Crystalline form of vibegron hemihydrate

Abstract

Described herein is a crystalline form of a hemihydrate of the β-3 adrenergic receptor agonist vibegron. The disclosure also relates to preparations of the crystalline form, pharmaceutical compositions thereof, methods of making the crystalline form, and methods of using the crystalline form in the treatment of overactive bladder.

Description

CRYSTALLINE FORM OF VIBEGRON HEMIHYDRATECROSS-REFERENCES TO RELATED APPLICATIONS

[0001] The present application claims priority to U.S. Provisional Patent Application No. 63 / 660,955, filed June 17, 2024 which is incorporated by reference herein in its entirety.TECHNICAL FIELD

[0002] The present application relates to a crystalline form of a hemihydrate of the Beta-3 adrenergic receptor (P3-AR) agonist vibegron. Pharmaceutical preparations of the crystalline form, as well as uses in the treatment of overactive bladder, are described.BACKGROUND

[0003] Vibegron (referred to herein as Compound 1-7, also known as (6S)-N-[4- [[(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl]methyl]phenyl]-4-oxo-7,8- dihydro-6H-pyrrolo[l,2-a]pyrimidine-6-carboxamide, is a potent and highly selective P3-AR agonist demonstrating >9,000 fold selectivity for activation of P3-AR over P2-AR and Pi-AR in cell based in vitro assays. See, e.g., Edmondson etal., J. Med. Chem. 59:609-623 (2016); United States Patent Nos. 8,399,480 and 8,247,415, and Publication No. US20210077495.Compound 1-7

[0004] A crystalline form of vibegron, and methods for preparing vibegron, are disclosed, for example, in United States Patent Nos. 10,287,289; 10,696,681; 11,091,493; and 11,649,243.

[0005] Overactive bladder (OAB) is a chronic and sometimes debilitating condition of the lower urinary tract. OAB is characterized by the symptoms of urinary urgency, with or without urgency urinary incontinence, usually associated with frequency and nocturia. The prevalence of OAB in the United States and Europe has been estimated at 16 to 17% in both women and men over the age of 18 years. Overactive bladder is most often classified as idiopathic, but can also be secondary to neurological condition, bladder outlet obstruction, and other causes.

[0006] P3-AR activation is an effective way of relaxing the bladder detrusor in normal and pathogenic states. Functional evidence in support of an important role for the P3-AR in urine storage emanates from studies in vivo. P3-AR agonists such as vibegron have demonstrated efficacy in alleviating symptoms of OAB.BRIEF DESCRIPTION OF THE DRAWINGS

[0007] FIG. 1 shows a powder X-ray diffraction (XPRD) pattern of a crystalline form of Compound I-7H.

[0008] FIG. 2 shows a differential scanning calorimetry (DSC) thermogram of a crystalline form of Compound I-7H.

[0009] FIG. 3 shows a thermogravimetric analysis (TGA) thermogram of a crystalline form of Compound I-7H.

[0010] FIG. 4 shows a powder X-ray diffraction (XPRD) pattern of crystalline Form I of Compound 1-7.SUMMARY

[0011] In some aspects, the present disclosure provides a crystalline form of Compound I-7H:Compound I-7H,characterized by a powder X-ray diffraction (XRPD) pattern comprising °29 peaks at 6.20+0.20, 8.39 ±0.20, and 12.28+0.20. In some aspects, the crystalline form is characterized by the XRPD pattern further comprising a °29 peak at 10.13+0.20. In some aspects, the crystalline form is characterized by the XRPD pattern further comprising a °29 peak at 7.57+0.20.

[0012] In some aspects, the present disclosure provides a crystalline form of Compound I-7H characterized by a powder X-ray diffraction (XRPD) pattern comprising °20 peaks at 6.20+0.20, 8.39 ±0.20, and 12.28+0.20 and further comprising °29 peaks at 7.57+0.20 and 10.13+0.20.

[0013] In some aspects, the present disclosure provides a crystalline form as described in any of the previous aspects characterized by an XRPD pattern substantially similar to the one as shown in FIG. 1.

[0014] In some aspects, the present disclosure provides a crystalline form as described in any of the previous aspects characterized by a differential scanning calorimetry thermogram comprising an endotherm having an onset at about 105 °C to about 108 °C.

[0015] In some aspects, the present disclosure provides a crystalline form as described in any of the previous aspects characterized by a differential scanning calorimetry thermogram substantially similar to the one as shown in FIG. 2.

[0016] In some aspects, the present disclosure provides a crystalline form as described in any of the previous aspects characterized by a thermal gravimetric analysis thermogram substantially similar to the one as shown in FIG. 3.

[0017] In some aspects, the present disclosure provides a crystalline form as described in any of the previous aspects in substantially pure form.

[0018] In some aspects, the present disclosure provides a composition comprising the crystalline form of any of the previous aspects, wherein the composition contains between about 0.5% and about 10% of crystalline Form I of Compound 1-7:Compound 1-7.

[0019] In some aspects, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the crystalline form or composition of any one of the previous aspects.

[0020] In some aspects, the present disclosure provides a method of treating overactive bladder in a subject in need thereof, the method comprising administering to the subject the crystalline form, the composition, or the pharmaceutical composition of the previous aspects.

[0021] In some aspects, the present disclosure provides a crystalline form of any one of the previous aspects, prepared by dissolving Compound 1-7:Compound 1-7 into a solution of methanol and acetonitrile, flash cooling the resulting solution with a dry ice bath, and filtering the resulting slurry.

[0022] In some aspects, the present disclosure provides a process for preparing the crystalline form of any of the previous aspects, the process comprising dissolving Compound 1-7 :Compound 1-7 into a solution of methanol and acetonitrile, flash cooling the resulting solution with a dry ice bath, and filtering the resulting slurry. In some aspects, the ratio of methanol to acetonitrile is 1 : 1. In some aspects, the method further comprises adding additional acetonitrile to the solution after Compound 1-7 is dissolved in the solution of methanol and acetonitrile.

[0023] In some aspects, the present disclosure provides a crystalline form of CompoundI-7H:Compound I-7H, characterized by a powder X-ray diffraction (XRPD) pattern comprising °29 peaks at 6.20+0.20, 8.39+0.20, and 12.28+0.20; prepared by a process comprising dissolving Compound 1-7 :Compound 1-7into a solution of methanol and acetonitrile, flash cooling the resulting solution with a dry ice bath, and filtering the resulting slurry. In some aspects, the ratio of methanol to acetonitrile in the solution of methanol and acetonitrile is 1 : 1. In some aspects, the process further comprises adding additional acetonitrile to the solution after Compound I- 7 is dissolved in the solution of methanol and acetonitrile.

[0024] In some aspects, the present disclosure provides a crystalline form of Compound I-7H:Compound I-7H, characterized by a powder X-ray diffraction (XRPD) pattern comprising °29 peaks at 6.20+0.20, 8.39 ±0.20, and 12.28+0.20; prepared by a process described herein.

[0025] In some aspects, the present disclosure provides a crystalline form of Compound I-7H:Compound I-7H, prepared by a process described herein.DETAILED DESCRIPTION

[0026] The present disclosure provides a crystalline form of a hemihydrate of vibegron(Compound I-7H, shown below):Compound I-7H.

[0027] In order that the present description can be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the detailed description.I. Definitions

[0028] Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0029] All measurements are subject to experimental error and are within the spirit of the disclosure.

[0030] All patents, published or unpublished patent applications, and publications cited herein are incorporated by reference in their entireties.

[0031] Wherever aspects are described herein with the language “comprising,” otherwise analogous aspects described in terms of “consisting of’ and / or “consisting essentially of’ are also provided.

[0032] The term “about” as used in connection with a numerical value throughout the specification and the claims denotes an interval of accuracy, familiar and acceptable to a person skilled in the art. In some aspects, such interval of accuracy is ± 10 %. In other aspects, such interval of accuracy is ± 5 %.

[0033] As used herein, the term “approximately,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain aspects, the term “approximately” refers to a range of values that fall within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the statedreference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

[0034] “And / or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and / or” as used in a phrase such as “A and / or B” herein is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0035] As used herein, the term “DSC” refers to differential scanning calorimetry. The term “TGA” refers to thermogravimetric analysis.

[0036] The term “flash cooling” refers to the process of subjecting a substance to a very low temperature to induce a rapid decrease in temperature of that substance.

[0037] As used herein, a “polymorph” refers to a crystalline form(s) having the same chemical structure but different spatial arrangements of the molecules and / or ions forming the crystals. The terms “polymorph” and “crystalline form” are used herein interchangeably.

[0038] The term “room temperature” generally means approximately 22 °C, but can vary up or down by up to 7 °C.

[0039] By “subject” or “individual” or “animal” or “patient” or “mammal,” is meant any subject, particularly a mammalian subject, for whom therapy is desired. In aspects, the mammal is a human subject. In some aspects, the subject is a human. In some aspects, the subject is a human patient.

[0040] As used herein, “substantially pure,” when used in reference to a crystal form, means a compound having a purity greater than 90 weight %, including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 weight %, and also including equal to about 100 weight % of the crystal form of Compound I-7H, based on the weight of the compound. The remaining material comprises other form(s) of the compound (for example, Form I), and / or reaction impurities and / or processing impurities arising from its preparation. For example, a crystal form of Compound I-7H can be deemed substantially pure in that it has a purity greater than 90 weight %, as measured by means that are at this time known and generally accepted in the art, where the remaining less than 10 weight % of materialcomprises other form(s) of Compound I-7H and / or reaction impurities and / or processing impurities.

[0041] In general, the terms “treat,” “treating,” or “treatment” refer to countering the effects caused as a result of the disease or pathological condition of interest in a patient including (i) inhibiting the progress of the disease or pathological condition, in other words, slowing or stopping the development or progression thereof, or one or more symptoms of such disorder or condition; (ii) relieving the disease or pathological condition, in other words, causing said disease or pathological condition, or the symptoms thereof, to regress; (iii) stabilizing the disease or pathological condition or one or more symptoms of such disorder or condition, (iv) reversing the disease or pathological condition or one or more symptoms of such disorder or condition to a normal state, (v) preventing the disease or pathological condition or one or more symptoms of such disorder or condition, and (vi) any combination thereof.IL Compound I- 7 / Compound I- 7H

[0042] Described herein is a polymorph of Compound I-7H and methods of use thereof. In some aspects, the disclosure provides a crystalline form of a hemihydrate of Compound 1-7.

[0043] As used herein, the terms “PXRD” and “XPRD” are used interchangeably, and refer to a compound’s powder X-ray diffraction pattern. When the PXRD or XPRD pattern is described as “comprising” or having a number of peaks selected from a specified group of peaks, it is intended to include patterns having additional peaks that are not included in the specified group of peaks.

[0044] In some aspects, the crystalline form of Compound I-7H has a powder x-ray diffraction pattern substantially similar to the one as shown in FIG. 1.

[0045] In some aspects, the crystalline form of Compound I-7H has a powder x-ray diffraction pattern comprising °29 peaks at 6.20+0.20, 8.39 ±0.20, and 12.28+0.20. In some aspects, the crystalline form of Compound I-7H has a powder x-ray diffraction pattern comprising °20 peaks at 6.20+0.20, 8.39 ±0.20, 10.13±.20, and 12.28±0.20. In some aspects, the crystalline form of Compound I-7H has a powder x-ray diffraction pattern comprising °20 peaks at 6.20±0.20, 8.39 ±0.20, 12.28+0.20, and 16.87+0.20. In some aspects, the crystalline form of Compound I-7H has a powder x-ray diffractionpattern comprising °29 peaks at 6.20+0.20, 7.57+0.20, 8.39 +0.20, 10.13+0.20, and 12.28+0.20. In some aspects, the crystalline form of Compound I-7H has a powder x-ray diffraction pattern comprising °29 peaks at 6.20+0.20, 8.39 +0.20, 10.13+0.20, 12.28+0.20, and 16.87+0.20. In some aspects, the crystalline form of Compound I-7H has a powder x-ray diffraction pattern comprising °29 peaks at 6.20+0.20, 8.39 +0.20, 10.13+0.20, 12.28+0.20, and 18.09+0.20. In some aspects, the crystalline form of Compound I-7H has a powder x-ray diffraction pattern comprising °29 peaks at 6.20+0.20, 8.39+0.20, 12.28+0.20, 16.87+0.20, and 18.09+0.20.

[0046] In some aspects, the crystalline form of Compound I-7H has a powder x-ray diffraction pattern comprising two or more °29 peaks selected from 5.14+0.20, 6.20+0.20, 7.57+0.20, 8.39+0.20, 10.13+0.20, 12.28+0.20, 15.27+0.20, 16.87+0.20, 18.09+0.20, 19.56+0.20, 22.90+0.20, 25.59+0.20, 27.40+0.20, 29.12+0.20, 31.17+0.20, 35.01+0.20, and 39.91+0.20. In some aspects, the crystalline form of Compound I-7H has a powder x- ray diffraction pattern comprising three or more °29 peaks selected from 5.14+0.20, 6.20+0.20, 7.57+0.20, 8.39+0.20, 10.13+0.20, 12.28+0.20, 15.27+0.20, 16.87+0.20, 18.09+0.20, 19.56+0.20, 22.90+0.20, 25.59+0.20, 27.40+0.20, 29.12+0.20, 31.17+0.20, 35.01+0.20, and 39.91+0.20. In some aspects, the crystalline form of Compound I-7H has a powder x-ray diffraction pattern comprising four or more °20 peaks selected from 5.14+0.20, 6.20+0.20, 7.57+0.20, 8.39+0.20, 10.13+0.20, 12.28+0.20, 15.27+0.20, 16.87+0.20, 18.09+0.20, 19.56+0.20, 22.90+0.20, 25.59+0.20, 27.40+0.20, 29.12+0.20, 31.17+0.20, 35.01+0.20, and 39.91+0.20. In some aspects, the crystalline form of Compound I-7H has a powder x-ray diffraction pattern comprising five or more °29 peaks selected from 5.14+0.20, 6.20+0.20, 7.57+0.20, 8.39+0.20, 10.13+0.20, 12.28+0.20, 15.27+0.20, 16.87+0.20, 18.09+0.20, 19.56+0.20, 22.90+0.20, 25.59+0.20, 27.40+0.20, 29.12+0.20, 31.17+0.20, 35.01+0.20, and 39.91+0.20. In some aspects, the crystalline form of Compound I-7H has a powder x-ray diffraction pattern comprising six or more °20 peaks selected from 5.14+0.20, 6.20+0.20, 7.57+0.20, 8.39+0.20, 10.13+0.20, 12.28+0.20, 15.27+0.20, 16.87+0.20, 18.09+0.20, 19.56+0.20, 22.90+0.20, 25.59+0.20, 27.40+0.20, 29.12+0.20, 31.17+0.20, 35.01+0.20, and 39.91+0.20. In some aspects, the crystalline form of Compound I-7H has a powder x-ray diffraction pattern comprising seven or more peaks °29 peaks selected from 5.14+0.20, 6.20+0.20, 7.57+0.20,8.39+0.20, 10.13+0.20, 12.28+0.20, 15.27+0.20, 16.87+0.20, 18.09+0.20, 19.56+0.20, 22.90+0.20, 25.59+0.20, 27.40+0.20, 29.12+0.20, 31.17+0.20, 35.01+0.20, and 39.91+0.20. In some aspects, the crystalline form of Compound I-7H has a powder x-ray diffraction pattern comprising eight or more °29 peaks selected from 5.14+0.20, 6.20+0.20, 7.57+0.20, 8.39+0.20, 10.13+0.20, 12.28+0.20, 15.27+0.20, 16.87+0.20, 18.09+0.20, 19.56+0.20, 22.90+0.20, 25.59+0.20, 27.40+0.20, 29.12+0.20, 31.17+0.20, 35.01+0.20, and 39.91+0.20. In some aspects, the crystalline form of Compound I-7H has a powder x-ray diffraction pattern comprising nine or more °20 peaks selected from 5.14+0.20, 6.20+0.20, 7.57+0.20, 8.39+0.20, 10.13+0.20, 12.28+0.20, 15.27+0.20, 16.87+0.20, 18.09+0.20, 19.56+0.20, 22.90+0.20, 25.59+0.20, 27.40+0.20, 29.12+0.20, 31.17+0.20, 35.01+0.20, and 39.91+0.20. In some aspects, the crystalline form of Compound I-7H has a powder x-ray diffraction pattern comprising ten or more °29 peaks selected from 5.14+0.20, 6.20+0.20, 7.57+0.20, 8.39+0.20, 10.13+0.20, 12.28+0.20, 15.27+0.20, 16.87+0.20, 118.09+0.20, 9.56+0.20, 22.90+0.20, 25.59+0.20, 27.40+0.20, 29.12+0.20, 31.17+0.20, 35.01+0.20, and 39.91+0.20. In some aspects, the crystalline form of Compound I-7H has a powder x-ray diffraction pattern comprising eleven or more °29 peaks selected from 5.14+0.20, 6.20+0.20, 7.57+0.20, 8.39+0.20, 10.13+0.20, 12.28+0.20, 15.27+0.20, 16.87+0.20, 18.09+0.20, 19.56+0.20, 22.90+0.20, 25.59+0.20, 27.40+0.20, 29.12+0.20, 31.17+0.20, 35.01+0.20, and 39.91+0.20. In some aspects, the crystalline form of Compound I-7H has a powder x-ray diffraction pattern comprising twelve or more °29 peaks selected from 5.14+0.20, 6.20+0.20, 7.57+0.20, 8.39+0.20, 10.13+0.20, 12.28+0.20, 15.27+0.20, 16.87+0.20, 18.09+0.20, 19.56+0.20, 22.90+0.20, 25.59+0.20, 27.40+0.20, 29.12+0.20, 31.17+0.20, 35.01+0.20, and 39.91+0.20. In some aspects, the crystalline form of Compound I-7H has a powder x-ray diffraction pattern comprising thirteen or more °29 peaks selected from 5.14+0.20, 6.20+0.20, 7.57+0.20, 8.39+0.20, 10.13+0.20, 12.28+0.20, 15.27+0.20, 16.87+0.20, 18.09+0.20, 19.56+0.20, 22.90+0.20, 25.59+0.20, 27.40+0.20, 29.12+0.20, 31.17+0.20, 35.01+0.20, and 39.91+0.20. In some aspects, the crystalline form of Compound I-7H has a powder x-ray diffraction pattern comprising fourteen or more °29 peaks selected from 5.14+0.20, 6.20+0.20, 7.57+0.20, 8.39+0.20, 10.13+0.20, 12.28+0.20, 15.27+0.20, 16.87+0.20, 18.09+0.20, 19.56+0.20, 22.90+0.20, 25.59+0.20, 27.40+0.20, 29.12+0.20, 31.17+0.20,35.01+0.20, and 39.91+0.20. In some aspects, the crystalline form of Compound I-7H has a powder x-ray diffraction pattern comprising fifteen or more °29 peaks selected from 5.14+0.20, 6.20+0.20, 7.57+0.20, 8.39+0.20, 10.13+0.20, 12.28+0.20, 15.27+0.20, 16.87+0.20, 18.09+0.20, 19.56+0.20, 22.90+0.20, 25.59+0.20, 27.40+0.20, 29.12+0.20, 31.17+0.20, 35.01+0.20, and 39.91+0.20. In some aspects, the crystalline form of Compound I-7H has a powder x-ray diffraction pattern comprising sixteen or more °20 peaks selected from 5.14+0.20, 6.20+0.20, 7.57+0.20, 8.39+0.20, 10.13+0.20, 12.28+0.20, 15.27+0.20, 16.87+0.20, 18.09+0.20, 19.56+0.20, 22.90+0.20, 25.59+0.20, 27.40+0.20, 29.12+0.20, 31.17+0.20, 35.01+0.20, and 39.91+0.20. In some aspects, the crystalline form of Compound I-7H has a powder x-ray diffraction pattern comprising °20 peaks selected from 5.14+0.20, 6.20+0.20, 7.57+0.20, 8.39+0.20, 10.13+0.20, 12.28+0.20, 15.27+0.20, 16.87+0.20, 18.09+0.20, 19.56+0.20, 22.90+0.20, 25.59+0.20, 27.40+0.20, 29.12+0.20, 31.17+0.20, 35.01+0.20, and 39.91+0.20.

[0047] In some aspects, the crystalline form of Compound I-7H has a differential scanning calorimetry thermogram substantially similar to the one as shown in FIG. 2. In some aspects, the crystalline form of Compound I-7H has a differential scanning calorimetry thermogram comprising an endotherm having an onset at about 105 °C to about 108 °C.

[0048] In some aspects, the crystalline form of Compound I-7H has a thermal gravimetric analysis thermogram substantially similar to the one as shown in FIG. 3.

[0049] In some aspects, the present disclosure describes a pharmaceutical composition comprising a therapeutically effective amount of crystalline Compound I-7H and a pharmaceutically acceptable carrier. In some aspects, the crystalline form of Compound I- 7H is substantially pure. In some aspects, the crystalline Compound I-7H is at least about 90 wt.%, at least about 91 wt.%, at least about 92 wt.%, at least about 93 wt.%, at least about 94 wt.%, at least about 95 wt.%, at least about 96 wt.%, at least about 97 wt.%, at least about 98 wt.%, at least about 99 wt.% pure, or about 100 wt.% pure. As used herein, the abbreviation “wt ” and the term “weight” are used interchangeably.

[0050] In some aspects, the present disclosure provides a composition comprising crystalline Compound I-7H and crystalline Form I of Compound 1-7:Compound 1-7.Crystalline Form I of Compound 1-7 is a distinct crystalline form that differs from the presently described crystalline form of Compound I-7H, and crystalline Form I of Compound 1-7 has been described in, for example, U.S. Patent Nos. 10,287,289;10,696,681; 11,091,493; and 11,649,243. In some aspects, crystalline Form I of Compound 1-7 is anhydrous. In some aspects, crystalline Form I of Compound 1-7 is characterized by a powder X-ray diffraction pattern comprising °29 peaks at 5.49+0.20, 8.75+0.20, and 11.0+0.20. In some aspects, crystalline Form I of Compound 1-7 is characterized by a powder X-ray diffraction pattern comprising °29 peaks at 5.49+0.20, 8.75+0.20, 11.04+0.20, and 17.50+0.20. In some aspects, crystalline Form I of Compound 1-7 is characterized by a powder X-ray diffraction pattern comprising °20 peaks at 5.49+0.20, 8.75+0.20, 11.04+0.20, 17.50+0.20, and 22.74+0.20.

[0051] In some aspects, crystalline Form I of Compound 1-7 is characterized by a powder X-ray diffraction pattern comprising the following reflections with d-spacing:Table 1

[0052] In some aspects, crystalline Form I of Compound 1-7 has an XPRD pattern substantially similar to the one as shown in Fig. 4.

[0053] In some aspects of the compositions described herein, the composition comprising crystalline Compound I-7H contains between about 0.1 wt.% and about 10 wt.% of crystalline Form I of Compound 1-7. In some aspects, the composition comprising crystalline Compound I-7H contains between about 0.2 wt.% and about 10 wt.% of crystalline Form I of Compound 1-7. In some aspects, the composition comprising crystalline Compound I-7H contains between about 0.3 wt.% and about 10 wt.% of crystalline Form I of Compound 1-7. In some aspects, the composition comprising crystalline Compound I-7H contains between about 0.4 wt.% and about 10 wt.% of crystalline Form I of Compound 1-7. In some aspects the composition comprising crystalline Compound I-7H contains between about 0.5 wt.% and about 10 wt.% of crystalline Form I of Compound 1-7. In some aspects, the composition comprising crystalline Compound I-7H contains between about 0.6 wt.% and about 10 wt.% of crystalline Form I of Compound 1-7. In some aspects, the composition comprising crystalline Compound I-7H contains between about 0.7 wt.% and about 10 wt.% of crystalline Form I of Compound 1-7. In some aspects, the composition comprising crystalline Compound I-7H contains between about 0.8 wt.% and about 10 wt.% of crystalline Form I of Compound 1-7. In some aspects, the composition comprising crystalline Compound I-7H contains between about 0.9 wt.% and about 10 wt.% of crystalline Form I of Compound 1-7. In some aspects, the composition comprising crystalline Compound I-7H contains between about 1.0 wt.% and about 10 wt.% of crystalline Form I of Compound 1-7. In some aspects, the composition comprising crystalline Compound I-7H contains between about 2.0 wt.% and about 10 wt.% of crystalline Form I of Compound 1-7. In some aspects, the composition comprising crystalline Compound I-7H contains between about 3.0 wt.% and about 10 wt.% of crystalline Form I of Compound 1-7. In some aspects, the composition comprising crystalline Compound I-7H contains between about 4.0 wt.% and about 10 wt.% of crystalline Form I of Compound 1-7. In some aspects, the composition comprising crystalline Compound I-7H contains between about 5.0 wt.% and about 10 wt.% of crystalline Form I of Compound 1-7. In some aspects, the composition comprisingcrystalline Compound I-7H contains between about 6.0 wt.% and about 10 wt.% of crystalline Form I of Compound 1-7. In some aspects, the composition comprising crystalline Compound I-7H contains between about 7.0 wt.% and about 10 wt.% of crystalline Form I of Compound 1-7. In some aspects, the composition comprising crystalline Compound I-7H contains between about 8.0 wt.% and about 10 wt.% of crystalline Form I of Compound 1-7. In some aspects, the composition comprising crystalline Compound I-7H contains between about 9.0 wt.% and about 10 wt.% of crystalline Form I of Compound 1-7. In some aspects, the composition comprising crystalline Compound I-7H contains about 0.1 wt. %, about 0.5 wt.%, about 1.0 wt.%, about 1.5 wt.%, about 2.0 wt.%, about 2.5 wt.%, about 3.0 wt.%, about 3.5 wt.%, about 4.0 wt.%, about 4.5 wt.%, about 5.0 wt.%, about 5.5 wt.%, about 6.0 wt.%, about 6.5 wt.%, about 7.0 wt.%, about 7.5 wt.%, about 8.0 wt.%, about 8.5 wt.%, about 9.0 wt.%, about 9.5 wt.%, or about 10 wt.% of crystalline Form I of Compound 1-7.

[0054] In some aspects of the compositions described herein, the composition comprising the crystalline form of Compound I-7H does not contain crystalline Form I of Compound 1-7.

[0055] In some aspects, the crystalline form of Compound I-7H is obtained by dissolving Compound 1-7 in a mixture of methanol and acetonitrile followed by adding additional acetonitrile, flash cooling the resulting solution with an ice bath, and collecting the resulting solid by filtration. While the crystalline form of Compound I-7H was prepared using the processes described herein, the present crystalline form was not obtained using standard recrystallization techniques used in polymorph screening. Without being bound by a particular theory, it is believed that the process of flash cooling facilitates the formation of the crystalline form of Compound I-7H described herein.

[0056] In some aspects, the present disclosure provides a crystalline form of Compound I-7H:Compound I-7H,characterized by a powder X-ray diffraction (XRPD) pattern comprising °29 peaks at 6.20+0.20, 8.39+0.20, and 12.28+0.20; prepared by a process comprising dissolving Compound 1-7 :Compound 1-7 into a solution of methanol and acetonitrile, flash cooling the resulting solution with a dry ice bath, and filtering the resulting slurry. In some aspects, the ratio of methanol to acetonitrile in the solution of methanol and acetonitrile is 1 : 1. In some aspects, the process further comprises adding additional acetonitrile to the solution after Compound I- 7 is dissolved in the solution of methanol and acetonitrile.

[0057] In some aspects, the present disclosure provides a crystalline form of Compound I-7H:Compound I-7H, characterized by a powder X-ray diffraction (XRPD) pattern comprising °20 peaks at 6.20+0.20, 8.39 +0.20, and 12.28+0.20; prepared by a process described herein.

[0058] In some aspects, the present disclosure provides a crystalline form of Compound I-7H:Compound I-7H, prepared by a process described herein.III. Compositions

[0059] In some aspects, the present disclosure provides compositions comprising crystalline Compound I-7H. The term “composition” as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term in relation to pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier or excipient, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredient. Accordingly, the pharmaceutical compositions of the present disclosure encompass any composition made by mixing a compound of the present disclosure and a pharmaceutically acceptable excipient.

[0060] In preparing a pharmaceutical composition, a form of the active ingredient is sought that has a balance of desired properties, such as, for example, dissolution rate, solubility, bioavailability, and / or storage stability. For example, a form of the active ingredient is sought having sufficient solubility, bioavailability, and storage stability to prevent the sufficiently soluble and bioavailable form from converting, during the manufacture, preparation, and / or storage of the pharmaceutical composition, to another form having an undesirable solubility and / or bioavailability profile. In addition, a form of the active ingredient may also be sought that permits the active ingredient to be isolated and / or purified during, for example, a preparative process.

[0061] In some aspects, the present disclosure provides pharmaceutical compositions which comprise Compound I-7H as described herein, and at least one pharmaceutically acceptable excipient. The present disclosure provides pharmaceutical compositions comprising a dosage of crystalline Compound I-7H disclosed herein, wherein the composition is suitable for oral administration. Oral dosage forms are recognized by those skilled in the art to include, for example, such forms as liquid formulations, tablets, capsules, and gelcaps. In some aspects, the compositions are solid dosage forms, such as tablets and capsules. In some aspects, the compositions are tablets.

[0062] Pharmaceutically acceptable excipients are excipients generally recognized as safe such as lactose, microcrystalline cellulose, starch, calcium carbonate, magnesium stearate, stearic acid, talc, colloidal silicon dioxide, mannitol, croscarmellose sodium, hydroxypropyl cellulose. In some aspects, the pharmaceutical unit dose composition disclosed herein comprises a diluent, a disintegrant, a binder, and a lubricant. See, e.g., Remington: The Science and Practice of Pharmacy, 23rd ed., (2020), which is incorporated herein by reference in its entirety.

[0063] In some aspects, the pharmaceutical compositions of the present disclosure can be crushed. In some aspects, the pharmaceutical compositions of the present disclosure are crushed before oral administration.

[0064] In some aspects, the present disclosure provides a pharmaceutical composition for oral administration comprising crystalline form of Compound I-7H, one or more diluents, one or more disintegrants, one or more binders, and one or more lubricants. In some aspects, the present disclosure provides a pharmaceutical composition for oral administration comprising crystalline form of Compound I-7H, mannitol, microcrystalline cellulose, croscarmallose sodium, hydroxpropyl cellulose, and magnesium stearate. In some aspects, a pharmaceutical composition for oral administration comprises an amount of the crystalline form of Compound I-7H that is equivalent to about 1 mg, about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg or more than about 150 mg of Compound 1-7.IV. Methods of Treatment

[0065] The crystalline form of Compound I-7H described herein can be used in the treatment of overactive bladder. The term “overactive bladder” generally refers to a clinical syndrome characterized by urinary urgency, with or without urge incontinence, which can be accompanied by frequency and nocturia. The term “overactive bladder” is defined by the International Continence Society (ICS) as follows: Overactive bladder (OAB) is a symptom complex consisting of urgency with or without urge incontinence, usually with frequency and nocturia, in the absence of local pathologic or hormonal factors (Abrams P et al., Urology 2003, 61(1): 37-49; Abrams P et al., Urology 2003, 62(Supplement 5B): 28-37 and 40-42). Synonyms of overactive bladder (OAB) include “urge syndrome” and “urge frequency syndrome.”

[0066] The term “urinary urgency” refers to a sudden compelling desire to urinate or void which is difficult to defer or a complaint of a sudden, compelling desire to urinate void which is difficult to defer. In some aspects, the compositions and methods disclosed herein can be used to treat urinary urgency.

[0067] The term “urge incontinence” refers to involuntary loss of urine or a complaint of involuntary loss of urine. In some aspects, the compositions and methods disclosed herein can be used to treat urge incontinence.

[0068] The term “urgency urinary incontinence” (UUI) as used herein refers to a complaint of involuntary loss of urine associated with urgency and can be used interchangeably with “urge urinary incontinence.” UUI is distinguished from stress urinary incontinence, which is the involuntary loss of urine on effort or physical exertion (e.g., sporting activities), or on sneezing or coughing. In some aspects, the compositions and methods disclosed herein can be used to treat urgency urinary incontinence.

[0069] The term “urinary frequency” refers to a need for frequent emptying of or voiding of the bladder or a complaint by the patient who considers that they experiences too many micturitions by day. In some aspects, the compositions and methods disclosed herein can be used to treat urinary frequency.

[0070] The term “nocturia” refers to frequent urination that occurs at night and interrupts sleep or a complaint of interruption of sleep one or more times because of the need to micturate. Each void is preceded and followed by sleep. In some aspects, the compositions and methods disclosed herein can be used to treat nocturia.

[0071] In some aspects, the present disclosure provides a method of improving Health- related Quality of Life (HRQL) in a subject suffering from overactive bladder symptoms, the method comprising orally administering to the subject in need thereof crystalline form of Compound I-7H over a treatment period, In some aspects, the HRQL includes one or more subscales selected from coping, concern, sleep, social interaction, and combinations thereof.

[0072] In some aspects, the crystalline form of Compound L7H described herein can be used in reducing detrusor overactivity. The term “detrusor overactivity” as used herein refers to the occurrence of involuntary detrusor contractions during filling cystometry. These contractions, which can be spontaneous or provoked, are unable to be suppressed by the patient. They can take a wave (phasic) form, of variable duration and amplitude, on the cystometrogram. Urinary incontinence may or may not occur. These contractions can be voiding contractions, partially-voiding contractions, non-voiding contractions (NVC) or combinations thereof. The term “detrusor overactivity” is defined by the International Continence Society (ICS) as follows: Detrusor overactivity is a urodynamic observation characterized by involuntary detrusor contractions during the filling phase that can be spontaneous or provoked (Abrams P et al., Urology 2003, 62(Supplement 5B): 28-37 and 40-42).

[0073] In some aspects, the crystalline form of Compound L7H described herein can be used in increasing bladder smooth muscle relaxation. In some aspects, the crystalline form of Compound L7H described herein can be used in the treatment of overactive bladder symptoms in men or a subject with benign prostatic hyperplasia (BPH). The term” benign prostatic hyperplasia” is a histologic diagnosis that refers to the proliferation of smooth muscle and epithelial cells within the prostatic transition zone.

[0074] Additional definitions related to urological conditions can be found, e.g., in Chapple et al. (2018) “Terminology report from the International Continence Society (ICS) Working Group on Underactive Bladder (UAB)” Neurology and Urodynamics 37:2928-2931. Additional definitions related to benign prostatic hyperplasia can be found, e.g., at the “Guidelines for Management of Benign Prostatic Hyperplasia,” available at auanet.org / beni gn-prostatic-hyperplasia-(2010-reviewed-and-validity- confirmed-2014). All these documents are herein incorporated by reference in their entireties.EXAMPLES

[0075] Crystal forms can be prepared by a variety of methods, including for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a supercritical fluid, and jet spraying. Techniques for crystallization or recrystallization of co-crystal forms from a solvent mixture include, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, crystal seeding a supersaturated solvent mixture of the molecule and / or salt, freeze drying the solvent mixture, and addition of antisolvents (countersolvents) to the solvent mixture.

[0076] For crystallization techniques that employ solvent, the choice of solvent or solvents is typically dependent upon one or more factors, such as solubility of the compound, crystallization technique, and vapor pressure of the solvent. Combinations of solvents can be employed, for example, the compound can be solubilized into a first solvent to afford a solution, followed by the addition of an antisolvent to decrease the solubility of the compound in the solution and to afford the formation of crystals. An antisolvent is a solvent in which the compound has low solubility.

[0077] In one method to prepare crystals, vibegron is dissolved in a mixture of methanol and acetonitrile and flash cooled to produce the desired crystalline form.

[0078] The presence of more than one polymorph in a sample can be determined by techniques such as powder x-ray diffraction (PXRD) or by Raman or IR spectroscopy solid state nuclear magnetic resonance spectroscopy. For example, the presence of extra peaks in the comparison of an experimentally measured PXRD pattern with a simulated PXRD pattern can indicate more than one polymorph in the sample. The simulated PXRD can be calculated from single crystal x-ray data. See Smith, D.K., “A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns,” Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963).

[0079] The crystalline form of Compound L7H as described herein can be characterized using various techniques, the operation of which are well known to those of ordinary skill in the art. The forms can be characterized by various means, such as, but not limited to, powder x-ray diffraction analysis in which the diffraction profile is compared to a simulated profile representing pure powder material, both run at the same analytical temperature.

[0080] Other means of characterizing the form can be used, such as solid state nuclear magnetic resonance (SSNMR), differential scanning calorimetry, therm ogravimetric analysis, FT-Raman, and FT-IR. These techniques can also be used in combination to characterize the subject form. In addition to the techniques specifically described herein, the presence of a particular crystalline form can be determined by other suitable analytical methods.Example 1

[0081] Vibegron (0.55 g) was added into a round-bottom flask, treated with methanolacetonitrile (1 :1, v / v, water content of the mixture solvent is 0.0774 wt.% by KF titration) 30.24 g, and stirred at 20 °C for 30 min, until the solid dissolved completely. Acetonitrile (20.22 g, water content is 0.007 Iwt. % by KF), was added and the mixture was stirred for 60 min at 20 °C.

[0082] Dry ice was used as the cooling media to flash cool the process stream while keeping the mixture agitated. The mixture was held for 3 hours, the dry ice bath was removed, and the process stream was warmed back up to room temperature over 2 hours. The slurry was filtered, and the solids were air-dried at ambient temperature.

[0083] The analytical data for the crystalline Compound I-7H described herein were obtained using the following procedures.Powder X-Ray Diffraction (PXRD)

[0084] PXRD diffractogram was acquired for the crystalline Compound I-7H described herein using a 40 kV, 15 mA X-ray generator and MiniFlex 300 / 600 Goniometer with a D / teX Ultra 2 detector. A representative PXRD spectra is shown in Fig. 1. Table 2 shows the peak listings:Table 2Differential Scanning Calorimetry (DSC)

[0085] DSC was conducted on a TA Discover DSC 250 using a Tzero pan and Tzero lid. The temperature range was 40 °C to 250 °C and the heating rate was 10 °C / min. Nitrogen flow was 50mL / min and the sample mass was about 3 mg.

[0086] Results of the DSC analysis are shown in Figure 2. As shown in the figure, there is an endothermic peak onset at around 105 - 108 °C, likely a dehydration peak.Thermal Gravimetric Analysis (TGA)

[0087] TGA thermograms were obtained with a TA Instruments Q500 thermogravimetric analyzer. The profile is shown in Figure 3. As shown in the figure, there is a slow weight loss from 40 °C to 100 °C, then a stage between 100 °C - 120 °C (around 2.3%- 2.6% weight loss), which is corresponding to the DSC peak from 100-120 °C. The weight loss before the stage most probably is due to the residual solvent, and the stage could be due to desol vati on / dehy drati on .Karl-Fisher Titration

[0088] Karl-Fisher Titration was performed on a Mettler Toledo C20 Coulametric KF Titrator with CombiCoulomat fritless reagent to acquire the water content in the sample.The titration results showed that the water content of the claimed form (2.15%) matches its weight loss from the TGA profile described above.

[0089] Table 3 shows the calculation of the theoretical water content required to form hemihydrate / hydrate form of vibegron. As shown in the table, around 1.95% water is required to from hemihydrate vibegron. The results from DSC / TGA and KF support the conclusion that the claimed form is a hemihydrate form vibegron.Table 3

[0090] It is to be appreciated that the Detailed Description section, and not the Summary and Abstract sections, is intended to be used to interpret the claims. The Summary and Abstract sections may set forth one or more but not all exemplary aspects of the present disclosure as contemplated by the inventor(s), and thus, are not intended to limit the present disclosure and the appended claims in any way.

[0091] The present disclosure has been described above with the aid of functional building blocks illustrating the implementation of specified functions and relationships thereof. The boundaries of these functional building blocks have been arbitrarily defined herein for the convenience of the description. Alternate boundaries can be defined so long as the specified functions and relationships thereof are appropriately performed.

[0092] The foregoing description of the specific aspects will so fully reveal the general nature of the disclosure that others can, by applying knowledge within the skill of the art, readily modify and / or adapt for various applications such specific aspects, without undue experimentation, without departing from the general concept of the present disclosure. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed aspects, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology herein is for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance.

[0093] The breadth and scope of the present disclosure should not be limited by any of the above-described exemplary aspects, but should be defined only in accordance with the following claims and their equivalents.

Claims

WHAT IS CLAIMED IS:

1. A crystalline form of Compound I-7H:Compound I-7H, characterized by a powder X-ray diffraction (XRPD) pattern comprising °29 peaks at 6.20+0.20, 8.39+0.20, and 12.28+0.20.

2. The crystalline form of claim 1, wherein the crystalline form is characterized by the XRPD pattern further comprising a °29 peak at 10.13+0.20.

3. The crystalline form of claim 1, wherein the crystalline form is characterized by the XRPD pattern further comprising a °29 peak at 7.57+0.20.

4. The crystalline form of claim 1, wherein the crystalline form is characterized by the XRPD pattern further comprising °29 peaks at 7.57+0.20 and 10.13+0.20.

5. The crystalline form of any one of claims 1 to 4, characterized by an XRPD pattern substantially similar to the one as shown in FIG. 1.

6. The crystalline form of any one of claims 1 to 5, wherein the form is characterized by a differential scanning calorimetry thermogram comprising an endotherm having an onset at about 105 °C to about 108 °C.

7. The crystalline form of any one of claims 1 to 6, wherein the crystalline form is characterized by a differential scanning calorimetry thermogram substantially similar to the one as shown in FIG. 2.

8. The crystalline form of any one of claims 1 to 7, wherein the crystalline form is characterized by a thermal gravimetric analysis thermogram substantially similar to the one as shown in FIG. 3.

9. The crystalline form of any one of claims 1 to 8, in substantially pure form.

10. A composition comprising the crystalline form of any one of claims 1 to 8, wherein the composition contains between about 0.5% and about 10% of crystalline Form I of Compound 1-7 :Compound 1-7.

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the crystalline form of any one of claims 1 to 9 or the composition of claim 10.

12. A method of treating overactive bladder in a subject in need thereof, the method comprising administering to the subject the crystalline form of any one of claims 1 to 9, the composition of claim 10, or the pharmaceutical composition of claim 11.

13. The crystalline form of any one of claims 1 to 9, prepared by dissolving Compound 1-7:Compound 1-7into a solution of methanol and acetonitrile, flash cooling the resulting solution with a dry ice bath, and filtering the resulting slurry.

14. A process for preparing the crystalline form of any one of claims 1 to 9, the process comprising dissolving Compound 1-7:Compound 1-7 into a solution of methanol and acetonitrile, flash cooling the resulting solution with a dry ice bath, and filtering the resulting slurry.

15. The process of claim 14, wherein the ratio of methanol to acetonitrile is 1 : 1.

16. The process of claim 14, further comprising adding additional acetonitrile to the solution after Compound 1-7 is dissolved in the solution of methanol and acetonitrile.

17. A crystalline form of Compound I-7H:Compound I-7H, characterized by a powder X-ray diffraction (XRPD) pattern comprising °29 peaks at 6.20+0.20, 8.39+0.20, and 12.28+0.20; prepared by a process comprising dissolving Compound 1-7 :Compound 1-7 into a solution of methanol and acetonitrile, flash cooling the resulting solution with a dry ice bath, and filtering the resulting slurry.

18. The crystalline form of claim 17, wherein the ratio of methanol to acetonitrile in the solution of methanol and acetonitrile is 1 :1.

19. The crystalline form of claim 17, wherein the process further comprises adding additional acetonitrile to the solution after Compound 1-7 is dissolved in the solution of methanol and acetonitrile.

20. A crystalline form of Compound I-7H:Compound I-7H, characterized by a powder X-ray diffraction (XRPD) pattern comprising °29 peaks at 6.20+0.20, 8.39 ±0.20, and 12.28+0.20; prepared by the process described in any one of claims 14 to 16.

21. A crystalline form of Compound I-7H:Compound I-7H, prepared by the process described in any one of claims 14 to 16.

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