable acetonitrile / water solvate / hydrate or a metastable polymorph.

[0316] Besides crystalline form B (i.e., Type B), no further polymorphs were observed during the remainder of the screening. However, since crystalline form B (i.e., Type B) can easily revert to crystalline form A (i.e., Type A) upon drying, it is concluded that crystalline form A (i.e., Type A) is the most stable form under the conditions tested in this study and is recommended for further development.

[0317] Example 4. Synthesis of Compounds of Formula III The synthetic scheme for preparing malalixibat chloride (Formula III) starting from the compound of Formula I is shown below: Table 4-1 shows the abbreviations for the reagents used in the synthesis. [ka] [Table 4-1]

[0318] The synthesis of the compound of Formula III is a three-stage (four synthetic steps) linear synthesis process. Formula I is demethylated to Formula II, which is then fitted into the three-step process to obtain crude maralixibat. No intermediates are isolated. The crude maralixibat is crystallized to produce maralixibat. Typical batch sizes of maralixibat drug substance vary depending on commercial demand and are expected to be approximately 15-20 kg. Some of the examples provided herein were carried out on a smaller scale (approximately 5 kg). Unless otherwise indicated, all reactions are stirred under a nitrogen atmosphere.

[0319] Step 1 - Synthesis of Compounds of Formula II from Compounds of Formula I Methanesulfonic acid is charged to a reaction vessel, followed by methionine and the compound of Formula I. The mixture is heated and an in-process check (IPC) is performed by HPLC to confirm that the conversion is ≥ 98%. The reaction mixture is diluted with water and extracted with methyl isobutyl ketone (MIBK). The aqueous phase is back-extracted with MIBK. The combined organic phase is washed with aqueous sodium bicarbonate, followed by water. The organic phase is filtered through carbon and distilled to the target volume. The resulting slurry is diluted with heptane to complete the precipitation. The mixture is cooled, and the product is collected by filtration and washed with a mixture of heptane and MIBK. The product is dried under reduced pressure to give the compound of Formula II in approximately 90% yield and 99% purity.

[0320] Step 2 - Synthesis of crude malalixibat from the compound of formula II Step 1—Synthesis of Compounds of Formula IV from Compounds of Formula II A reaction vessel is charged with the compound of formula II, potassium phosphate, 4-(chloromethyl)benzyl alcohol (CMBA, C-003838), and acetone and heated to reflux. HPLC analysis is used for in-process control to confirm that the conversion to the compound of formula IV is ≥97%.

[0321] 1,4-diazabicyclo-[2.2.2]octane is added to the reaction mixture to consume any unreacted CMBA reagent. After in-process control confirms that the CMBA content is 0.05% or less, the mixture is cooled, diluted with toluene, and the organic phase is washed with water. The phases are separated, and the organic phase is concentrated to a target volume under reduced pressure to obtain crude (4R,5R)-3,3-dibutyl-5-[4-[[4-(hydroxymethyl)phenyl]methoxy]phenyl]-7-(dimethylamino)-2,3,4,5-tetrahydro-l-benzothiepin-4-ol 1,1-dioxide (Formula IV) in toluene. The organic solution containing the compound of Formula IV is used in the next step without further purification.

[0322] Step 2—Synthesis of Compounds of Formula V from Compounds of Formula IV The organic solution containing the compound of Formula IV from the previous step is reacted with thionyl chloride diluted in toluene while maintaining the temperature between 20°C ± 5°C. The solution is stirred, and in-process controls are used to ensure that conversion to Formula V reaches ≥ 99%. The reaction mixture is washed with water. After phase separation, the organic phase is washed with 7.4% sodium bicarbonate solution, followed by two additional water washes after each phase separation. The organic phase is concentrated to the target volume under reduced pressure. (4R,5R)-3,3-dibutyl-5-(4-((4-(chloromethyl)benzyl)oxy)phenyl)-7-(dimethylamino)-4-hydroxy-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (Formula V) is used in the next step without further purification.

[0323] Step 3 - Synthesis of crude maralixibat from compound of formula V The solution containing the compound of formula V is added to a heated solution of DABCO in MEK / water containing C-025325 seeds. An HPLC check is performed to confirm that the conversion is ≥99.5%. After the reaction is complete, MEK is added to complete the precipitation of the product. The suspension is cooled, and the solid is collected by filtration and dried to give crude malalixibat. An overall yield of approximately 90% is obtained over the three steps.

[0324] Step 3 - Purification of crude malalixibat Crude maralixibat is dissolved in MEK / water / DABCO, seeded with C-025325, and heated. MEK is added to the solution to crystallize the product. The suspension is cooled, filtered, and dried to form recrystallized maralixibat in approximately 90% yield and with a purity of >99% and chiral purity of 100%.

[0325] Example 4. Characterization of Compounds of Formula II 4.1 Crystalline Form X of the Compound of Formula II A sample prepared according to Step 1 of Example 3 from the compound of Formula I prepared as described in Example 2.1 was characterized by XRPD, TGA / DSC, and PLM using the same parameters as above. Based on the XRPD pattern shown in Figure 6, crystals of Form X of the compound of Formula II were identified. As shown by the TGA and DSC data in Figure 7, the material is anhydrous and melts at 216.1 °C, as determined by the onset of the melting endotherm. Rod-like crystals were observed by PLM (Figure 8). Based on the thermal data, the starting material was determined to be anhydrous.

[0326] Example 5. Polymorph Screening of Compounds of Formula II Polymorph screening experiments were set up using the slurry method at different temperatures, slow cooling, liquid and solid vapor diffusion, slow evaporation, antisolvent addition, and ionic liquid methods. However, the data showed that under all these conditions, the only crystalline form was Form X. No new polymorphs were observed during the screening.

[0327] The approximate solubility of the compound of Formula II (starting material) was determined in 20 different solvents at room temperature. Approximately 2 mg of material was added to a 2 mL glass vial. Solvent was then added incrementally to the vial until the solid dissolved or a total volume of 1 mL was reached. (Note: This is not an estimate of thermodynamic solubility; vortexing and sonication were applied between each solvent addition to accelerate dissolution.) The results, summarized in Table 5-1, were used to guide solvent selection for polymorph screening. Starting with the starting material, polymorph screening experiments were set up using the slurry method at different temperatures, slow cooling, liquid and solid vapor diffusion, slow evaporation, antisolvent addition, and ionic liquid methods. The methods utilized and the crystalline forms identified are summarized in Table 5-2. No new polymorphs were observed during screening. Type X and crystalline form X are used interchangeably. [Table 5-1] [Table 5-2]

[0328] 5.1 Slurry method at room temperature (RT) A total of 15 room-temperature slurry experiments were performed. For each experiment, approximately 20 mg of starting material was weighed into a 2 mL glass vial, and 0.2 mL of the corresponding solvent was added to the suspension of crystalline form X (i.e., type X). The suspension was magnetically stirred at room temperature (25°C) for 3 days. After 3 days, the suspension was removed from the vial, and a 4-minute XRPD analysis of the wet cake was performed.

[0329] The experimental summary in Table 5-3 below indicates the solvent used in each experiment, its corresponding volume, and indicates that crystalline form X (i.e., Type X) was the only solid form obtained in these experiments. [Table 5-3]

[0330] 5.2 Slurry method at 65°C A total of 15 slurry experiments were performed at 65°C. For each experiment, approximately 20 mg of starting material was weighed into a 2 mL glass vial, and 0.2 mL of the corresponding solvent was added to a suspension of crystalline form X (i.e., type X). The suspension was magnetically stirred at 65°C for 3 days. After 3 days, the suspension was skimmed from the vial for 4 min XRPD analysis of the wet cake. The experimental summary in Table 5-4 below indicates the solvent used in each experiment, its corresponding volume, and indicates that crystalline form X (i.e., type X) was the only solid form obtained in these experiments. [Table 5-4]

[0331] 5.3 Antisolvent addition method A total of 11 anti-solvent addition experiments were performed. For each experiment, approximately 20 mg of starting material was weighed into a 20 mL glass vial and then dissolved in 0.2 mL of the corresponding solvent to obtain a clear solution. While magnetically stirring these solutions at room temperature (25 °C), the corresponding anti-solvent was added dropwise continuously (every 1 second) until crystallization was observed. In these experiments, no crystallization was observed, so the anti-solvent addition was stopped at 10 mL and all samples were transferred to 5 °C for 3 days. The resulting solid was removed from the vial for 4 min XRPD analysis of the wet cake.

[0332] The experimental summary in Table 5-5 below indicates the solvent used in each experiment, its corresponding volume, and indicates that only crystalline form X (ie, Type X) was obtained in these experiments. [Table 5-5]

[0333] 5.4 Solid Vapor Diffusion Method A total of 10 solid vapor diffusion experiments were performed. For each experiment, approximately 20 mg of starting material was weighed into an uncapped 4 mL glass vial and placed in a 20 mL vial filled with approximately 3 mL of volatile solvent. The 20 mL vial was then sealed with a cap and kept at room temperature for 7 days, allowing the solvent vapor to interact with the starting material within the 4 mL vial. After 7 days, the solid was removed from the vial for 4-min XRPD analysis of the wet cake.

[0334] The experimental summaries in Tables 5-6 below indicate the solvent used in each experiment, its corresponding volume, and indicate that only crystalline form X (ie, Type X) was obtained in these experiments. [Table 5-6]

[0335] 5.5 Liquid Vapor Diffusion Method A total of eight liquid vapor diffusion experiments were performed. For each experiment, approximately 20 mg of starting material was weighed into a 4 mL glass vial and dissolved in the corresponding solvent to obtain a clear solution. This vial was then placed, unsealed, in a 20 mL vial filled with approximately 3 mL of a volatile antisolvent. The 20 mL vial was then sealed with a cap and kept at room temperature (RT) for 7 days to allow the antisolvent vapor to interact with the solution in the 4 mL vial. After 7 days, solids were removed from the vial for 4-min XRPD analysis of the wet cake. Vials in which no solids were observed were set to undergo slow evaporation for 5 days (the vial was covered with Parafilm® with 3–5 pinholes and left at room temperature (RT) for slow evaporation). After this period, the resulting solids were removed from the vial for 4-min XRPD analysis of the wet cake.

[0336] The experimental summaries in Tables 5-7 below indicate the solvent and antisolvent used in each experiment, their corresponding volumes, and indicate that crystalline form X (i.e., Type X) and amorphous were the only solid forms obtained in these experiments. [Table 5-7]

[0337] 5.6 Slow evaporation A total of 10 slow evaporation experiments were performed. For each experiment, approximately 20 mg of starting material was weighed into a 2 mL vial and then dissolved in 0.2 mL of the corresponding solvent to obtain a clear solution. The vial was then covered with Parafilm® with three pinholes and allowed to evaporate at room temperature for 7 days. Since no solids were observed after this period, the sample was transferred to 5 °C for 3 days to induce precipitation.

[0338] The resulting solid was removed from the vial for 4 min XRPD analysis of the wet cake. The experimental summaries in Tables 5-8 below indicate the solvent used in each experiment, its corresponding volume, and indicate which crystalline form X (i.e., Type X) and amorphous material were obtained in these experiments. [Table 5-8]

[0339] 5.7 Ionic Liquids A total of 10 ionic liquid experiments were performed. For each experiment, approximately 20 mg of starting material was weighed into a 2 mL glass vial and then dissolved in 0.1 mL of the corresponding solvent to obtain a clear solution. Approximately 5 mg of the ionic liquid 1-butyl-3-methylimidazolium chloride was added to each glass vial. All samples were allowed to evaporate at room temperature for 7 days to induce precipitation. After this period, no solids were observed, so all samples were transferred to 5 °C for 3 days.

[0340] The resulting solid was removed from the vial for 4 min XRPD analysis of the dry cake. The experimental summaries in Tables 5-9 below indicate the solvent used in each experiment, its corresponding volume, and indicate which crystalline form X (i.e., Type X) and amorphous material were obtained in these experiments. [Table 5-9]

[0341] 5.8 Slow cooling method A total of 10 slow-cooling experiments were performed. For each experiment, approximately 20 mg of starting material was weighed into a 2 mL glass vial, and then 0.1 mL of the corresponding solvent was added to form a saturated solution. These solutions were then cooled from 50 °C to 5 °C over 7.5 hours in an incubator. After this period, all solutions were clear (no solids). They were then allowed to slowly evaporate at room temperature for 5 days. No solids were observed. They were then transferred to -14 °C for 3 days. After this period, the resulting solids were removed from the vials for 4-minute XRPD analysis of the dried cakes.

[0342] The experimental summaries in Tables 5-10 below indicate the solvent used in each experiment, its corresponding volume, and indicate that only crystalline form X (ie, Type X) was obtained in these experiments. [Table 5-10]

[0343] The data showed that under all these conditions, the only crystalline form of the compound of formula II was crystalline form X. Therefore, it is concluded that crystalline form X is the most stable form under the conditions tested in this study. The molecular structure was determined by single crystal X-ray diffraction.

[0344] Example 6. Wetcake Stability Study of Compound of Formula II A wet cake drying test for the compound of Formula II was performed on a sample (98.67% pure compound of Formula II) in an open dish held under vacuum at 40°C. The sample was analyzed after one week (98.79% pure compound of Formula II), and the sample was stable, so the test was extended for an additional month. The solid could be kept under vacuum at 40°C for at least one month (98.74% pure compound of Formula II).

[0345] Example 7. Characterization of the amorphous form of the compound of formula III An amorphous sample of the compound of formula III was obtained by rotary evaporation of a methanol solution, and its XRPD is shown in Figure 9. The DSC curve of the amorphous sample is shown in Figure 10. As shown in Figure 10, no obvious glass transition signal was observed in the DSC of the amorphous sample.

[0346] Example 8. Characterization of the Compound of Formula III in Crystalline Form 8.1 Anhydrous Crystalline Form II of the Compound of Formula III The anhydrous crystalline Form II of the compound of Formula III was characterized by XRPD, TGA, DSC, and HPLC. As shown in the XRPD results (Figure 11), the sample was crystalline and consistent with crystalline Form II. Its HPLC purity was determined to be 99.78 area %. As shown in Figure 12, a 1.0% weight loss up to 225°C in TGA and one sharp endothermic peak at 286.3°C (onset temperature) in DSC were observed. PLM image shows rod-like crystals (Figure 13). Crystalline Form II is a stable form of the compound of Formula III.

[0347] 8.2 Hydrate Crystalline Form I of the Compound of Formula III Crystalline Form I of the compound of formula III was obtained via slurrying Crystalline Form II in MeOH, then air-dried for about 1 hour before characterization. Its HPLC purity was determined to be 99.83 area %. The XRPD pattern is shown in Figure 14, and the TGA / DSC curve is shown in Figure 15. The results showed that Crystalline Form I was crystalline with a weight loss of 4.5% by 150°C in TGA and two endothermic peaks at 48.2°C and 238.7°C (onset temperature) in DSC. References

[0348] Abetz-Webb L, Kennedy C, Hepburn B, Gauthier M, Johnson N, Medendorp S, et al. The burden of pruritus on patients with Alagille syndrome: results from a qualitative study with pediatric patients and their caregivers. Hepatology. 2014;60:526A-527A. Alissa FT, Jaffe R, Shneider BL. Update on progressive familial intrahepatic cholestasis. Journal of pediatric gastroenterology and nutrition. 2008;46(3):241-52. Arnell, H., Papadogiannakis, N., Zemack, H., Knisely, A. S., Nemeth, A.and Fischler, B. Follow-up in children with progressive familial intrahepatic cholestasis after partial external biliary diversion. J Pediatr Gastroenterol Nutr. 2010; 51:494-9. Coates A, Nostrant T, Wilson J, Dobbins W, Agha F. Gastric xanthomatosis and cholestasis. A causal relationship. Dig Dis Sci. 1986;31(9):925-928. Danks DM, Campbell PE, Jack I, Rogers J, Smith AL. Studies of the aetiology of neonatal hepatitis and biliary atresia. Archives of disease in childhood. 1977;52(5):360-7. Davit-Spraul, A., Gonzales, E., Baussan, C.and Jacquemin, E. Progressive familial intrahepatic cholestasis. Orphanet J Rare Dis. 2009; 4:1. Davit-Spraul A, Fabre M, Branchereau S, Baussan C, Gonzales E, Stieger B, et al. ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): phenotypic differences between PFIC1 and PFIC2 and natural history. Hepatology (Baltimore, Md). 2010;51(5):1645-55. Elisofon SA, Emerick KM, Sinacore JM, Alonso EM. Health status of patients with Alagille syndrome. Journal of pediatric gastroenterology and nutrition. 2010;51(6):759-65. Emerick K, Rand E, Goldmuntz E, Krantz I, Spinner N, Piccoli D. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology. 1999;29(3):822-829. Emerick KM, Whitington PF. Partial external biliary diversion for intractable pruritus and xanthomas in Alagille syndrome. Hepatology (Baltimore, Md). 2002;35(6):1501-6. Emerick KM, Elias MS, Melin-Aldana H, Strautnieks S, Thompson RJ, Bull LN, et al. Bile composition in Alagille Syndrome and PFIC patients having Partial External Biliary Diversion. BMC gastroenterology. 2008;8:47. Englert C, Grabhorn E, Richter A, Rogiers X, Burdelski M, Ganschow R. Liver transplantation in children with progressive familial intrahepatic cholestasis. Transplantation. 2007;84(10):1361-3. Halaweish, I.and Chwals, W. J. Long-term outcome after partial external biliary diversion for progressive familial intrahepatic cholestasis. J Pediatr Surg. 2010; 45:934-7. Jericho, H. Bile Acid Pool Dynamics in Progressive Familial lntrahepatic Cholestasis With Partial External Bile Diversion. Journal of Pediatric Gastroenterology and Nutrition. 2015; 60:368-374. Kamath BM, Abetz-Webb L, Kennedy C, et al. Development of a novel tool to assess the impact of itching in pediatric cholestasis. Patient. 2018a;11:69-82. Kamath BM, Baker A, Houwen R, Todorova L, Kerkar N. Systematic review: the epidemiology, natural history, and burden of Alagille syndrome. J Pediatr Gastroenterol Nutr. 2018b;67(2):148-156. Modi B, Suh M, Jonas M, Lillehei C, Kim H. Ileal exclusion for refractory symptomatic cholestasis in Alagille syndrome. J Pediatr Surg. 2007;42(5):800-805. Perez M, Briz O. Bile-acid-induced cell injury and protection. World J Gastroenterol. 2009;15(14):1677-1689. Sambrotta, M. Mutations in TJP2 cause progressive cholestatic liver disease. Nature Genetics. 2014;46, 326-328,0023-0024. Schukfeh, N., Metzelder, M. L., Petersen, C., Reismann, M., Pfister, E. D., Ure, B. M.and Kuebler, J. F. Normalization of serum bile acids after partial external biliary diversion indicates an excellent long-term outcome in children with progressive familial intrahepatic cholestasis. J Pediatr Surg. 2012; 47, 501-5. Sira A, Sira M. Progressive familial intrahepatic cholestasis. In: Abdeldayem H, editor. Hepatic Surgery. InTech, DOI: 10.5772 / 51769 [cited 2017 Feb 02]. Available from: http: / / www.intechopen.com / books / hepatic-surgery / progressive-familial-intrahepatic-cholestasis. 2013. Yang, H., Porte, RJ, Verkade, HJ, De Langen, ZJand Hulscher, JB 2009. Partial external biliary diversion in children with progressive familial intrahepatic cholestasis and Alagille disease. J Pediatr Gastroenterol Nutr, 49, 216-21. Zhou S, Hertel PM, Finegold MJ, Wang L, Kerkar N, Wang J, et al. Hepatocellular carcinoma associated with tight-junction protein 2 deficiency. Hepatology (Baltimore, Md). 2015;62(6):1914-6. * * *

[0349] It is intended that all subject matter contained in the above description or defined in the appended claims be interpreted as illustrative and exemplary of the invention, as various changes can be made therein without departing from the scope and spirit of the invention. Many modifications and variations of the present invention are possible in light of the above teachings. Accordingly, the present description is intended to embrace all such alternatives, modifications, and variations that fall within the scope of the appended claims.

[0350] All patents, applications, publications, test methods, literature, and other materials referenced herein are incorporated by reference in their entirety as if physically present herein.

Claims

1. (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (Formula I): 【Chemical 1】 A crystalline form of the formula (I), which is crystalline form A.

2. 2. The crystalline form A of claim 1, characterized by an X-ray powder diffractogram (XRPD) having at least three peak signals at 2θ values ​​selected from 4.7±0.2, 6.6±0.2, 9.3±0.2, 10.4±0.2, 13.3±0.2, 16.8±0.2, 19.3±0.2, and 23.4±0.

2.

3. 3. Crystalline form A of claim 1 or 2, characterized by an XRPD pattern substantially similar to the XRPD pattern of Figure 1.

4. Crystalline form A according to any one of claims 1 to 3, characterized by a melting point of about 133°C to about 135°C.

5. Crystalline form A according to any one of claims 1 to 4, characterized by a melting point of about 134.7°C.

6. 6. The crystalline form A of any one of claims 1 to 5, characterized by a DSC thermogram having an onset of about 130.8°C, an endotherm with a peak at about 134.7°C, and an exotherm at about 145°C.

7. 7. Crystalline form A according to any one of claims 1 to 6, characterized by a thermogravimetric analysis / differential scanning calorimetry (TGA / DSC) thermogram substantially similar to the thermogram of Figure 2.

8. 8. The crystalline form A of any one of claims 1 to 7, which has no weight loss between about 25°C and about 225°C as measured by thermogravimetric analysis (TGA).

9. The crystalline form A according to any one of claims 1 to 8, which is anhydrous.

10. The crystalline form A according to any one of claims 1 to 8, which is a hydrate.

11. The crystalline form A of any one of claims 1 to 10, comprising rod-shaped crystals when observed under a polarizing microscope.

12. 12. The crystalline form A of any one of claims 1 to 11, wherein at least about 95% of the crystalline form is the R,R stereoisomer.

13. 13. The crystalline form A of any one of claims 1 to 12, wherein at least about 96% of the crystalline form is the R,R stereoisomer.

14. 14. The crystalline form A of any one of claims 1 to 13, wherein at least about 97% of the crystalline form is the R,R stereoisomer.

15. 15. The crystalline form A of any one of claims 1 to 14, wherein at least about 98% of the crystalline form is the R,R stereoisomer.

16. 16. The crystalline form A of any one of claims 1 to 15, wherein at least about 99% of the crystalline form is the R,R stereoisomer.

17. 17. The crystalline form A of any one of claims 1 to 16, wherein about 100% of the crystalline form is the R,R stereoisomer.

18. (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (Formula I): 【Chemistry 2】 A crystalline form of the formula (I), which is crystalline form B.

19. 19. The crystalline form B of claim 18, characterized by an X-ray powder diffractogram (XRPD) having at least five peak signals at 2θ values ​​selected from 4.4±0.2, 6.3±0.2, 7.2±0.2, 8.9±0.2, 9.9±10.8±0.2, 11.2±0.2, 11.6±0.2, 17.5±0.2, 18.4±0.2, 21.9±0.2, and having at least two peak signals at 2θ values ​​selected from 4.7±0.2, 6.6±0.2, 9.3±0.2, 13.3±0.2, 19.3±0.2, and 23.4±0.

2.

20. 20. Crystalline form B according to any one of claims 18 and 19, characterized by an XRPD pattern substantially similar to the XRPD pattern of Figure 4.

21. Crystalline form B according to any one of claims 18 to 20, characterized by a TGA thermogram substantially similar to the TGA thermogram of Figure 5.

22. 22. Crystalline form B according to any one of claims 18 to 21, having a weight loss of about 45% between about 21.5°C and about 100°C as measured by thermogravimetric analysis (TGA).

23. Crystalline form B according to any one of claims 18 to 22, which is a hydrate.

24. Crystalline form B according to any one of claims 18 to 23, wherein at least about 95% of the crystalline form is the R,R stereoisomer.

25. 25. The crystalline form B of any one of claims 18 to 24, wherein at least about 96% of the crystalline form is the R,R stereoisomer.

26. 26. Crystalline form B according to any one of claims 18 to 25, wherein at least about 97% of the crystalline form is the R,R stereoisomer.

27. 27. Crystalline form B according to any one of claims 18 to 26, wherein at least about 98% of the crystalline form is the R,R stereoisomer.

28. 28. Crystalline form B according to any one of claims 18 to 27, wherein at least about 99% of the crystalline form is the R,R stereoisomer.

29. Crystalline form B according to any one of claims 18 to 28, wherein about 100% of the crystalline form is the R,R stereoisomer.

30. A highly pure compound having the structure of formula I, (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide: 【Chemistry 3】 A highly pure compound of formula I, wherein the purity of the compound of formula I is at least about 95%.

31. 31. The highly pure compound of formula I of claim 30, wherein the purity of the compound of formula I is at least about 96%.

32. 32. The highly pure compound of formula I of any one of claims 30 and 31, wherein the purity of the compound of formula I is at least about 97%.

33. 33. The highly pure compound of formula I of any one of claims 30 to 32, wherein the purity of the compound of formula I is at least about 98%.

34. 34. The highly pure compound of formula I of any one of claims 30 to 33, wherein the purity of the compound of formula I is at least about 99%.

35. 35. The highly pure compound of formula I according to any one of claims 30 to 34, wherein the purity of the compound of formula I is about 100%.

36. 36. The highly pure compound of formula I according to any one of claims 30 to 35, wherein the compound of formula I is in crystalline form.

37. 36. The highly pure compound of formula I according to any one of claims 30 to 35, wherein the compound of formula I is in amorphous form.

38. 37. The highly pure compound of formula I according to claim 36, wherein the crystalline form is crystalline form A.

39. 37. The highly pure compound of formula I according to claim 36, wherein the crystalline form is crystalline form B.

40. 37. The highly pure compound of formula I according to claim 36, wherein the crystalline forms include crystalline form A and crystalline form B.

41. 41. A process for preparing crystalline form A of any one of claims 1 to 17, 38, and 40, comprising the step of: (a) mixing a compound of formula I with a solvent.

42. 42. The process for preparing crystalline form A of claim 41, further comprising the step of: (b) stirring the mixture in a slurry at about 25°C.

43. 42. The process for preparing crystalline form A of claim 41, further comprising the step of: (b) stirring the mixture in a slurry at about 65°C.

44. 44. The process for preparing crystalline form A of any one of claims 42-43, wherein step (b) further comprises stirring the mixture in the slurry for about 3 days.

45. 42. The process for preparing crystalline form A of claim 41, wherein step (a) further comprises obtaining a clear solution of the mixture, and the process further comprises the step of (b) adding an anti-solvent.

46. 46. ​​The process for preparing crystalline form A of claim 45, wherein step (b) further comprises stirring the mixture at about 25°C.

47. 42. The process for preparing crystalline form A of claim 41, wherein the solvent in step (a) is a volatile solvent, and step (a) further comprises contacting the solid form of the compound of formula I with vapors of the volatile solvent.

48. 48. The process for preparing crystalline form A of claim 47, wherein the contact with the vapor of a volatile solvent is carried out at about 25°C.

49. 49. The process for preparing crystalline form A of claim 48, wherein the contacting continues for about 7 days.

50. 42. The process for preparing crystalline form A of claim 41, wherein step (a) further comprises obtaining a clear solution of the mixture, and the process further comprises the step of (b) contacting the mixture with vapors of a volatile anti-solvent.

51. 51. The process for preparing crystalline form A of claim 50, wherein the contacting with vapors of a volatile anti-solvent is carried out at about 25°C.

52. 52. The process for preparing crystalline form A of any one of claims 50 and 51, wherein the contacting continues for about 7 days.

53. 42. The process for preparing crystalline form A of claim 41, wherein step (a) further comprises obtaining a clear solution of the mixture, and the process further comprises the step of (b) evaporating the solvent.

54. 54. The process for preparing crystalline form A of claim 53, wherein the evaporation is carried out at about 25°C.

55. 55. The process for preparing crystalline form A of any one of claims 53 and 54, wherein the evaporation continues for about 7 days.

56. 42. The process for preparing crystalline form A of claim 41, wherein step (a) further comprises obtaining a clear solution of the mixture, and the process further comprises the step of (b) adding an ionic liquid.

57. 57. The process for preparing crystalline form A according to claim 56, wherein the ionic liquid is 1-butyl-3-methylimidazolium chloride.

58. 58. The process for preparing crystalline form A of any one of claims 56 and 57, further comprising the step of: (c) evaporating the solvent.

59. 59. The process for preparing crystalline form A of claim 58, wherein the evaporation is carried out at about 25°C.

60. 60. The process for preparing crystalline form A of any one of claims 58 and 59, wherein the evaporation continues for about 7 days.

61. 61. The process for preparing crystalline form A of any one of claims 58 to 60, further comprising the step of: (d) placing the mixture at about 5°C.

62. 62. The process for preparing crystalline form A of any one of claims 58 to 61, further comprising the step of: (d) placing the mixture at about 5°C for about 3 days.

63. 42. The process for preparing crystalline form A of claim 41, wherein step (a) further comprises forming a saturated solution, and the process further comprises (b) cooling the solution to form a clear solution.

64. 64. The process for preparing crystalline form A of claim 63, wherein the cooling is from about 50°C to about 5°C.

65. 65. The process for preparing crystalline form A of claim 64, wherein the cooling time ranges from about 6 hours to about 9 hours.

66. 66. The process for preparing crystalline form A of any one of claims 63 to 65, further comprising the step of: (c) evaporating the solvent.

67. 67. The process for preparing crystalline form A of claim 66, wherein the evaporation is carried out at about 25°C.

68. 68. The process for preparing crystalline form A of any one of claims 66 and 67, wherein the evaporation continues for about 5 days.

69. 69. The process for preparing crystalline form A of any one of claims 66 to 68, further comprising the step of: (d) placing the mixture at about -14°C.

70. 70. The process for preparing crystalline form A of any one of claims 66 to 69, further comprising the step of: (d) placing the mixture at about -14°C for about 3 days.

71. 42. The process for preparing crystalline form A of claim 41, wherein the solvent in step (a) comprises one or more selected from the group consisting of acetone, acetonitrile (ACN), n-butyl acetate, cyclohexane, dichloromethane (DCM), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl acetate (EtOAc), ethanol (EtOH), water, n-heptane, isopropyl alcohol (IPA), isopropyl acetate (IPAc), methanol (MeOH), methyl tetrahydrofuran (MeTHF), methyl isobutyl ketone (MIBK), methyl tert-butyl ether (MTBE), NMP, pentane, and toluene.

72. 43. The process for preparing crystalline form A of claim 42, wherein the solvent in step (a) is selected from the group consisting of cyclohexane, water, n-heptane, IPA, MTBE, pentane, cyclohexane / acetone (3:2, vol:vol), cyclohexane / DCM (3:2, vol:vol), water / DMSO (3:2, vol:vol), water / EtOH (3:2, vol:vol), n-heptane / toluene (3:2, vol:vol), IPA / toluene (3:2, vol:vol), MTBE / DMSO (3:2, vol:vol), pentane / DCM (3:2, vol:vol), and pentane / acetone (3:2, vol:vol).

73. 44. The process for preparing crystalline form A of claim 43, wherein the solvent in step (a) is selected from the group consisting of cyclohexane, water, n-heptane, IPA, MTBE, pentane, cyclohexane / toluene (3:2, vol:vol), cyclohexane / DCM (3:2, vol:vol), n-heptane / butyl acetate (3:2, vol:vol), n-heptane / toluene (3:2, vol:vol), IPA / acetone (2:1, vol:vol), IPA / DMF (2:1, vol:vol), MTBE / ACN (2:1, vol:vol), MTBE / DMSO (2:1, vol:vol), and MTBE / n-butyl acetate (2:1, vol:vol).

74. 46. ​​The process for preparing crystalline form A of claim 45, wherein the anti-solvent in step (b) is selected from the group consisting of cyclohexane, water, n-heptane, IPA, MTBE, and pentane.

75. 48. The process for preparing crystalline form A of claim 47, wherein the volatile solvent is selected from the group consisting of acetone, ACN, n-butyl acetate, DCM, DMF, DMSO, EtOAc, MeOH, NMP, and MIBK.

76. 51. The process for preparing crystalline form A of claim 50, wherein the solvent in step (a) is n-butyl acetate, EtOAc, or toluene.

77. 77. The process for preparing crystalline form A according to claim 50 or claim 76, wherein the anti-solvent in step (b) is selected from the group consisting of cyclohexane, water, n-heptane, IPA, MTBE, and pentane.

78. 57. The process for preparing crystalline form A of claim 53 or claim 56, wherein the solvent in step (a) is selected from the group consisting of DMF, MeTHF, MIBK, NMP, toluene, DCM, acetone, ACN, n-butyl acetate, and DMSO.

79. 64. The process for preparing crystalline form A of claim 63, wherein the solvent in step (a) is selected from the group consisting of EtOH, IPAc, MeOH, MTBE, MIBK, CAN, acetone, NMP, toluene, and MeTHF.

80. 30. A process for preparing crystalline form B of any one of claims 18 to 29, comprising the steps of: (a) mixing the compound of formula I with a solvent; and (b) adding an anti-solvent, wherein the anti-solvent is a mixture of acetonitrile (ACN) and water.

81. A crystalline form of (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-hydroxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (Formula II), which is crystalline form X. 【Chemistry 4】

82. 82. The crystalline form X of claim 81, characterized by an X-ray powder diffractogram (XRPD) having at least nine peak signals at 2θ values ​​selected from 5.0±0.2, 8.7±0.2, 10.0±0.2, 12.5±0.2, 13.3±0.2, 14.9±0.2, 15.8±0.2, 17.0±0.2, 17.8±0.2, 19.3±0.2, 19.9±0.2, 21.7±0.2, 22.6±0.2, 23.2±0.2, 24.5±0.2, 24.9±0.2, 25.8±0.2, 26.4±0.2, 28.0±0.2, and 29.4±0.

2.

83. 83. Crystalline form X of any one of claims 81 and 82, characterized by an XRPD pattern substantially similar to the XRPD pattern of Figure 6.

84. 84. The crystalline form X of any one of claims 81 to 83, characterized by a melting point of about 216.7°C to about 217.7°C.

85. 85. Crystalline form X according to any one of claims 81 to 84, characterized by a melting point of about 217.2°C.

86. 86. The crystalline form X of any one of claims 81-85, characterized by a DSC thermogram having an onset at about 216.1°C, an endotherm with a peak at about 217.2°C, and an exotherm at about 218.3°C.

87. 87. Crystalline form X according to any one of claims 81 to 86, characterized by a TGA / DSC thermogram substantially similar to the thermogram of Figure 7.

88. 88. The crystalline form X of any one of claims 81 to 87, having a weight loss of less than about 0.1% between about 95.1°C and about 200.0°C as measured by thermogravimetric analysis (TGA).

89. 89. The crystalline form X of any one of claims 81 to 88, having a weight loss of about 0.07% between about 95.1°C and about 200.0°C as measured by thermogravimetric analysis (TGA).

90. 90. The crystalline form X of any one of claims 81 to 89, which is anhydrous.

91. 90. The crystalline form X of any one of claims 81 to 89, which is a hydrate.

92. 92. The crystalline form X of any one of claims 81 to 91, comprising rod-shaped crystals when observed under a polarizing microscope.

93. 93. The crystalline form X of any one of claims 81 to 92, wherein at least about 95% of the crystalline form is the R,R stereoisomer.

94. 94. The crystalline form X of any one of claims 81 to 93, wherein at least about 96% of the crystalline form is the R,R stereoisomer.

95. 95. The crystalline form X of any one of claims 81 to 94, wherein at least about 97% of the crystalline form is the R,R stereoisomer.

96. 96. The crystalline form X of any one of claims 81 to 95, wherein at least about 98% of the crystalline form is the R,R stereoisomer.

97. 97. The crystalline form X of any one of claims 81 to 96, wherein at least about 99% of the crystalline form is the R,R stereoisomer.

98. 97. The crystalline form X of any one of claims 81 to 96, wherein at least about 99% to about 100% of the crystalline form is the R,R stereoisomer.

99. 98. The crystalline form X of any one of claims 81 to 97, wherein about 100% of the crystalline form is the R,R stereoisomer.

100. The highly pure compound (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-hydroxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (Formula II): 【Chemistry 5】 A highly pure compound of formula II, wherein said compound has a purity of at least about 95%.

101. 101. The highly pure compound of formula II of claim 100, wherein the purity of the compound of formula II is at least about 96%.

102. 102. The highly pure compound of formula II of any one of claims 100 and 101, wherein the purity of the compound of formula II is at least about 97%.

103. 103. The highly pure compound of formula II of any one of claims 100-102, wherein the purity of the compound of formula II is at least about 98%.

104. 104. The highly pure compound of formula II of any one of claims 100-103, wherein the purity of the compound of formula II is at least about 99%.

105. 105. The highly pure compound of formula II according to any one of claims 100 to 104, wherein the purity of the compound of formula II is about 100%.

106. 106. The highly pure compound of formula II according to any one of claims 100 to 105, wherein the compound of formula II is in crystalline form.

107. 106. The highly pure compound of formula II according to any one of claims 100 to 105, wherein the compound of formula II is in amorphous form.

108. 107. The highly pure compound of formula II of claim 106, wherein the crystalline form of the compound of formula II is crystalline form X.

109. 107. The highly pure compound of formula II of claim 106, wherein the crystalline form of the compound of formula II is crystalline form Y.

110. 107. The highly pure compound of formula II of claim 106, wherein the crystalline forms of the compound of formula II include crystalline form X and crystalline form Y.

111. A process for preparing a highly pure compound of formula II according to any one of claims 100 to 110, comprising the step of obtaining the highly pure compound (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (formula I): 【Chemistry 6】 with DL-methionine to form a mixture, wherein the highly purified compound of formula I has a purity of at least 95%.

112. The mixture was heated at about 85°C under CH ３ SO ３ 112. A process for preparing a highly pure compound of formula II according to claim 111, further comprising contacting with H.

113. 112. The process for preparing a highly pure compound of formula II according to claim 111, wherein the purity of the compound of formula I is at least about 96%.

114. 112. The process for preparing a highly pure compound of formula II according to claim 111, wherein the purity of the compound of formula I is at least about 97%.

115. 112. The process for preparing a highly pure compound of formula II according to claim 111, wherein the purity of the compound of formula I is at least about 98%.

116. 112. The process for preparing a highly pure compound of formula II according to claim 111, wherein the purity of the compound of formula I is at least about 99%.

117. 112. The process for preparing a highly pure compound of formula II according to claim 111, wherein the purity of the compound of formula I is about 100%.

118. 118. A process for preparing a highly pure compound of formula II according to any one of claims 111 to 117, wherein the compound of formula I is in crystalline form.

119. 119. The process for preparing highly pure compound of formula II according to any one of claims 111 to 118, wherein the crystalline form of compound of formula I is crystalline form A.

120. 119. The process for preparing highly pure compound of formula II according to any one of claims 111 to 118, wherein the crystalline form of compound of formula I is crystalline form B.

121. 119. A process for preparing a highly pure compound of formula II according to any one of claims 111 to 118, wherein the crystalline form of the compound of formula I comprises crystalline form A and crystalline form B.

122. 109. A process for preparing crystalline form X of any one of claims 81-99 and 108, comprising the step of: (a) mixing a compound of formula II with a solvent.

123. 123. The process for preparing crystalline form X of claim 122, further comprising the step of: (b) stirring the mixture in a slurry at about 25°C.

124. 123. The process for preparing crystalline form X of claim 122, further comprising the step of: (b) stirring the mixture in a slurry at about 65°C.

125. 125. The process for preparing crystalline form X of any one of claims 122 to 124, wherein step (b) further comprises stirring the mixture in the slurry for about 3 days.

126. 123. The process for preparing crystalline form X of claim 122, wherein step (a) further comprises obtaining a clear solution of the mixture, and the process further comprises the step of (b) adding an anti-solvent.

127. 127. The process for preparing crystalline form X of claim 126, wherein step (b) further comprises stirring at about 25°C.

128. 123. The process for preparing crystalline form X of claim 122, wherein the solvent in step (a) is a volatile solvent, and step (a) further comprises contacting the solid form of the compound of formula I with vapor of the volatile solvent.

129. 129. The process for preparing crystalline form X of claim 128, wherein the contacting with vapors of a volatile solvent occurs at about 25°C.

130. 130. The process for preparing crystalline form X of claim 129, wherein the contacting continues for about 7 days.

131. 123. The process for preparing crystalline form X of claim 122, wherein step (a) further comprises obtaining a clear solution of the mixture, and the process further comprises the step of (b) contacting the mixture with vapors of a volatile anti-solvent.

132. 132. The process for preparing crystalline form X of claim 131, wherein the contacting with the vapor of the volatile anti-solvent occurs at about 25°C.

133. 133. The process for preparing crystalline form X of any one of claims 131 and 132, wherein the contacting continues for about 7 days.

134. 123. The process for preparing crystalline form X of claim 122, wherein step (a) further comprises obtaining a clear solution of the mixture, and the process further comprises the step of (b) evaporating the solvent.

135. 135. The process for preparing crystalline form X of claim 134, wherein the evaporation is carried out at about 25°C.

136. 136. The process for preparing crystalline form X of any one of claims 134 and 135, wherein the evaporation continues for about 7 days.

137. 123. The process for preparing crystalline form X of claim 122, wherein step (a) further comprises obtaining a clear solution of the mixture, and the process further comprises the step of (b) adding an ionic liquid.

138. 138. The process for preparing crystalline form X of claim 137, wherein the ionic liquid is 1-butyl-3-methylimidazolium chloride.

139. 139. The process for preparing crystalline form X of any one of claims 137 and 138, further comprising the step of: (c) evaporating the solvent.

140. 140. The process for preparing crystalline form X of claim 139, wherein the evaporation is carried out at about 25°C.

141. 141. The process for preparing crystalline form X of any one of claims 139 and 140, wherein the evaporation continues for about 7 days.

142. 142. The process for preparing crystalline form X of any one of claims 139-141, further comprising the step of: (d) placing the mixture at about 5°C.

143. 143. The process for preparing crystalline form X of any one of claims 139-142, further comprising the step of: (d) placing the mixture at about 5°C for about 3 days.

144. 123. The process for preparing crystalline form X of claim 122, wherein step (a) further comprises forming a saturated solution, and the process further comprises (b) cooling the solution to form a clear solution.

145. 145. The process for preparing crystalline form X of claim 144, wherein the cooling is from about 50°C to about 5°C.

146. 146. The process for preparing crystalline form X of claim 145, wherein the cooling is from about 50° C. to about 5° C., or the cooling time ranges from about 6 hours to about 9 hours.

147. 147. The process for preparing crystalline form X of any one of claims 144 to 146, further comprising the step of: (c) evaporating the solvent.

148. 148. The process for preparing crystalline form X of claim 147, wherein the evaporation is carried out at about 25°C.

149. 149. The process for preparing crystalline form X of any one of claims 147 and 148, wherein the evaporation continues for about 5 days.

150. 150. The process for preparing crystalline form X of any one of claims 147-149, further comprising the step of: (d) placing the mixture at about -14°C.

151. 151. The process for preparing crystalline form X of any one of claims 147-150, further comprising the step of: (d) placing the mixture at about −14° C. for about 3 days.

152. 123. The process for preparing crystalline form X of claim 122, wherein the solvent in step (a) comprises one or more selected from the group consisting of acetone, acetonitrile (ACN), n-butyl acetate, cyclohexane, dichloromethane (DCM), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl acetate (EtOAc), ethanol (EtOH), water, n-heptane, isopropyl alcohol (IPA), isopropyl acetate (IPAc), methanol (MeOH), methyl tetrahydrofuran (MeTHF), methyl isobutyl ketone (MIBK), methyl tert-butyl ether (MTBE), NMP, pentane, and toluene.

153. 124. The process for preparing crystalline form X of claim 123, wherein the solvent in step (a) is selected from the group consisting of cyclohexane, water, n-heptane, IPA, MTBE, EtOH, pentane, toluene, cyclohexane / acetone (3:2, vol:vol), water / DMF (2:1, vol:vol), n-heptane / ethyl acetate (3:2, vol:vol), pentane / acetone (3:2, vol:vol), toluene / DMSO (3:2, vol:vol), toluene / DMF (3:2, vol:vol), and butyl acetate / ACN (1:1, vol:vol).

154. 125. The process for preparing crystalline form X of claim 124, wherein the solvent in step (a) is selected from the group consisting of cyclohexane, water, n-heptane, IPA, MTBE, EtOH, pentane, toluene, butyl acetate / DCM (1:1, vol:vol), cyclohexane / butyl acetate (1:1, vol:vol), EtOH / DMF (3:2, vol:vol), EtOH / DMSO (3:2, vol:vol), n-heptane / acetone (3:2, vol:vol), water / DMF (3:2, vol:vol), and water / DMSO (3:3, vol:vol).

155. 127. The process for preparing crystalline form X of claim 126, wherein the anti-solvent in step (b) is selected from the group consisting of water, n-heptane, toluene, and pentane.

156. 129. The process for preparing crystalline form X of claim 128, wherein the volatile solvent is selected from the group consisting of acetone, DMF, DMSO, EtOAc, MeTHF, NMP, MIBK, DMF / ethyl acetate (3:2, vol:vol), DMSO / ethyl acetate (3:2, vol:vol), and acetone / DMF (2:3 vol:vol).

157. 132. The process for preparing crystalline form X of claim 131, wherein the solvent in step (a) is DMF, DMSO, acetone, and EtOAc.

158. 132. The process for preparing crystalline form X of claim 131, wherein the anti-solvent in step (b) is selected from the group consisting of toluene, water, n-heptane, and pentane.

159. 135. The process for preparing crystalline form X of claim 134, wherein the solvent in step (a) is selected from the group consisting of NMP, acetone, DMF, DMSO, EtOAc, MeTHF, MIBK, DMF / ethyl acetate (3:2, vol:vol), and DMSO / ethyl acetate (3:2, vol:vol).

160. 138. The process for preparing crystalline form X of claim 137, wherein the solvent in step (a) is selected from the group consisting of NMP, acetone, DMF, DMSO, EtOAc, MeTHF, MIBK, acetone / DMF (2:3, vol:vol), acetone / DMSO (2:3, vol:vol), and DMF / ethyl acetate (3:2, vol:vol).

161. 145. The process for preparing crystalline form X of claim 144, wherein the solvent in step (a) is selected from the group consisting of DMSO, EtOAc, MeTHF, MIBK, NMP, DMF, DMF / EtOAc (3:2, vol:vol), DMSO / EtOAc (3:2, vol:vol), acetone / DMF (2:3, vol:vol), and acetone / DMSO (2:3, vol:vol).

162. 1-(4-((4-((4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b]thiepin-5-yl)phenoxy)methyl)benzyl)-1,4-diazabicyclo[2.2.2]octan-1-ium chloride (Formula III): 【Chemistry 7】 10. An amorphous form of the formula (I) characterized by an amorphous content of at least about 80% and characterized by an XRPD pattern substantially similar to the XRPD pattern of FIG.

163. 163. The amorphous form of claim 162, characterized by a DSC thermogram substantially similar to the DSC thermogram of Figure 10.

164. 164. The amorphous form of any one of claims 162-163, characterized by an amorphous content of at least about 85%.

165. 165. The amorphous form of any one of claims 162 to 164, characterized by an amorphous content of at least about 90%.

166. 166. The amorphous form of any one of claims 162 to 165, characterized by an amorphous content of at least about 95%.

167. 167. The amorphous form of any one of claims 162-166, characterized by an amorphous content of at least about 96%.

168. 168. The amorphous form of any one of claims 162-167, characterized by an amorphous content of at least about 97%.

169. 169. The amorphous form of any one of claims 162-168, characterized by an amorphous content of at least about 98%.

170. 170. The amorphous form of any one of claims 162 to 169, characterized by an amorphous content of at least about 99%.

171. 171. The amorphous form of any one of claims 162 to 170, characterized by an amorphous content of about 100%.

172. 172. A process for preparing the amorphous form of any one of claims 162-171, comprising the steps of: (a) mixing a compound of formula III with methanol; and (b) evaporating the solvent by rotary evaporation or other similar known evaporation techniques.

173. The highly pure compound 1-(4-((4-((4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b]thiepin-5-yl)phenoxy)methyl)benzyl)-1,4-diazabicyclo[2.2.2]octan-1-ium chloride (Formula III): 【Chemistry 8】 1. A process for producing a highly pure compound (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (Formula I): 【Chemistry 9】 to the highly pure compound (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-hydroxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (Formula II): 【Chemistry 10】 The process further comprises converting

174. 174. The process for producing a highly pure compound of formula III according to claim 173, wherein the purity of the compound of formula I is at least about 90%.

175. 174. The process for producing a highly pure compound of formula III according to claim 173, wherein the purity of the compound of formula I is at least about 95%.

176. 174. The process for producing a highly pure compound of formula III according to claim 173, wherein the purity of the compound of formula I is at least about 96%.

177. 174. The process for producing a highly pure compound of formula III according to claim 173, wherein the purity of the compound of formula I is at least about 97%.

178. 174. The process for producing a highly pure compound of formula III according to claim 173, wherein the purity of the compound of formula I is at least about 98%.

179. 174. The process for producing a highly pure compound of formula III according to claim 173, wherein the purity of the compound of formula I is at least about 98.5%.

180. 174. The process for producing a highly pure compound of formula III according to claim 173, wherein the purity of the compound of formula I is at least about 99%.

181. 174. The process for producing a highly pure compound of formula III according to claim 173, wherein the purity of the compound of formula I is about 100%.

182. 182. The process for producing a highly pure compound of formula III according to any one of claims 173 to 181, wherein the purity of the compound of formula II is at least about 90%.

183. 182. The process for producing a highly pure compound of formula III according to any one of claims 173 to 181, wherein the purity of the compound of formula II is at least about 95%.

184. 182. The process for producing a highly pure compound of formula III according to any one of claims 173 to 181, wherein the purity of the compound of formula II is at least about 96%.

185. 182. The process for producing a highly pure compound of formula III according to any one of claims 173 to 181, wherein the purity of the compound of formula II is at least about 97%.

186. 182. The process for producing a highly pure compound of formula III according to any one of claims 173 to 181, wherein the purity of the compound of formula II is at least about 98%.

187. 182. The process for producing a highly pure compound of formula III according to any one of claims 173 to 181, wherein the purity of the compound of formula II is at least about 99%.

188. 188. The process for producing a highly pure compound of formula III according to any one of claims 173 to 187, wherein the purity of the compound of formula II is about 100%.

189. 188. The process for producing a highly pure compound of formula III according to any one of claims 173 to 187, wherein the purity of the compound of formula III is at least about 90%.

190. 188. The process for producing a highly pure compound of formula III according to any one of claims 173 to 187, wherein the purity of the compound of formula III is at least about 95%.

191. 188. The process for producing a highly pure compound of formula III according to any one of claims 173 to 187, wherein the purity of the compound of formula III is at least about 96%.

192. 188. The process for producing a highly pure compound of formula III according to any one of claims 173 to 187, wherein the purity of the compound of formula III is at least about 97%.

193. 188. The process for producing a highly pure compound of formula III according to any one of claims 173 to 187, wherein the purity of the compound of formula III is at least about 98%.

194. 188. The process for producing a highly pure compound of formula III according to any one of claims 173 to 187, wherein the purity of the compound of formula III is at least about 99%.

195. 188. The process for producing a highly pure compound of formula III according to any one of claims 173 to 187, wherein the purity of the compound of formula III is about 100%.

196. 196. The process for preparing a highly pure compound of formula III according to any one of claims 173 to 195, wherein the compound of formula I is in crystalline form.

197. 197. The process for preparing a highly pure compound of formula III according to any one of claims 173 to 196, wherein the compound of formula I is in crystalline form A.

198. 198. The process for preparing a highly pure compound of formula III according to any one of claims 173 to 197, wherein the compound of formula II is in crystalline form.

199. 199. The process for preparing a highly pure compound of formula III according to any one of claims 173 to 198, wherein the compound of formula II is in crystalline form X.

200. 200. The process for producing a highly pure compound of formula III according to any one of claims 173 to 199, wherein the compound of formula III is in crystalline form.

201. 201. The process for producing a highly pure compound of formula III according to claim 200, wherein the compound of formula III is in crystalline form I.

202. 201. The process for producing a highly pure compound of formula III according to claim 200, wherein the compound of formula III is in crystalline form II.

203. The highly pure compound 1-(4-((4-((4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b]thiepin-5-yl)phenoxy)methyl)benzyl)-1,4-diazabicyclo[2.2.2]octan-1-ium chloride (Formula III): 【Chemistry 11】 18. A process for producing the compound (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (Formula I) according to any one of claims 1 to 17: 【Chemistry 12】 The compound (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-hydroxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (formula II) according to any one of claims 81 to 99: 【Chemistry 13】 to form X of the formula:

204. 204. The process for producing a highly pure compound of formula III according to claim 203, wherein the purity of the compound of formula III is at least about 90%.

205. 204. The process for producing a highly pure compound of formula III according to claim 203, wherein the purity of the compound of formula III is at least about 95%.

206. 204. The process for producing a highly pure compound of formula III according to claim 203, wherein the purity of the compound of formula III is at least about 96%.

207. 204. The process for producing a highly pure compound of formula III according to claim 203, wherein the purity of the compound of formula III is at least about 97%.

208. 204. The process for producing a highly pure compound of formula III according to claim 203, wherein the purity of the compound of formula III is at least about 98%.

209. 204. The process for producing a highly pure compound of formula III according to claim 203, wherein the purity of the compound of formula III is at least about 99%.

210. 204. The process for producing a highly pure compound of formula III according to claim 203, wherein the purity of the compound of formula III is about 100%.

211. 211. The process for preparing a highly pure compound of formula III according to any one of claims 203 to 210, wherein the compound of formula III is in crystalline form.

212. 212. The process for producing a highly pure compound of formula III according to claim 211, wherein the compound of formula III is in crystalline form I.

213. 212. The process for producing a highly pure compound of formula III according to claim 211, wherein the compound of formula III is in crystalline form II.

214. A method for treating a cholestatic liver disease or condition in a subject in need thereof, comprising administering a therapeutically effective amount of crystalline Form II of the highly pure compound of Formula III prepared by the process of claim 202 or 213.

215. A method for treating a cholestatic liver disease or condition in a subject in need thereof, comprising administering a therapeutically effective amount of crystalline Form II of the highly pure compound of Formula III prepared by the process of claim 201 or 212.

216. 172. A method of treating a cholestatic liver disease or condition in a subject in need thereof, comprising administering a therapeutically effective amount of an amorphous form of the compound of formula III of any one of claims 162-171.

217. The cholestatic liver disease or condition is selected from the group consisting of obstructive cholestasis, non-obstructive cholestasis, extrahepatic cholestasis, intrahepatic cholestasis, primary intrahepatic cholestasis, secondary intrahepatic cholestasis, progressive familial intrahepatic cholestasis (PFIC), PFIC type 1, PFIC type 2, PFIC type 3, benign recurrent intrahepatic cholestasis (BRIC), BRIC type 1, BRIC type 2, BRIC type 3, total parenteral nutrition-associated cholestasis, paraneoplastic cholestasis, Stauffer's syndrome, intrahepatic cholestasis of pregnancy, contraceptive-associated cholestasis, and drug-associated cholestasis. , infection-associated cholestasis, Dubin-Johnson syndrome, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), gallstone disease, Alagille syndrome, Dubin-Johnson syndrome, biliary atresia, biliary atresia after Kasai operation, biliary atresia after liver transplantation, cholestasis after liver transplantation, post-liver transplant-associated liver disease, intestinal failure-associated liver disease, bile acid-mediated liver injury, MRP2 deficiency syndrome, and neonatal sclerosing cholangitis.

218. 218. The method of any one of claims 214 to 217, wherein the cholestatic liver disease or condition is Alagille syndrome (ALGS).

219. 218. The method of any one of claims 214 to 217, wherein the cholestatic liver disease is associated with progressive familial intrahepatic cholestasis (PFIC).

220. 220. The method of any one of claims 214-219, wherein the compound of formula III reduces serum or liver bile acid levels in the patient by at least about 20%.

221. 220. The method of any one of claims 214-219, wherein the compound of formula III reduces serum or liver bile acid levels in the patient by at least about 30%.

222. 220. The method of any one of claims 214-219, wherein the compound of formula III reduces serum or liver bile acid levels in the patient by at least about 40%.

223. 223. The method of any one of claims 214-222, wherein less than 10% of the compound of formula III is systemically absorbed upon oral administration.

224. 224. The method of any one of claims 214-223, wherein the compound of formula III is administered at a dosage of about 10 μg / kg / day to about 10 mg / kg / day.

225. 225. The method of any one of claims 214-224, wherein the compound of formula III is administered at a dosage of about 140 μg / kg / day to about 1 mg / kg / day.

226. 226. The method of any one of claims 214-225, wherein the compound of formula III is administered at a dosage of about 280 μg / kg / day to about 800 μg / kg / day.

227. 227. The method of any one of claims 214-226, wherein the compound of formula III is administered in a dosage comprising from about 0.1 mg to about 40 mg.

228. 228. The method of any one of claims 214-227, wherein the compound of formula III reduces serum or liver bile acid levels, decreases bilirubin, decreases liver enzymes, decreases intestinal bile acids / salts, or reduces necrosis of and / or damage to liver cell structures.

229. 229. The method of any one of claims 214-228, wherein the compound of formula III relieves pruritus.

230. 230. The method of any one of claims 214-229, wherein the compound of formula III is administered with a second agent selected from a bile acid sequestrant or bile acid binder.

231. 231. The method of any one of claims 214-230, wherein the compound of formula III is administered before ingestion of food.

232. 232. The method of claim 231, wherein the compound of formula III is administered less than about 60 minutes or less than about 30 minutes before ingestion of food.

233. 233. The method of any one of claims 214-232, wherein the compound of formula III is administered orally.

234. 234. The method of any one of claims 214-233, wherein the compound of formula III is administered in an ileal pH sensitive release formulation or an enteric coated formulation.

235. 235. The method of any one of claims 214-234, wherein the compound of formula III is administered with a vitamin supplement.

236. 236. The method of claim 235, wherein the vitamin supplement comprises a fat-soluble vitamin.

237. 237. The method of claim 236, wherein the fat-soluble vitamin is selected from the group consisting of vitamins A, D, E, or K.

238. High purity 1-(4-((4-((4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b]thiepin-5-yl)phenoxy)methyl)benzyl)-1,4-diazabicyclo[2.2.2]octan-1-ium chloride (Formula III): 【Chemistry 14】 2. The method of claim 1, wherein the crystalline form I, crystalline form II, and / or amorphous form of highly pure (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (Formula I): 【Chemistry 15】 Crystalline Form A of the compound of formula II was prepared by the synthesis of highly pure (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-hydroxyphenyl)-2,3,4,5-tetrahydrobenzo[b]thiepine 1,1-dioxide (formula II): 【Chemistry 16】 High purity crystalline Form I, crystalline Form II, and / or amorphous form of Formula III prepared by a process comprising converting crystalline Form I, crystalline Form II, and / or amorphous form of Formula III to crystalline Form X of Formula III.

239. A method for treating a cholestatic liver disease or condition in a subject in need thereof, comprising administering a therapeutically effective amount of crystalline Form I, crystalline Form II, and / or amorphous form of the highly pure compound of Formula III described in claim 238.

240. The cholestatic liver disease or condition is selected from the group consisting of obstructive cholestasis, non-obstructive cholestasis, extrahepatic cholestasis, intrahepatic cholestasis, primary intrahepatic cholestasis, secondary intrahepatic cholestasis, progressive familial intrahepatic cholestasis (PFIC), PFIC type 1, PFIC type 2, PFIC type 3, benign recurrent intrahepatic cholestasis (BRIC), BRIC type 1, BRIC type 2, BRIC type 3, total parenteral nutrition-associated cholestasis, paraneoplastic cholestasis, Stauffer's syndrome, intrahepatic cholestasis of pregnancy, contraceptive-associated cholestasis, and drug-associated cholestasis. cholestasis, infection-associated cholestasis, Dubin-Johnson syndrome, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), gallstone disease, Alagille syndrome, Dubin-Johnson syndrome, biliary atresia, biliary atresia after Kasai operation, biliary atresia after liver transplantation, cholestasis after liver transplantation, post-liver transplant-related liver disease, intestinal failure-associated liver disease, bile acid-mediated liver injury, MRP2 deficiency syndrome, and neonatal sclerosing cholangitis.

241. 241. The method of any one of claims 239-240, wherein the cholestatic liver disease or condition is Alagille syndrome (ALGS).

242. 241. The method of any one of claims 239 to 240, wherein the cholestatic liver disease is associated with progressive familial intrahepatic cholestasis (PFIC).

243. 243. The method of any one of claims 239-242, wherein the compound of formula III reduces serum or liver bile acid levels in the patient by at least about 20%.

244. 243. The method of any one of claims 239-242, wherein the compound of formula III reduces serum or liver bile acid levels in the patient by at least about 30%.

245. 243. The method of any one of claims 239-242, wherein the compound of formula III reduces serum or liver bile acid levels in the patient by at least about 40%.

246. 246. The method of any one of claims 239-245, wherein less than 10% of the compound of formula III is systemically absorbed upon oral administration.

247. 247. The method of any one of claims 239-246, wherein the compound of formula III is administered at a dosage of about 10 μg / kg / day to about 10 mg / kg / day.

248. 248. The method of any one of claims 239-247, wherein the compound of formula III is administered at a dosage of about 140 μg / kg / day to about 1 mg / kg / day.

249. 249. The method of any one of claims 239-248, wherein the compound of formula III is administered at a dosage of about 280 μg / kg / day to about 800 μg / kg / day.

250. 250. The method of any one of claims 239-249, wherein the compound of formula III is administered in a dosage comprising from about 0.1 mg to about 40 mg.

251. 251. The method of any one of claims 239-250, wherein the compound of formula III reduces serum or liver bile acid levels, decreases bilirubin, decreases liver enzymes, decreases intestinal bile acids / salts, or reduces necrosis and / or damage to liver cell structure.

252. 252. The method of any one of claims 239-251, wherein the compound of formula III relieves pruritus.

253. 253. The method of any one of claims 239-252, wherein the compound of formula III is administered with a second agent selected from a bile acid sequestrant or bile acid binder.

254. 254. The method of any one of claims 239-253, wherein the compound of formula III is administered before ingestion of food.

255. 255. The method of claim 254, wherein the compound of formula III is administered less than about 60 minutes or less than about 30 minutes before ingestion of food.

256. 256. The method of any one of claims 239-255, wherein the compound of formula III is administered orally.

257. 257. The method of any one of claims 239-256, wherein the compound of formula III is administered in an ileal pH sensitive release formulation or an enteric coated formulation.

258. 258. The method of any one of claims 239-257, wherein the compound of formula III is administered with a vitamin supplement.

259. 259. The method of claim 258, wherein the vitamin supplement comprises a fat-soluble vitamin.

260. 260. The method of claim 259, wherein the fat-soluble vitamin is selected from the group consisting of vitamins A, D, E, or K.

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