Crystalline carbazole derivatives

Abstract

Provided herein are crystalline carbazole derivatives, pharmaceutical compositions thereof, and methods of treatment.

Description

[Technical field]

[0001] REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 185,209, filed May 6, 2021, the entirety of which is incorporated herein by reference. [Background technology]

[0002] Fat-related disorders pose many aesthetic and health problems, and although progress has been made in recent years, there remains a need for new treatments for fat-related disorders. Summary of the Invention

[0003] In one aspect, provided herein is crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A).

[0004] [ka] or a hydrate thereof, and the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride is (a) An X-ray powder diffraction pattern measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å, the X-ray powder diffraction pattern including peaks at 4.0±0.2°2-θ, 16.5±0.2°2-θ, and 15.5±0.2°2-θ; (b) an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å; (c) A differential scanning calorimetry (DSC) thermogram, i) an endotherm in the range of about 260-270 ° C; ii) an endotherm in the range of about 175 to 195 °C; A differential scanning calorimetry (DSC) thermogram, (d) A differential scanning calorimetry (DSC) thermogram, i) an endotherm with an onset of about 265° C. and a peak of about 266° C. ii) an endotherm with an onset of about 180° C. and a peak of about 190° C. A differential scanning calorimetry (DSC) thermogram, (e) A differential scanning calorimetry (DSC) thermogram substantially the same as that shown in FIG. (f) Thermogravimetric analysis (TGA) thermogram substantially the same as that shown in FIG. (g) Unaltered XRPD after storage at 40° C. and 75% relative humidity (RH) for 7 days; (h) XRPD unchanged after storage at 80°C for 7 days; or (i) any combination thereof The present invention is characterized by having the following.

[0005] In some embodiments, the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or a hydrate thereof, is characterized by having an X-ray powder diffraction pattern including peaks at 4.0±0.2 degrees 2-θ, 16.5±0.2 degrees 2-θ, and 15.5±0.2 degrees 2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0006] In some embodiments, the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or a hydrate thereof, is characterized by having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0007] In some embodiments, the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or a hydrate thereof, has a differential scanning calorimetry (DSC) thermogram: i) an endotherm in the range of about 260-270°C, and ii) Endothermic in the range of about 175-195°C The compound is characterized by a differential scanning calorimetry (DSC) thermogram, which includes:

[0008] In some embodiments, the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or a hydrate thereof, has a differential scanning calorimetry (DSC) thermogram: i) an endotherm with an onset of about 265° C. and a peak of about 266° C. ii) an endotherm with an onset of about 180° C. and a peak of about 190° C. The compound is characterized by a differential scanning calorimetry (DSC) thermogram, which includes:

[0009] In some embodiments, the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or a hydrate thereof, is characterized by a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in FIG.

[0010] In some embodiments, the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or a hydrate thereof, is characterized by a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in FIG.

[0011] In one aspect, provided herein is crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A).

[0012] [ka] or a hydrate thereof, and the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride is (a) An X-ray powder diffraction pattern measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å, the X-ray powder diffraction pattern including peaks at 28.4±0.2°2-θ, 18.5±0.2°2-θ, and 12.1±0.2°2-θ; (b) an X-ray powder diffraction pattern substantially the same as that shown in FIG. 7 measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å; or (c) Combinations of these The present invention is characterized by having the following.

[0013] In some embodiments, the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or a hydrate thereof, is characterized by having an X-ray powder diffraction pattern comprising peaks at 28.4±0.2 degrees 2-θ, 18.5±0.2 degrees 2-θ, and 12.1±0.2 degrees 2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0014] In some embodiments, the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or a hydrate thereof, is characterized by having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 7, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0015] In another aspect, provided herein is a pharmaceutical composition comprising crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or a hydrate thereof, provided herein, and at least one pharma- ceutically acceptable excipient.

[0016] In some embodiments, the pharmaceutical compositions are formulated for administration to a mammal by parenteral administration.

[0017] In another aspect, provided herein is a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or a hydrate thereof, provided herein, or a pharmaceutical composition provided herein.

[0018] In some embodiments, the disease or disorder is fat-related disorder.In some embodiments, the fat-related disorder is obesity, abnormal fat distribution, diabetes, cardiovascular disease, obstructive sleep apnea, lipoma, cancer, osteoarthritis, endocrine disease, reproductive disease, neurological disease, psychiatric disease, rheumatic disease, or orthopedic disease.In some embodiments, the fat-related disorder is cellulite, excess fat in various body regions, lipoma, lipomatous disease, disorder associated with fat accumulation, Dercum's disease, lipedema, or edema.

[0019] In some embodiments, the disease or disorder is fibrosis associated with a second disease or disorder. In some embodiments, the second disease or disorder is pulmonary fibrosis, liver cirrhosis, endomyocardial fibrosis, old myocardial infarction, atrial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, carpal tunnel syndrome, joint fibrosis, Crohn's disease, keloids, scleroderma, arthrofibrosis, Peyronie's disease, Dupuytren's contracture, or adhesive capsulitis.

[0020] In some embodiments, the disease or disorder is liposarcoma or a solid tumor.

[0021] In some embodiments, the disease or disorder is a lipoma.

[0022] In some embodiments, the disease or disorder is angiolipoma.

[0023] In another aspect, provided herein is the use of crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride provided herein, or a hydrate thereof, or a composition provided herein, in the manufacture of a medicament for treating a disease or disorder in a subject in need thereof.

[0024] In some embodiments, the disease or disorder is fat-related disorder.In some embodiments, the fat-related disorder is obesity, abnormal fat distribution, diabetes, cardiovascular disease, obstructive sleep apnea, lipoma, cancer, osteoarthritis, endocrine disease, reproductive disease, neurological disease, psychiatric disease, rheumatic disease, or orthopedic disease.In some embodiments, the fat-related disorder is cellulite, excess fat in various body regions, lipoma, lipomatous disease, disorder associated with fat accumulation, Dercum's disease, lipedema, or edema.

[0025] In some embodiments, the disease or disorder is fibrosis associated with a second disease or disorder. In some embodiments, the second disease or disorder is pulmonary fibrosis, liver cirrhosis, endomyocardial fibrosis, old myocardial infarction, atrial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, carpal tunnel syndrome, arthrofibrosis, Crohn's disease, keloid, scleroderma, arthrofibrosis, Peyronie's disease, Dupuytren's contracture, or adhesive capsulitis.

[0026] In some embodiments, the disease or disorder is liposarcoma or a solid tumor.

[0027] In some embodiments, the disease or disorder is a lipoma.

[0028] In some embodiments, the disease or disorder is angiolipoma.

[0029] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Brief description of the drawings]

[0030] The novel features of the invention are set forth with particularity in the appended claims. To better understand the features and advantages of the present invention, reference should be made to the following detailed description that sets forth illustrative embodiments in which the principles of the invention are utilized and the accompanying drawings in which:

[0031] [Figure 1] 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline Compound A Form 1. [Diagram 2] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline Compound A Form 1. [Diagram 3] 1 shows a thermogravimetric analysis (TGA) pattern of crystalline Compound A Form 1. [Figure 4] 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline Compound A Form 2. [Diagram 5] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline Compound A Form 2. [Figure 6] 1 shows a thermogravimetric analysis (TGA) pattern of crystalline Compound A Form 2. [Figure 7] 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline Compound A Form 3. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] Small molecule inhibitors are often first evaluated for their activity when dissolved in solution, but solid state properties such as polymorphism are also important. Polymorphic forms of a drug substance can have different physical properties, including melting point, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct impact on the ability to process or manufacture the drug substance and drug product. Furthermore, differences in these properties can, and often do, result in different pharmacokinetic profiles for different polymorphic forms of a drug. Thus, polymorphism is often an important factor under regulatory review of the "identity" of drug products from various manufacturers. For example, polymorphism has been evaluated in multi-million, and sometimes hundreds of billion dollar drugs, such as warfarin sodium, famotidine, and ranitidine. Polymorphism can affect the quality, safety, and / or efficacy of a drug product. Thus, there remains a need for polymorphs of drug products. The present disclosure addresses this need and provides related advantages.

[0033] Compound A As used herein, compound A refers to 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, having the chemical structure shown below.

[0034] [ka]

[0035] Compound A, 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, has been previously prepared (see WO2013 / 072915 and U.S. Pat. No. 9,447,040).

[0036] In some embodiments disclosed herein, Compound A is amorphous. In some embodiments disclosed herein, Compound A is crystalline.

[0037] I. Crystalline Form of Compound A Compound A exhibits polymorphism, and the crystalline form of Compound A produced according to the methods described herein can be characterized by any methodology known in the art. For example, crystalline Compound A can be characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot stage microscopy, as well as other analytical methods such as solid-state nuclear magnetic resonance (ssNMR), spectroscopy, and infrared (IR) spectroscopy. In some embodiments, the crystallinity of the solid form is determined by X-ray powder diffraction (XRPD).

[0038] XRPD: The crystalline forms of Compound A according to the present invention can be characterized by XRPD as shown in Figure 1, Figure 4, or Figure 7. The relative intensities of the XRPD peaks can vary depending on particle size, sample preparation technique, sample mounting procedure, and the particular instrument utilized. Additionally, instrument variations and other factors can affect the 2-theta values. Thus, the assignments of the XRPD peaks can vary by plus or minus about 0.2 degrees.

[0039] DSC: The crystalline form of Compound A according to the present invention can also be identified by its characteristic DSC thermogram, as shown in Figure 2 or Figure 5. For DSC, it is known that the observed temperatures will depend on the sample preparation technique and the particular instrument utilized, as well as the rate of temperature change. Thus, the values ​​reported herein for the DSC thermograms may vary, for example, by plus or minus about 4°C.

[0040] TGA: The crystalline form of Compound A may produce different temperature characteristics from that of amorphous material or another polymorphic form. The temperature characteristics may be measured in the laboratory by thermogravimetric analysis (TGA), which may be used to distinguish one polymorphic form from another. In one embodiment, the crystalline form may be characterized by thermogravimetric analysis. The crystalline Compound A may be identified by its characteristic TGA thermogram as shown in Figure 3 or Figure 6.

[0041] Crystalline forms of Compound A are useful for the manufacture of pharmaceutical formulations and can be obtained by a crystallization process. Semicrystalline forms can also be obtained. In some embodiments, semicrystalline forms of Compound A include one or more of the crystalline forms described herein and / or amorphous Compound A. In some embodiments, a solidification process is used to obtain the amorphous form. In various embodiments, crystallization is carried out by either forming the desired compound (e.g., Compound A) in a reaction mixture and isolating the desired crystalline form from the reaction mixture, or dissolving the raw compound in a solvent, optionally using heat, and then crystallizing / solidifying by cooling (including active cooling) or adding an anti-solvent. Following crystallization or solidification, drying can be carried out under controlled conditions until the desired water content for the desired crystalline form is reached.

[0042] In various embodiments, the crystalline compound A disclosed herein is stable at room temperature. In some examples, the crystalline compound A can be stored at room temperature for an extended period of time without significant chemical decomposition or change in crystalline form. In some examples, the crystalline compound A can be stored at room temperature for a period of at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days. In some examples, the crystalline compound A can be stored at room temperature for a period of more than about 7 days. In some examples, the crystalline compound A can be stored at room temperature for 10 to 20 days. In some examples, the crystalline compound A can be stored at room temperature for 10 to 15 days. In some examples, the crystalline compound A can be stored at room temperature for 15 to 20 days. In some examples, the crystalline compound A can be stored at room temperature for 10 to 12 days. In some examples, the crystalline compound A can be stored at room temperature for 12 to 14 days. In some examples, the crystalline compound A can be stored at room temperature for 14 to 16 days. In some examples, the crystalline compound A can be stored at room temperature for 16 to 18 days. In some examples, the crystalline compound A can be stored at room temperature for 18 to 20 days. In some examples, the crystalline compound A can be stored at room temperature for a period of 1 to 2 days, 1 to 3 days, 1 to 4 days, 1 to 5 days, 1 to 6 days, 1 to 7 days, 2 to 3 days, 2 to 4 days, 2 to 5 days, 2 to 6 days, 2 to 7 days, 3 to 4 days, 3 to 5 days, 3 to 6 days, 3 to 7 days, 4 to 5 days, 4 to 6 days, 4 to 7 days, 5 to 6 days, 5 to 7 days, or 6 to 7 days. In some examples, the crystalline compound A can be stored at room temperature for a period of at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days. In some embodiments, the crystalline compound A can be stored at room temperature for a period of at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months. In some embodiments, crystalline Compound A can be stored at room temperature for more than one year without significant chemical decomposition or change in crystalline form.In some embodiments, crystalline compound A can be stored at room temperature for a period of at least 12 months, at least 14 months, at least 16 months, at least 18 months, at least 20 months, at least 22 months, or at least 24 months. In some embodiments, crystalline compound A can be stored at room temperature for 1-2 years without significant chemical decomposition or change in crystalline form. In some embodiments, crystalline compound A can be stored at room temperature for 2 years or more. In some embodiments, crystalline compound A can be stored at room temperature for a period of at least 24 months, at least 30 months, or at least 36 months. In some embodiments, crystalline compound A can be stored at room temperature for 36 months. In some embodiments, crystalline compound A can be stored at room temperature for a period of 12-18 months, 14-20 months, 16-22 months, 18-24 months, 20-26 months, 22-38 months, or 24-40 months.

[0043] In various embodiments, the crystalline compound A disclosed herein is stable at temperatures higher than room temperature and / or at high relative humidity (RH). In some examples, crystalline compound A can be stored at about 40° C. and about 75% RH for an extended period of time without significant chemical decomposition or change in crystalline form. In some examples, crystalline compound A can be stored at about 40° C. and about 75% RH for at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days. In some examples, crystalline compound A can be stored at about 40° C. and about 75% RH for more than about 7 days. In some examples, the polymorph may be stored at about 40° C. and about 75% RH for a period of 1-2 days, 1-3 days, 1-4 days, 1-5 days, 1-6 days, 1-7 days, 2-3 days, 2-4 days, 2-5 days, 2-6 days, 2-7 days, 3-4 days, 3-5 days, 3-6 days, 3-7 days, 4-5 days, 4-6 days, 4-7 days, 5-6 days, 5-7 days, or 6-7 days. In some examples, crystalline Compound A may be stored at about 40° C. and about 75% RH for a period of at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days.

[0044] In various embodiments, the crystalline compound A disclosed herein is stable at high temperatures. In some examples, the crystalline compound A can be stored at about 80° C. for an extended period of time without significant chemical decomposition or change in crystalline form. In some examples, the crystalline compound A can be stored at about 80° C. for a period of at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days. In some examples, the crystalline compound A can be stored at about 80° C. for a period of more than about 7 days. In some examples, the crystalline compound A can be stored at about 80° C. for a period of 1-2 days, 1-3 days, 1-4 days, 1-5 days, 1-6 days, 1-7 days, 2-3 days, 2-4 days, 2-5 days, 2-6 days, 2-7 days, 3-4 days, 3-5 days, 3-6 days, 3-7 days, 4-5 days, 4-6 days, 4-7 days, 5-6 days, 5-7 days, or 6-7 days. In some examples, crystalline Compound A can be stored at about 80° C. for a period of at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days.

[0045] Crystalline Compound A Form 1 FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline Compound A Form 1.

[0046] FIG. 2 shows a differential scanning calorimetry (DSC) thermogram of crystalline Compound A Form 1.

[0047] FIG. 3 shows a thermogravimetric analysis (TGA) pattern of crystalline Compound A Form 1.

[0048] In one aspect, provided herein is crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A). Some embodiments provide a composition comprising crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride. In some embodiments, the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride Form 1 (Compound A Form 1) is (a) An X-ray powder diffraction pattern measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å, the X-ray powder diffraction pattern including peaks at 4.0±0.2°2-θ, 16.5±0.2°2-θ, and 15.5±0.2°2-θ; (b) An X-ray powder diffraction pattern substantially the same as that shown in FIG. (c) A differential scanning calorimetry (DSC) thermogram, i) an endotherm in the range of about 260-270 ° C; ii) an endotherm in the range of about 175 to 195 °C; A differential scanning calorimetry (DSC) thermogram, (d) A differential scanning calorimetry (DSC) thermogram, i) an endotherm with an onset of about 265° C. and a peak of about 266° C. ii) an endotherm with an onset of about 180° C. and a peak of about 190° C. A differential scanning calorimetry (DSC) thermogram, (e) A differential scanning calorimetry (DSC) thermogram substantially the same as that shown in FIG. (f) Thermogravimetric analysis (TGA) thermogram substantially the same as that shown in FIG. (g) XRPD unchanged after storage at 40° C. and 75% relative humidity (RH) for 7 days; (h) XRPD unchanged after storage at 80°C for 7 days; or (i) any combination thereof The present invention is characterized by having the following.

[0049] In some embodiments, crystalline Compound A Form 1 is characterized by having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0050] In some embodiments, crystalline Compound A Form 1 is characterized by having an X-ray powder diffraction pattern including peaks at 4.0±0.2°2-θ, 16.5±0.2°2-θ, and 15.5±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, crystalline Compound A Form 1 is characterized by having an X-ray powder diffraction pattern including peaks at 4.0±0.1°2-θ, 16.5±0.1°2-θ, and 15.5±0.1°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, crystalline Compound A Form 1 is characterized by having an X-ray powder diffraction pattern including peaks at about 4.0°2-θ, about 16.5°2-θ, and about 15.5°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0051] In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 1 further comprises at least one peak selected from 24.1±0.2°2-θ, 26.0±0.2°2-θ, and 26.1±0.2°2-θ, measured with Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 1 further comprises at least one peak selected from 24.1±0.1°2-θ, 26.0±0.1°2-θ, and 26.1±0.1°2-θ, measured with Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 1 further comprises at least one peak selected from about 24.1° 2-θ, about 26.0° 2-θ, and about 26.1° 2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0052] In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 1 further comprises at least one peak selected from 19.9±0.2°2-θ, 23.8±0.2°2-θ, and 26.5±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 1 further comprises at least one peak selected from 19.9±0.1°2-θ, 23.8±0.1°2-θ, and 26.5±0.1°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 1 further comprises at least one peak selected from about 19.9° 2-θ, about 23.8° 2-θ, and about 26.5° 2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0053] In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 1 comprises at least one peak selected from 4.0±0.2°2-θ, 15.5±0.2°2-θ, 16.5±0.2°2-θ, 19.9±0.2°2-θ, 23.8±0.2°2-θ, 24.1±0.2°2-θ, 26.0±0.2°2-θ, 26.1±0.2°2-θ, and 26.5±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 1 comprises at least two peaks selected from 4.0±0.2°2-θ, 15.5±0.2°2-θ, 16.5±0.2°2-θ, 19.9±0.2°2-θ, 23.8±0.2°2-θ, 24.1±0.2°2-θ, 26.0±0.2°2-θ, 26.1±0.2°2-θ, and 26.5±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 1 comprises at least three peaks selected from 4.0±0.2°2-θ, 15.5±0.2°2-θ, 16.5±0.2°2-θ, 19.9±0.2°2-θ, 23.8±0.2°2-θ, 24.1±0.2°2-θ, 26.0±0.2°2-θ, 26.1±0.2°2-θ, and 26.5±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 1 comprises at least four peaks selected from 4.0±0.2°2-θ, 15.5±0.2°2-θ, 16.5±0.2°2-θ, 19.9±0.2°2-θ, 23.8±0.2°2-θ, 24.1±0.2°2-θ, 26.0±0.2°2-θ, 26.1±0.2°2-θ, and 26.5±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 1 comprises at least five peaks selected from 4.0±0.2°2-θ, 15.5±0.2°2-θ, 16.5±0.2°2-θ, 19.9±0.2°2-θ, 23.8±0.2°2-θ, 24.1±0.2°2-θ, 26.0±0.2°2-θ, 26.1±0.2°2-θ, and 26.5±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 1 comprises at least six peaks selected from 4.0±0.2°2-θ, 15.5±0.2°2-θ, 16.5±0.2°2-θ, 19.9±0.2°2-θ, 23.8±0.2°2-θ, 24.1±0.2°2-θ, 26.0±0.2°2-θ, 26.1±0.2°2-θ, and 26.5±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 1 comprises at least seven peaks selected from 4.0±0.2°2-θ, 15.5±0.2°2-θ, 16.5±0.2°2-θ, 19.9±0.2°2-θ, 23.8±0.2°2-θ, 24.1±0.2°2-θ, 26.0±0.2°2-θ, 26.1±0.2°2-θ, and 26.5±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 1 comprises at least eight peaks selected from 4.0±0.2°2-θ, 15.5±0.2°2-θ, 16.5±0.2°2-θ, 19.9±0.2°2-θ, 23.8±0.2°2-θ, 24.1±0.2°2-θ, 26.0±0.2°2-θ, 26.1±0.2°2-θ, and 26.5±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 1 includes peaks at 4.0±0.2°2-θ, 15.5±0.2°2-θ, 16.5±0.2°2-θ, 19.9±0.2°2-θ, 23.8±0.2°2-θ, 24.1±0.2°2-θ, 26.0±0.2°2-θ, 26.1±0.2°2-θ, and 26.5±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 1 includes peaks at 4.0±0.1°2-θ, 15.5±0.1°2-θ, 16.5±0.1°2-θ, 19.9±0.1°2-θ, 23.8±0.1°2-θ, 24.1±0.1°2-θ, 26.0±0.1°2-θ, 26.1±0.1°2-θ, and 26.5±0.1°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 1 includes peaks at about 4.0°2-θ, about 15.5°2-θ, about 16.5°2-θ, about 19.9°2-θ, about 23.8°2-θ, about 24.1°2-θ, about 26.0°2-θ, about 26.1°2-θ, and about 26.5°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0054] In some embodiments, crystalline Compound A Form 1 is characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in Figure 2. In some embodiments, crystalline Compound A Form 1 is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 260-270°C and an endotherm in the range of about 175-195°C. In some embodiments, crystalline Compound A Form 1 is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 265°C and a peak at about 266°C and an endotherm with an onset of about 180°C and a peak at about 190°C.

[0055] In some embodiments, crystalline Compound A Form 1 is characterized by an endotherm in the range of about 260-270° C., such as about 260-270° C., 260-268° C., 260-266° C., 260-264° C., 260-262° C., 262-270° C., 262-268° C., 262-266° C., 262-264° C., 264-270° C., 264-268° C., 264-266° C., 266-270° C., 266-268° C., or about 26-270° C. In some examples, crystalline Compound A Form 1 is characterized by an endotherm at about 266° C. in a DSC thermogram.

[0056] In some embodiments, crystalline Compound A Form 1 is further characterized by an endotherm in the range of about 175-195° C., e.g., about 175-195° C., 175-190° C., 175-185° C., 175-180° C., 180-195° C., 180-190° C., 180-185° C., 185-195° C., 185-190° C., or about 190-195° C. In some examples, crystalline Compound A Form 1 is further characterized by an endotherm at about 190° C. in a DSC thermogram.

[0057] In some embodiments, crystalline Compound A Form 1 is characterized by a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in Figure 3. In various embodiments, crystalline Compound A Form 1 decomposes at a temperature above about 150°C, about 200°C, about 250°C, about 300°C, about 350°C, about 400°C, about 450°C, about 500°C, about 550°C, or 600°C. In some examples, crystalline Compound A Form 1 decomposes at a temperature above about 250°C.

[0058] Crystalline Compound A Form 2 FIG. 4 shows the X-ray powder diffraction (XRPD) pattern of crystalline Compound A Form 2.

[0059] FIG. 5 shows a differential scanning calorimetry (DSC) thermogram of crystalline Compound A Form 2.

[0060] FIG. 6 shows a thermogravimetric analysis (TGA) pattern of crystalline Compound A Form 2.

[0061] In one aspect, provided herein is crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A). Some embodiments provide a composition comprising crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride. In some embodiments, the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride Form 2 (Compound A Form 2) is (a) X-ray powder diffraction pattern measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å, including peaks at 4.8±0.2°2-θ, 26.5±0.2°2-θ, and 24.8±0.2°2-θ; (b) An X-ray powder diffraction pattern substantially the same as that shown in FIG. (c) A differential scanning calorimetry (DSC) thermogram, i) Endothermic in the range of about 260-270°C A differential scanning calorimetry (DSC) thermogram, (d) A differential scanning calorimetry (DSC) thermogram, i) an endotherm with an onset of about 265° C. and a peak of about 266° C. A differential scanning calorimetry (DSC) thermogram, (e) A differential scanning calorimetry (DSC) thermogram substantially the same as that shown in FIG. (f) Thermogravimetric analysis (TGA) thermogram substantially the same as that shown in FIG. (g) XRPD unchanged after storage at 80 °C for 7 days; or (h) Combinations thereof The present invention is characterized by having the following.

[0062] In some embodiments, crystalline Compound A Form 2 is characterized by having an X-ray powder diffraction pattern substantially the same as that shown in FIG.

[0063] In some embodiments, crystalline Compound A Form 2 is characterized by having an X-ray powder diffraction pattern including peaks at 4.8±0.2°2-θ, 26.5±0.2°2-θ, and 24.8±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, crystalline Compound A Form 2 is characterized by having an X-ray powder diffraction pattern including peaks at 4.8±0.1°2-θ, 26.5±0.1°2-θ, and 24.8±0.1°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, crystalline Compound A Form 2 is characterized by having an X-ray powder diffraction pattern including peaks at about 4.8°2-θ, about 26.5°2-θ, and about 24.8°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0064] In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 2 further comprises at least one peak selected from 17.5±0.2°2-θ, 17.9±0.2°2-θ, and 21.0±0.2°2-θ, measured with Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 2 further comprises at least one peak selected from 17.5±0.1°2-θ, 17.9±0.1°2-θ, and 21.0±0.1°2-θ, measured with Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 2 further comprises at least one peak selected from about 17.5° 2-θ, about 17.9° 2-θ, and about 21.0° 2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0065] In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 2 further comprises at least one peak selected from 19.6±0.2°2-θ, 25.5±0.2°2-θ, and 20.4±0.2°2-θ, measured with Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 2 further comprises at least one peak selected from 19.6±0.1°2-θ, 25.5±0.1°2-θ, and 20.4±0.1°2-θ, measured with Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 2 further comprises at least one peak selected from about 19.6° 2-θ, about 25.5° 2-θ, and about 20.4° 2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0066] In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 2 comprises at least one peak selected from 4.8±0.2°2-θ, 17.5±0.2°2-θ, 17.9±0.2°2-θ, 19.6±0.2°2-θ, 20.4±0.2°2-θ, 21.0±0.2°2-θ, 24.8±0.2°2-θ, 25.5±0.2°2-θ, and 26.5±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 2 comprises at least two peaks selected from 4.8±0.2°2-θ, 17.5±0.2°2-θ, 17.9±0.2°2-θ, 19.6±0.2°2-θ, 20.4±0.2°2-θ, 21.0±0.2°2-θ, 24.8±0.2°2-θ, 25.5±0.2°2-θ, and 26.5±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 2 comprises at least three peaks selected from 4.8±0.2°2-θ, 17.5±0.2°2-θ, 17.9±0.2°2-θ, 19.6±0.2°2-θ, 20.4±0.2°2-θ, 21.0±0.2°2-θ, 24.8±0.2°2-θ, 25.5±0.2°2-θ, and 26.5±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 2 comprises at least four peaks selected from 4.8±0.2°2-θ, 17.5±0.2°2-θ, 17.9±0.2°2-θ, 19.6±0.2°2-θ, 20.4±0.2°2-θ, 21.0±0.2°2-θ, 24.8±0.2°2-θ, 25.5±0.2°2-θ, and 26.5±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 2 comprises at least five peaks selected from 4.8±0.2°2-θ, 17.5±0.2°2-θ, 17.9±0.2°2-θ, 19.6±0.2°2-θ, 20.4±0.2°2-θ, 21.0±0.2°2-θ, 24.8±0.2°2-θ, 25.5±0.2°2-θ, and 26.5±0.2°5θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 2 comprises at least six peaks selected from 4.8±0.2°2-θ, 17.5±0.2°2-θ, 17.9±0.2°2-θ, 19.6±0.2°2-θ, 20.4±0.2°2-θ, 21.0±0.2°2-θ, 24.8±0.2°2-θ, 25.5±0.2°2-θ, and 26.5±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 2 comprises at least seven peaks selected from 4.8±0.2°2-θ, 17.5±0.2°2-θ, 17.9±0.2°2-θ, 19.6±0.2°2-θ, 20.4±0.2°2-θ, 21.0±0.2°2-θ, 24.8±0.2°2-θ, 25.5±0.2°2-θ, and 26.5±0.2°7θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 2 comprises at least eight peaks selected from 4.8±0.2°2-θ, 17.5±0.2°2-θ, 17.9±0.2°2-θ, 19.6±0.2°2-θ, 20.4±0.2°2-θ, 21.0±0.2°2-θ, 24.8±0.2°2-θ, 25.5±0.2°2-θ, and 26.5±0.2°8θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 2 contains peaks at 4.8±0.2°2-θ, 17.5±0.2°2-θ, 17.9±0.2°2-θ, 19.6±0.2°2-θ, 20.4±0.2°2-θ, 21.0±0.2°2-θ, 24.8±0.2°2-θ, 25.5±0.2°2-θ, and 26.5±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 2 contains peaks at 4.8±0.1°2-θ, 17.5±0.1°2-θ, 17.9±0.1°2-θ, 19.6±0.1°2-θ, 20.4±0.1°2-θ, 21.0±0.1°2-θ, 24.8±0.1°2-θ, 25.5±0.1°2-θ, and 26.5±0.1°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 2 contains peaks at about 4.0°2-θ, about 15.5°2-θ, about 16.5°2-θ, about 19.9°2-θ, about 23.8°2-θ, about 24.1°2-θ, about 26.0°2-θ, about 26.1°2-θ, and about 26.5°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0067] In some embodiments, crystalline Compound A Form 2 is characterized by a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in Figure 5. In some embodiments, crystalline Compound A Form 2 is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of 260-270°C. In some embodiments, crystalline Compound A Form 2 is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm having an onset of about 265°C and a peak at about 266°C.

[0068] In some embodiments, crystalline Compound A Form 2 is characterized by an endotherm in the range of about 260-270° C., such as an endotherm in the range of about 260-270° C., 260-268° C., 260-266° C., 260-264° C., 260-262° C., 262-270° C., 262-268° C., 262-266° C., 262-264° C., 264-270° C., 264-268° C., 264-266° C., 266-270° C., 266-268° C., or about 268-270° C. In some embodiments, crystalline Compound A Form 2 is characterized by an endotherm at about 266° C. in a DSC thermogram.

[0069] In some embodiments, crystalline Compound A Form 2 is characterized by a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in FIG.

[0070] Crystalline Compound A Form 3 FIG. 7 shows the X-ray powder diffraction (XRPD) pattern of crystalline Compound A Form 3.

[0071] In one aspect, provided herein is crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A). Some embodiments provide a composition comprising crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride. In some embodiments, the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride Form 3 (Compound A Form 3) is (a) An X-ray powder diffraction pattern measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å, the X-ray powder diffraction pattern including peaks at 28.4±0.2°2-θ, 18.5±0.2°2-θ, and 12.1±0.2°2-θ; (b) an X-ray powder diffraction pattern substantially the same as that shown in FIG. 7, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å; or (c) A combination of these The present invention is characterized by having the following.

[0072] In some embodiments, crystalline Compound A Form 3 is characterized by having an X-ray powder diffraction pattern substantially the same as that shown in FIG.

[0073] In some embodiments, crystalline Compound A Form 3 is characterized by having an X-ray powder diffraction pattern including peaks at 28.4±0.2°2-θ, 18.5±0.2°2-θ, and 12.1±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, crystalline Compound A Form 3 is characterized by having an X-ray powder diffraction pattern including peaks at 28.4±0.1°2-θ, 18.5±0.1°2-θ, and 12.1±0.1°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, crystalline Compound A Form 3 is characterized by having an X-ray powder diffraction pattern including peaks at about 28.4°2-θ, about 18.5°2-θ, and about 12.1°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0074] In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 3 further comprises at least one peak selected from 26.8±0.2°2-θ, 31.7±0.2°2-θ, and 23.3±0.2°2-θ, measured with Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 3 further comprises at least one peak selected from 26.8±0.1°2-θ, 31.7±0.1°2-θ, and 23.3±0.1°2-θ, measured with Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 3 further comprises at least one peak selected from about 26.8° 2-θ, about 31.7° 2-θ, and about 23.3° 2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0075] In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 3 further comprises at least one peak selected from 20.7±0.2°2-θ, 30.8±0.2°2-θ, and 21.8±0.2°2-θ, measured with Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 3 further comprises at least one peak selected from 20.7±0.1°2-θ, 30.8±0.1°2-θ, and 21.8±0.1°2-θ, measured with Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 3 further comprises at least one peak selected from about 20.7° 2-θ, about 30.8° 2-θ, and about 21.8° 2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0076] In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 3 comprises at least one peak selected from 12.1±0.2°2-θ, 18.5±0.2°2-θ, 20.7±0.2°2-θ, 21.8±0.2°2-θ, 23.3±0.2°2-θ, 26.8±0.2°2-θ, 28.4±0.2°2-θ, 30.8±0.2°2-θ, and 31.7±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 3 comprises at least two peaks selected from 12.1±0.2°2-θ, 18.5±0.2°2-θ, 20.7±0.2°2-θ, 21.8±0.2°2-θ, 23.3±0.2°2-θ, 26.8±0.2°2-θ, 28.4±0.2°2-θ, 30.8±0.2°2-θ, and 31.7±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 3 comprises at least three peaks selected from 12.1±0.2°2-θ, 18.5±0.2°2-θ, 20.7±0.2°2-θ, 21.8±0.2°2-θ, 23.3±0.2°2-θ, 26.8±0.2°2-θ, 28.4±0.2°2-θ, 30.8±0.2°2-θ, and 31.7±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 3 comprises at least four peaks selected from 12.1±0.2°2-θ, 18.5±0.2°2-θ, 20.7±0.2°2-θ, 21.8±0.2°2-θ, 23.3±0.2°2-θ, 26.8±0.2°2-θ, 28.4±0.2°2-θ, 30.8±0.2°2-θ, and 31.7±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 3 comprises at least five peaks selected from 12.1±0.2°2-θ, 18.5±0.2°2-θ, 20.7±0.2°2-θ, 21.8±0.2°2-θ, 23.3±0.2°2-θ, 26.8±0.2°2-θ, 28.4±0.2°2-θ, 30.8±0.2°2-θ, and 31.7±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 3 comprises at least six peaks selected from 12.1±0.2°2-θ, 18.5±0.2°2-θ, 20.7±0.2°2-θ, 21.8±0.2°2-θ, 23.3±0.2°2-θ, 26.8±0.2°2-θ, 28.4±0.2°2-θ, 30.8±0.2°2-θ, and 31.7±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 3 comprises at least seven peaks selected from 12.1±0.2°2-θ, 18.5±0.2°2-θ, 20.7±0.2°2-θ, 21.8±0.2°2-θ, 23.3±0.2°2-θ, 26.8±0.2°2-θ, 28.4±0.2°2-θ, 30.8±0.2°2-θ, and 31.7±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 3 comprises at least eight peaks selected from 12.1±0.2°2-θ, 18.5±0.2°2-θ, 20.7±0.2°2-θ, 21.8±0.2°2-θ, 23.3±0.2°2-θ, 26.8±0.2°2-θ, 28.4±0.2°2-θ, 30.8±0.2°2-θ, and 31.7±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 3 contains peaks at 12.1±0.2°2-θ, 18.5±0.2°2-θ, 20.7±0.2°2-θ, 21.8±0.2°2-θ, 23.3±0.2°2-θ, 26.8±0.2°2-θ, 28.4±0.2°2-θ, 30.8±0.2°2-θ, and 31.7±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 3 contains peaks at 12.1±0.1°2-θ, 18.5±0.1°2-θ, 20.7±0.1°2-θ, 21.8±0.1°2-θ, 23.3±0.1°2-θ, 26.8±0.1°2-θ, 28.4±0.1°2-θ, 30.8±0.1°2-θ, and 31.7±0.1°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 2 contains peaks at about 12.1°2-θ, about 18.5°2-θ, about 20.7°2-θ, about 21.8°2-θ, about 23.3°2-θ, about 26.8°2-θ, about 28.4°2-θ, about 30.8°2-θ, and about 31.7°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0077] II. Methods for preparing compound A and its polymorphs In one embodiment, the present invention provides compound A

[0078] [ka] The present invention provides a method for producing a crystalline form of

[0079] In some embodiments, compound A is prepared according to the Examples herein.

[0080] The crystalline compound A according to the present invention is not limited by the starting material used to prepare compound A.

[0081] In one aspect, the present invention relates to a method for preparing a crystalline form of Compound A or a pharma- ceutically acceptable salt and / or solvate thereof by isolating the desired crystalline form as the first solid form following synthesis of Compound A or by isolating the desired crystalline form as a transition from a prior solid form of Compound A. The transition from one form to another is within the scope of the present invention, as it may be an alternative manufacturing method to obtain a form that is desirable for the manufacture of a pharmaceutical formulation.

[0082] Isolation and purification of the chemicals and intermediates described herein can be carried out by any suitable separation or purification procedure, for example, filtration, extraction, crystallization, column chromatography, thin or thick layer chromatography, or a combination of these procedures, if desired. Specific illustrations of suitable separation and isolation procedures can be obtained by referring to the following examples. However, other equivalent separation or isolation procedures can also be used. Prior to crystallization, compound A can be isolated with about 50% chemical purity, 55% chemical purity, 60% chemical purity, 65% chemical purity, 70% chemical purity, 75% chemical purity, 80% chemical purity, 90% chemical purity, 91% chemical purity, 92% purity, 93% chemical purity, 94% chemical purity, 95% chemical purity, 96% chemical purity. It is isolated with 97% chemical purity, 98% chemical purity, 99% chemical purity, about 98% chemical purity, or about 100% chemical purity.

[0083] In some embodiments, the crystalline forms disclosed herein are obtained by crystallizing Compound A with a chemical purity of less than about 98%, less than about 97%, less than about 96%, less than about 95%, less than about 94%, less than about 93%, less than about 92%, less than about 91%, less than about 90%, less than about 89%, less than about 88%, less than about 87%, less than about 86%, less than about 85%, less than about 84%, less than about 83%, less than about 82%, less than about 81%, less than about 80%, less than about 78%, less than about 76%, less than about 74%, less than about 72%, or less than about 70%. In some embodiments, the crystalline form is obtained by crystallizing Compound A with a chemical purity in the range of about 70% to about 99%, 80% to about 96%, about 85% to about 96%, about 90% to about 96%, about 80% to 98%, about 85% to about 98%, about 90% to about 98%, about 92% to about 98%, about 94% to 98%, or about 96% to about 98%.

[0084] In some embodiments, isolating the desired crystalline form of Compound A comprises crystallization of the crude reaction product from a single solvent system. In various embodiments, isolating the desired crystalline form of Compound A comprises crystallization of the crude product from a binary, ternary, or more solvent system, collectively understood as a multiple solvent system.

[0085] In some embodiments, crystallization is performed by producing the desired compound A in a reaction mixture and isolating the desired crystalline form from the reaction mixture. In some embodiments, the reaction mixture is formed by adding (5-bromopentyl)-trimethyl-ammonium bromide, potassium carbonate, and brine to a solution of 3,6-dibromocarbazole to form dissolved 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (compound A). In other embodiments, the reaction mixture is formed by dissolving compound A in a solvent.

[0086] Preparation of crystalline compound A In some embodiments, crystalline Compound A is obtained from a solution formed by addition of a solvent to Compound A. In some embodiments, the solvent is selected from 1-butanol, 2-propanol, acetone, acetonitrile, benzyl alcohol, dichloromethane, dimethylsulfoxide, ethanol, ethyl acetate, isopropyl acetate, methanol, methyl ethyl ketone, propylene glycol, methyl isobutyl ketone, tert-butyl methyl ether, tetrahydrofuran, toluene, Tween 80, water, and combinations thereof.

[0087] In some embodiments, crystalline Compound A is obtained by temperature cycling a solution of Compound A. In some embodiments, temperature cycling comprises cycling at a temperature between 0°C and 80°C, between 0°C and 70°C, between 0°C and 60°C, between 0°C and 50°C, between 5°C and 80°C, between 5°C and 70°C, between 5°C and 60°C, between 5°C and 50°C, between 10°C and 80°C, between 10°C and 70°C, between 10°C and 60°C, between 10°C and 50°C, between 15°C and 80°C, between 15°C and 70°C, between 15°C and 60°C, between 15°C and 50°C, between 20°C and 80°C, between 20°C and 70°C, between 20°C and 60°C, or between 20°C and 50°C. In some embodiments, temperature cycling comprises cycling at a temperature between 5°C and 50°C. In some embodiments, the temperature cycling includes hold periods at the lower and higher temperatures between 0.5 and 10 hours, such as 0.5 and 10 hours, 0.5 and 8 hours, 0.5 and 6 hours, 0.5 and 4 hours, 0.5 and 2 hours, 1 and 10 hours, 1 and 8 hours, 1 and 6 hours, 1 and 4 hours, 1 and 2 hours, 2 and 10 hours, 2 and 8 hours, 2 and 6 hours, 2 and 4 hours, 4 and 10 hours, 4 and 8 hours, 4 and 6 hours, 6 and 10 hours, 6 and 8 hours, or 8 and 10 hours. In some embodiments, the temperature cycling includes hold periods of 1 hour at the lower and higher temperatures. In some embodiments, the temperature cycling further includes the addition of an anti-solvent. In some embodiments, the anti-solvent is tert-butyl methyl ether.

[0088] In some embodiments, crystalline Compound A is obtained by crash-cooling a solution of Compound A. In some embodiments, crash-cooling comprises rapidly cooling the solution to a temperature between 0°C and 10°C, between 0°C and 8°C, between 0°C and 6°C, between 0°C and 4°C, between 0°C and 2°C, between 1°C and 10°C, between 1°C and 8°C, between 1°C and 6°C, between 1°C and 4°C, between 1°C and 2°C, between 2°C and 10°C, between 2°C and 8°C, between 2°C and 6°C, between 2°C and 4°C, between 4°C and 10°C, between 4°C and 8°C, between 4°C and 6°C, between 6°C and 10°C, between 6°C and 8°C, or between 8°C and 10°C. In some embodiments, crash-cooling comprises rapidly cooling the solution to a temperature of 6°C. In some embodiments, crash cooling is performed at temperatures between 0°C and -20°C, between 0°C and -18°C, between 0°C and -16°C, between 0°C and -14°C, between 0°C and -12°C, between 0°C and -10°C, between 0°C and -8°C, between 0°C and -6°C, between 0°C and -4°C, between 0°C and -2°C, between -2°C and -20°C, between -2°C and -18°C, between -2°C and -16°C, between -2°C and -14 ... between -12°C, between -2°C and -10°C, between -2°C and -8°C, between -2°C and -6°C, between -2°C and -4°C, between -4°C and -20°C, between -4°C and -18°C, between -4°C and -16°C, between -4°C and -14°C, between -4°C and -12°C, between -4°C and -10°C, between -4°C and -8°C, between -4°C and -6°C, between -6°C and -20°C, between -6°C and -18°C, between -6°C and -16°C between -6℃ and -14℃, between -6℃ and -12℃, between -6℃ and -10℃, between -6℃ and -8℃, between -8℃ and -20℃, between -8℃ and -18℃, between -8℃ and -16℃, between -8℃ and -14℃, between -8℃ and -12℃, between -8℃ and -10℃, between -10℃ and -20℃, between -10℃ and -18℃, between -10℃ and -16℃, between -10℃ and -14℃, between -10℃ and - It further comprises rapidly cooling the solution to a temperature between 0°C and -20°C, such as between 12°C, between -12°C and -20°C, between -12°C and -18°C, between -12°C and -16°C, between -12°C and -14°C, between -14°C and -20°C, between -14°C and -18°C, between -14°C and -16°C, between -16°C and -20°C, between -16°C and -18°C, or between -18°C and -20°C.In some embodiments, the crash cooling further comprises rapidly cooling the solution to a temperature of -18°C. In some embodiments, the crash cooling further comprises adding an anti-solvent. In some embodiments, the anti-solvent is added before cooling. In some embodiments, the anti-solvent is added after cooling. In some embodiments, the anti-solvent is added after the first cooling and before the second cooling. In some embodiments, the anti-solvent is tert-butyl methyl ether.

[0089] In various embodiments, the crystallization further comprises filtering the solution containing the obtained crystals of crystalline Compound A. In some embodiments, the crystallization optionally comprises washing the obtained crystals with a solvent, for example, with a recrystallization solvent, one or more times. In some embodiments, the crystallization optionally comprises drying the obtained crystals, for example, under vacuum at a temperature of about 20-30°C.

[0090] In some embodiments, the chemical purity of crystalline compound A is greater than 60%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, or greater than 99%. In some embodiments, the chemical purity of crystalline compound A is greater than about 90%. In some embodiments, the chemical purity of crystalline compound A is greater than about 95%. In some embodiments, the chemical purity of crystalline compound A is greater than about 99%. The chemical purity of crystalline compound A can be measured by any available analytical technique, for example, by HPLC analysis.

[0091] In various embodiments, crystalline Compound A is solvated. In some embodiments, crystalline Compound A is anhydrous (i.e., not hydrated). In various embodiments, crystalline Compound A is hydrated. In some embodiments, crystalline Compound A is hydrated and characterized as having 1-2 water molecules associated with the hydrate. In some embodiments, crystalline Compound A is hydrated and the average number of water molecules associated with the hydrate is about 1.5. In some embodiments, Compound A is multiply hydrated. In various embodiments, crystalline Compound A is a dihydrate. In some embodiments, crystalline Compound A comprises a water content. In some embodiments, crystalline Compound A comprises a water content (w / w%) of about 1 to about 10%. In some embodiments, crystalline Compound A comprises a water content of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% (w / w%). In some embodiments, the crystalline compound A comprises a water content (w / w%) of 2 to about 8%. In some embodiments, the crystalline compound A comprises a water content (w / w%) of 3 to about 6%. In some embodiments, the crystalline compound A comprises a water content (w / w%) of 3.5 to about 5.5%. In some embodiments, the water content is determined by Karl Fischer coulometric titration.

[0092] III. Additional Definitions As used herein, "active agent" is used to refer to a chemical entity that has biological activity. In certain embodiments, an "active agent" is a compound that has pharmaceutical utility.

[0093] As used herein, "modulation" refers to a change in activity, as a direct or indirect response to the presence of a chemical compound described herein, relative to activity in the absence of the chemical compound described herein. The change can be an increase in activity or a decrease in activity, and can be due to the direct interaction of the compound with the target, or can be due to the interaction of the compound with one or more other factors that affect the activity of the target. For example, the presence of a chemical compound can increase or decrease target activity, for example, by directly binding to the target, by causing (directly or indirectly) another factor that increases or decreases target activity, or by increasing or decreasing (directly or indirectly) the amount of target present in a cell or organism.

[0094] As used herein, a "therapeutically effective amount" of a chemical entity described herein refers to an amount that, when administered to a human or non-human subject, provides a therapeutic benefit, such as amelioration of symptoms, delaying disease progression, or prevention of disease.

[0095] "Treat" or "treatment" encompasses administration of Compound A, or a pharma- ceutically acceptable salt thereof, to a mammalian subject, particularly a human subject, in need of such administration, and includes (i) halting the progression of clinical symptoms of the disease, (ii) causing regression of clinical symptoms of the disease, and / or (iii) prophylactic treatment to prevent the onset of the disease.

[0096] As used herein, a "pharmaceutical acceptable" component is one that is suitable for use in humans and / or animals without undue adverse side effects (such as toxicity, irritation, and allergic reactions) and commensurate with a reasonable benefit / risk ratio.

[0097] "Pharmaceutically acceptable salts" include salts with inorganic acids, such as hydrochlorides, carbonates, phosphates, hydrogen phosphates, diphosphates, hydrobromides, sulfates, sulfamates, and nitrates, as well as malate, malonate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, gluconate, methanesulfonate, tris(hydroxymethylaminomethane) p-toluenesulfonate, prionate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, oxalate, pamoate, acetate, and HO2C-(CH2) n Salts include, but are not limited to, salts with organic acids, such as alkanoates, such as -CO2H (n is 0-4), and similar salts. Other salts include sulfates, metasulfonates, bromides, trifluoroacetates, picrates, sorbates, benzilates, salicylates, nitrates, phthalates, or morpholines. Pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0098] In addition, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharma- ceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharma-ceutically acceptable addition salts.

[0099] As used herein, "subject" refers to a mammal that has been or may be the object of treatment, observation, or experiment. The methods described herein can be useful in both human treatment and veterinary applications. In some embodiments, the subject is a human.

[0100] The term "mammal" is intended to have its standard meaning and includes, for example, humans, dogs, cats, sheep, and cows.

[0101] The compounds disclosed herein may be purchased in different isotopically enriched forms, e.g. 2 H, 3 H, 11 C. 13 C and / or 14 The C content may be enriched and used. In certain embodiments, the compound is deuterated at at least one position. Such deuterated forms can be made by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration improves the efficacy and duration of action of pharmaceuticals.

[0102] Deuterium substituted compounds are synthesized using a variety of methods, such as those described in Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0103] In one aspect, a compound is described having the structure:

[0104] [ka] wherein each R is independently selected from hydrogen or deuterium; X is an anion. In some embodiments, X is a halide (Cl, Br, or I). In some embodiments, X is Cl.

[0105] A "solvate" is formed by the interaction of a solvent with a compound. The term "compound" is intended to include solvates of a compound. Similarly, a "pharmaceutically acceptable salt" includes solvates of a pharmaceutically acceptable salt. Suitable solvates are pharmaceutically acceptable solvates such as hydrates, including monohydrates and hemihydrates. Also included are solvates formed with one or more solvents of crystallization.

[0106] Pharmaceutically acceptable forms of the compounds described herein include pharma- ceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures thereof.

[0107] A "chelate" is formed by the coordination of a compound to a metal ion at two (or more) points. The term "compound" is intended to include chelates of a compound. Similarly, "pharmaceutically acceptable salt" includes chelates of pharmaceutically acceptable salts.

[0108] A "non-covalent complex" is formed by the interaction of a compound with another molecule, where no covalent bond is formed between the compound and the other molecule. For example, complex formation can occur through van der Waals interactions, hydrogen bonds, and electrostatic interactions (also called ionic bonds). Such non-covalent complexes are included in the term "compound." Similarly, pharmaceutically acceptable salts include "non-covalent complexes" of pharmaceutically acceptable salts.

[0109] When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formula, all combinations and subcombinations of ranges, as well as specific embodiments therein, are intended to be included.

[0110] The term "about," when referring to a number or numerical range, means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary, for example, between 1% and 15% of the stated number or numerical range. In some examples of numerical ranges, "about" means ±10%.

[0111] As used herein, "significant" refers to any detectable change that is statistically significant in a standard parametric test of statistical significance, such as Student's T-test, where p<0.05.

[0112] IV.How to use In another aspect, provided herein is a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride provided herein, or a hydrate thereof, or a pharmaceutical composition provided herein.

[0113] In some embodiments, the disease or disorder is an adipose-related disorder. In some embodiments, the adipose-related disorder is obesity, abnormal fat distribution, diabetes, cardiovascular disease, obstructive sleep apnea, lipoma, cancer, osteoarthritis, endocrine disease, reproductive disease, neurological disease, psychiatric disease, rheumatic disease, or orthopedic disease. In some embodiments, the adipose-related disorder is cellulite, excess fat in various body regions, lipoma, lipotumor disease, disorders associated with fat accumulation, Dercam's disease, lipedema, or edema. In some embodiments, the adipose-related disorder is cellulite. In some embodiments, the adipose-related disorder is excess fat in various body regions. In some embodiments, the adipose-related disorder is lipoma. In some embodiments, the adipose-related disorder is lipotumor disease. In some embodiments, the adipose-related disorder is a disorder associated with fat accumulation. In some embodiments, the adipose-related disorder is Dercam's disease. In some embodiments, the adipose-related disorder is lipedema. In some embodiments, the adipose-related disorder is hibernoma.

[0114] In some embodiments, the disease or disorder is fibrosis associated with a second disease or disorder. In some embodiments, the second disease or disorder is pulmonary fibrosis, liver cirrhosis, endomyocardial fibrosis, old myocardial infarction, atrial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, carpal tunnel syndrome, arthrofibrosis, Crohn's disease, keloid, scleroderma, arthrofibrosis, Peyronie's disease, Dupuytren's contracture, or adhesive capsulitis.

[0115] In some embodiments, the disease or disorder is liposarcoma or a solid tumor. In some embodiments, the disease or disorder is liposarcoma. In some embodiments, the disease or disorder is liposarcoma or a solid tumor.

[0116] In some embodiments, the disease or disorder is angiolipoma.

[0117] In another aspect, provided herein is the use of crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride provided herein, or a hydrate thereof, or a composition provided herein, in the manufacture of a medicament for treating a disease or disorder in a subject in need thereof.

[0118] In some embodiments, the disease or disorder is an adipose-related disorder. In some embodiments, the adipose-related disorder is obesity, abnormal fat distribution, diabetes, cardiovascular disease, obstructive sleep apnea, lipoma, cancer, osteoarthritis, endocrine disease, reproductive disease, neurological disease, psychiatric disease, rheumatic disease, or orthopedic disease. In some embodiments, the adipose-related disorder is cellulite, excess fat in various body regions, lipoma, lipotumor disease, disorders associated with fat accumulation, Dercam's disease, lipedema, or edema. In some embodiments, the adipose-related disorder is cellulite. In some embodiments, the adipose-related disorder is excess fat in various body regions. In some embodiments, the adipose-related disorder is lipoma. In some embodiments, the adipose-related disorder is lipotumor disease. In some embodiments, the adipose-related disorder is a disorder associated with fat accumulation. In some embodiments, the adipose-related disorder is Dercam's disease. In some embodiments, the adipose-related disorder is lipedema. In some embodiments, the adipose-related disorder is hibernoma.

[0119] In some embodiments, the disease or disorder is fibrosis associated with a second disease or disorder. In some embodiments, the second disease or disorder is pulmonary fibrosis, liver cirrhosis, endomyocardial fibrosis, old myocardial infarction, atrial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, carpal tunnel syndrome, arthrofibrosis, Crohn's disease, keloid, scleroderma, arthrofibrosis, Peyronie's disease, Dupuytren's contracture, or adhesive capsulitis.

[0120] In some embodiments, the disease or disorder is liposarcoma or a solid tumor. In some embodiments, the disease or disorder is liposarcoma. In some embodiments, the disease or disorder is liposarcoma or a solid tumor.

[0121] In some embodiments, the disease or disorder is angiolipoma.

[0122] As used herein, a therapeutically effective amount of crystalline Compound A refers to an amount sufficient to achieve the intended use, including but not limited to disease treatment as defined herein. The subject method also contemplates the use of subtherapeutic amounts of crystalline Compound A to treat the intended disease state.

[0123] The amount of crystalline Compound A administered may vary depending on the intended use (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the method of administration, etc., which can be readily determined by one of skill in the art.

[0124] Measuring the biological effect of crystalline Compound A can include carrying out an assay on a biological sample, such as a sample from a subject.Depending on the assay, any of a variety of samples can be selected.Examples of samples include, but are not limited to, blood samples (e.g., plasma or serum), exhaled breath condensate samples, bronchoalveolar lavage fluid, sputum samples, urine samples, and tissue samples.

[0125] The subject being treated with crystalline compound A can be monitored to determine the effectiveness of the treatment, and the treatment regimen can be adjusted based on the subject's physiological response to the treatment. For example, if the inhibition of biological effect is above or below a threshold, the dosage or frequency can be decreased or increased, respectively. The method can further include continuing the treatment if the treatment is determined to be effective. The method can include maintaining, tapering, decreasing, or stopping the dosage of the compound in the treatment if the treatment is determined to be effective. The method can include increasing the dosage of the compound in the treatment if the treatment is determined to be ineffective. Alternatively, the method can include stopping the treatment if the treatment is determined to be ineffective. In some embodiments, the treatment with crystalline compound A is interrupted if the inhibition of biological effect is above or below a threshold, such as in a lack of response or an adverse reaction. The biological effect can be any change in various physiological indicators.

[0126] V. Compositions and Formulations The disclosure provides compositions, including pharmaceutical compositions, that include the crystalline forms of the present invention.

[0127] In some embodiments, the crystalline form of compound A is formulated into a pharmaceutical composition.In a specific embodiment, the pharmaceutical composition is formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries that facilitate the processing of active compound / crystalline form into pharma-ceutically usable preparations.The appropriate formulation depends on the route of administration selected.Any pharma-ceutically acceptable technology, carrier, and excipient described below can be used as suitable for formulating the pharmaceutical composition described herein. Remington: The Science and Practice of Pharmacy,Nineteenth Ed(Easton,Pa.:Mack Publishing Company,1995);Hoover,John E.,Remington's Pharmaceutical Sciences,Mack Publishing Co.,Easton,Pennsylvania 1975;Liberman,HAand Lachman,L.,Eds.,Pharmaceutical Dosage Forms,Marcel Decker,New York, NY, 1980; and Pharmaceutical Dosage Norms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999).

[0128] Provided herein is a pharmaceutical composition comprising a crystalline form of compound A and a pharma- ceutical acceptable diluent(s), excipient(s), or carrier(s).In some embodiments, the crystalline form of compound A is administered in combination therapy as a pharmaceutical composition in which the crystalline form is mixed with other active ingredients.All combinations of active substances disclosed in the combination therapy section below and throughout this disclosure are encompassed herein.In a specific embodiment, the pharmaceutical composition comprises a crystalline form of compound A.

[0129] Pharmaceutical composition, as used herein, refers to a mixture of a crystalline form of Compound A with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the crystalline form to an organism. In some embodiments, in carrying out the treatment methods or uses provided herein, a therapeutically effective amount of a crystalline form of Compound A described herein is administered as a pharmaceutical composition to a mammal suffering from a disease or disorder to be treated. In a specific embodiment, the mammal is a human. In certain embodiments, the therapeutically effective amount varies depending on the severity of the disease, the age and relative health of the subject, and other factors. The crystalline forms of Compound A described herein are used alone or in combination with one or more therapeutic agents as components of a mixture.

[0130] In one embodiment, the crystalline form of Compound A is formulated in an aqueous solution. In specific embodiments, the aqueous solution is selected from physiologically compatible buffers such as, by way of example only, Hank's solution, Ringer's solution, or physiological saline buffer. In other embodiments, the crystalline form of Compound A is formulated for transmucosal administration. In specific embodiments, the transmucosal formulation includes a penetrant appropriate for the barrier to be penetrated. In yet other embodiments, where the crystalline forms described herein are formulated for other parenteral injections, suitable formulations include aqueous or non-aqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and / or excipients. In some embodiments, the aqueous solution includes propylene glycol. In some embodiments, the aqueous solution includes water and 5-95% propylene glycol (v / v%). In some embodiments, the aqueous solution includes water and 10-90% propylene glycol (v / v%). In some embodiments, the aqueous solution includes water with 20-80% propylene glycol (v / v%). In some embodiments, the aqueous solution comprises water and 40-70% propylene glycol (v / v %). In some embodiments, the aqueous solution comprises water and 55-65% propylene glycol (v / v %). In some embodiments, the aqueous solution comprises water and 60% propylene glycol (v / v %).

[0131] In another embodiment, the crystalline form described herein is formulated for oral administration.The crystalline form of compound A is formulated by combining the crystalline form with, for example, pharma- ceutically acceptable carrier or excipient.In various embodiments, the crystalline form described herein is formulated into oral administration forms, including, but not limited to, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, etc.

[0132] In some embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipients with the crystalline forms described herein, optionally grinding the resulting mixture, and then processing the mixture of granules, after adding suitable auxiliaries as necessary, to obtain tablets or dragee cores. Suitable excipients include fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol, in particular, cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrants are optionally added. Disintegrants include, by way of example only, cross-linked sodium carmellose, polyvinylpyrrolidone, agar, or alginic acid or salts thereof, such as sodium alginate.

[0133] In one embodiment, dosage forms such as dragee cores and tablets are provided with one or more suitable coatings. In a specific embodiment, a concentrated sugar solution is used to coat the dosage form. The sugar solution optionally contains further components such as, by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Similarly, dyes and / or pigments are optionally added to the coating for identification purposes. Additionally, dyes and / or pigments are optionally utilized to characterize different combinations of active compound doses.

[0134] In some embodiments, the therapeutically effective amount of the crystalline forms described herein are formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin and sealed soft capsules made of gelatin and plasticizers such as glycerol or sorbitol. In certain embodiments, the push-fit capsules contain the active ingredient mixed with one or more fillers. Fillers include, by way of example only, binders such as lactose, starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In other embodiments, the soft capsules contain one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers are optionally added.

[0135] In other embodiments, the therapeutically effective amount of the crystalline form described herein is formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels. In still other embodiments, the crystalline form described herein is formulated for parenteral injection, including formulations suitable for bolus or continuous infusion. In specific embodiments, the formulation for injection is provided in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives are optionally added to the formulation for injection. In still other embodiments, the pharmaceutical composition of the crystalline form of Compound A is formulated in a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in an oily or aqueous vehicle. Parenteral injection formulations optionally include formulating agents such as suspending agents, stabilizing agents, and / or dispersing agents. In specific embodiments, the pharmaceutical formulation for parenteral administration includes an aqueous solution of the crystalline form active in water-soluble form. In some embodiments, the pharmaceutical formulation for parenteral administration includes propylene glycol. In some embodiments, pharmaceutical formulations for parenteral administration include propylene glycol and water. In additional embodiments, suspensions of the active crystalline forms are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents that increase the solubility of the crystalline forms to allow for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0136] In yet another embodiment, the crystalline form of Compound A is administered topically. The crystalline forms described herein are formulated into various topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments. Such pharmaceutical compositions optionally include solubilizers, stabilizers, isotonicity enhancers, buffers, and preservatives.

[0137] In yet other embodiments, the crystalline form of Compound A is formulated for transdermal administration. In specific embodiments, transdermal formulations utilize transdermal delivery devices and transdermal delivery patches, which may be lipophilic emulsions or buffered aqueous solutions dissolved and / or dispersed in polymers or adhesives. In various embodiments, such patches are constructed for continuous, pulsatile, or on-demand delivery of pharmaceuticals. In further embodiments, transdermal delivery of the crystalline form of Compound A is achieved by means of iontophoretic patches and the like. In certain embodiments, transdermal patches provide controlled delivery of the crystalline form of Compound A. In specific embodiments, the absorption rate is reduced by using a rate-controlling membrane or by trapping the compound in a polymer matrix or gel. In alternative embodiments, absorption enhancers are used to enhance absorption. The absorption enhancer or carrier comprises a pharma- ceutically acceptable absorbent solvent that aids in permeation through the skin. For example, in one embodiment, the transdermal device is in the form of a bandage that includes a support member, a reservoir containing the compound, optionally with a carrier, and optionally a rate-limiting barrier for delivering the compound to the host's skin at a controlled, predetermined rate over an extended period of time, and a means for securing the device to the skin.

[0138] In other embodiments, the crystalline form of Compound A is formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosol, mist, or powder. The crystalline form pharmaceutical composition of Compound A is conveniently delivered in the form of an aerosol spray from a pressurized package or nebulizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas). In a specific embodiment, the dosage unit of the pressurized aerosol is determined by providing a valve to deliver a metered amount. In some embodiments, capsules and cartridges, such as, by way of example only, gelatin, for use in an inhaler or insufflator, are formulated containing a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0139] In yet another embodiment, the crystalline form of Compound A is formulated into rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides, and synthetic polymers such as polyvinylpyrrolidone, PEG, etc. In the suppository form of the composition, a low melting wax, such as, but not limited to, a mixture of fatty acid glycerides, is first melted, optionally in combination with cocoa butter.

[0140] In some embodiments, pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries, which facilitate the processing of active crystalline forms into pharmaceutically usable preparations.The appropriate formulation depends on the route of administration selected.Any pharmaceutically acceptable technology, carriers, and excipients are optionally used as appropriate.The pharmaceutical compositions containing crystalline forms of compound A are produced in a conventional manner, using, for example, conventional mixing, dissolving, granulating, dragee making, pulverizing, emulsifying, encapsulating, encapsulating, or compressing processes.

[0141] The pharmaceutical composition comprises at least one pharma- ceutically acceptable carrier, diluent, or excipient, and comprises the crystalline form of Compound A described herein as an active ingredient. The active ingredient is in the form of a free acid or free base, or in the form of a pharma- ceutically acceptable salt. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. In addition, the compounds described herein include unsolvated forms as well as solvated forms with pharma- ceutically acceptable solvents, such as water and ethanol. The solvated forms of the compounds presented herein are considered to be disclosed herein as well. In addition, the pharmaceutical composition optionally includes other medicinal or therapeutic agents, carriers, adjuvants, such as preservatives, stabilizers, wetting agents, or emulsifiers, dissolution enhancers, salts for adjusting osmotic pressure, buffers, and / or other therapeutically valuable substances.

[0142] The method of preparing a composition comprising a crystalline form of Compound A described herein comprises formulating the crystalline form with one or more inert, pharma- ceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compound is dissolved, emulsions containing the compound, or solutions containing liposomes, micelles, or nanoparticles containing the compound as disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The forms of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for dissolving or suspending in liquid before use, or emulsions. These compositions also optionally contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and the like.

[0143] In some embodiments, pharmaceutical compositions comprising crystalline forms of Compound A are illustrative of liquid forms in which the drug is in solution, in suspension, or both. Generally, when the composition is administered as a solution or suspension, a first portion of the drug is in solution and a second portion of the drug is in particulate form in suspension in a liquid matrix. In some embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is aqueous.

[0144] In some embodiments, useful aqueous suspensions contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers, such as cellulose acid polymers (e.g., hydroxypropylmethylcellulose), and water-insoluble polymers, such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein contain mucoadhesive polymers, such as those selected from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0145] Useful pharmaceutical compositions also optionally contain a solubilizing agent to aid in the solubility of the crystalline form of Compound A. The term "solubilizing agent" generally includes agents that result in a micellar or true solution of the drug. Certain acceptable non-ionic surfactants, such as polysorbate 80, are useful as solubilizing agents, as are ophthalmically acceptable glycols, polyglycols, such as polyethylene glycol 400, and glycol ethers.

[0146] In addition, useful pharmaceutical compositions optionally contain one or more pH adjusting or buffering agents, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and trishydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in amounts required to maintain the pH of the composition in an acceptable range.

[0147] In addition, useful compositions also optionally include one or more salts in an amount necessary to bring the osmolality of the composition into an acceptable range. Such salts include sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0148] Other useful pharmaceutical compositions optionally contain one or more preservatives that inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal, stabilized chlorine dioxide, and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0149] Still other useful compositions contain one or more surfactants to improve physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkyl phenyl ethers, such as Octoxynol 10, Octoxynol 40, and the like.

[0150] Still other useful compositions may contain one or more antioxidants to enhance chemical stability where necessary. Suitable antioxidants include, by way of example only, ascorbic acid and sodium disulfite.

[0151] In some embodiments, the aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multi-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.

[0152] In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are utilized. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In some embodiments, organic solvents such as N-methylpyrrolidone are also utilized. In further embodiments, the crystalline forms described herein are delivered using sustained release systems, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. A variety of sustained release materials are useful herein. In some embodiments, sustained release capsules release the crystalline forms for several weeks up to 100 days. Depending on the chemical nature and biological stability of the therapeutic reagent, additional strategies for protein stabilization may be utilized.

[0153] In certain embodiments, the formulations described herein include one or more antioxidants, metal chelators, thiol-containing compounds, and / or other general stabilizing agents. Examples of such stabilizers include, but are not limited to, (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc, or (n) combinations thereof.

[0154] VI. Route of Administration Suitable routes of administration include, but are not limited to, oral administration, intravenous administration, rectal administration, aerosol administration, parenteral administration, subcutaneous administration, ocular administration, pulmonary administration, mucosal administration, transdermal administration, vaginal administration, auricular administration, nasal administration, and topical administration.Furthermore, merely by way of example, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.Administration can also be performed directly by injection into areas of excess fat, fat deposits, or lipid masses (such as, for example, lipomas).

[0155] In certain embodiments, the crystalline form of Compound A is administered locally rather than systemically, for example, via direct injection of the crystalline form into an organ, often in a depot or sustained release formulation. In specific embodiments, the long-acting formulation is administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such embodiments, the liposome targets and is selectively taken up by the organ. In still other embodiments, the crystalline form of Compound A is provided in the form of a rapid release formulation, in the form of a sustained release formulation, or in the form of a medium-term release formulation. In still other embodiments, the crystalline form of Compound A is administered locally. In some embodiments, the crystalline form of Compound A is administered subcutaneously.

[0156] VII. KITS / ARTICLES OF MANUFACTURE Kits and products are also provided for use in the therapeutic applications described herein.In some embodiments, such kits include a carrier, packaging, or container that is partitioned to receive one or more containers, such as vials, tubes, etc., each of which contains one of the separate elements used in the methods described herein.Suitable containers include, for example, bottles, vials, syringes, and test tubes.Containers may be formed from a variety of materials, such as glass or plastic.

[0157] The products provided herein include packaging materials. Packaging materials for use in packaging pharmaceutical products include, for example, those found in U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging materials suitable for the selected formulation and intended mode of administration and treatment. For example, the container contains the crystalline form described herein, optionally in a composition or in combination with another drug, as disclosed herein. The container optionally has a sterile access port (e.g., the container is an intravenous solution bag or vial with a stopper that can be pierced by a hypodermic needle). Such kits include the compound, optionally with identifying markings or labels, or instructions for use in the methods described herein.

[0158] For example, the kit typically includes one or more additional containers, each with one or more of the various materials (e.g., reagents, optionally in concentrated form, and / or devices) that are desirable from a commercial and user standpoint for the use of the compounds described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes, carriers, packaging, containers, vials, and / or tube labels listing the contents and / or instructions for use. A set of instructions is also typically included. The label is optionally on or associated with the container. For example, the label is on the container when the letters, numbers, or other symbols forming the label are applied, molded, or etched into the container itself, and the label is associated with the container when present in a receptacle or carrier that further holds the container, e.g., as a package insert. Additionally, the label is used to indicate that the contents are to be used for a particular therapeutic application. Additionally, the label indicates instructions for the use of the contents, such as in the methods described herein. In some embodiments, the pharmaceutical composition is provided in a pack or dispenser device that contains one or more unit dosage forms containing the compound provided herein. The pack comprises, for example, metal or plastic foil, such as a blister pack. Alternatively, the pack or dispenser device is provided with instructions for administration. Alternatively, the pack or dispenser is provided with a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the approval by the government agency of the drug form for human or animal administration. Such notice is, for example, a label approved by the U.S. Food and Drug Administration for prescription drugs, or an approved product insert. In some embodiments, a composition containing a crystalline form of Compound A formulated in a compatible pharmaceutical carrier is prepared, placed in a suitable container, and labeled for the treatment of an indicated disease. EXAMPLES

[0159] The following examples will serve to more fully illustrate how to use the present invention. These examples are presented for illustrative purposes only, and are not intended to limit the true scope of this invention in any way.

[0160] In some embodiments, 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (compound A) is prepared as described in WO2013 / 072915 and U.S. Patent No. 9,447,040, which are incorporated by reference for such synthesis. In some embodiments, compound A is prepared as described herein.

[0161] Example 1: Preparation of 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A) 3,6-Dibromocarbazole (1.00 g, 3.0 mM) was dissolved in dimethylformamide (100 mL). (5-Bromopentyl)-trimethyl-ammonium bromide (0.57 g, 3.0 mM) was added immediately. After 10 min of magnetic stirring, potassium carbonate (1.40 g, 10 mM) was added. After stirring for an additional 10 min, the temperature was raised to 50° C. and the mixture was stirred for 4 h. After cooling to room temperature, the solution was transferred to a separatory funnel and water (200 mL) and dichloromethane (200 mL) were added. The solvent mixture was shaken and the lower phase was collected. The upper aqueous phase was extracted four times with 3:1 dichloromethane / methanol (50 mL). The combined organics were washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated. The resulting residue was crystallized from water to obtain 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A) (1.28 g). 1H NMR(CD3OD,400MHz)δ 8.21(d,J=0.4Hz,2H),7.54(dd,J=2.0,0.4Hz,2H),7.47(d,J=2.0,2H),4.39(t,J=0.6,2H) ,3.16(m,2H),3.01(s,9H),1.93(m,2H),1.70(m,2H),1.31(m,2H).MS:m / z=451,453,455(M + , symmetrical 2Br triplet) and 452, 454, 456 (M+H + ,symmetrical 2Br triplet).

[0162] Example 2: Temperature Cycling Preparation of Crystalline 5-(3,6-Dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium Chloride Form 1 (Compound A Form 1) A known mass of 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (compound A) was diluted with 0.5 mL aliquots of solvent (1-butanol, 2-propanol, acetone, acetonitrile, benzyl alcohol, dichloromethane, dimethyl sulfoxide, ethanol, ethyl acetate, isopropyl acetate, methanol, methyl ethyl ketone, propylene glycol, methyl isobutyl ketone, tert-butyl methyl ether, tetrahydrofuran, toluene, Tween 80, water, tert-butyl methyl ether / water ( 2:98 v / v%), acetonitrile / 1-butanol / tert-butyl methyl ether / water (2:2:2:94 v / v%), acetonitrile / 1-butanol / tert-butyl methyl ether (25:25:50 v / v%), Tween 80 / propylene glycol / benzyl alcohol / water (10:60:3:27 w / w%), Tween 80 / propylene glycol / benzyl alcohol (14:81:5 w / w%), methanol / water (40:60 v / v%), and methanol / water (80:00 v / v%) were added until a moving slurry was observed. The reaction mixture was maintained at 50° C. with stirring during the solvent addition, and then temperature cycled between 5° C. and 50° C. with a 1 hour hold time and low and high temperatures. If the reaction mixture remained a clear solution after the 18 hour cycle, tert-butyl methyl ether was added until a slurry was observed or a total volume of 1.8 mL was reached. The reaction mixture was then left to continue temperature cycling for a total of 72 hours. The saturated solution was extracted, needle filtered, and stored at ambient temperature for further screening experiments. The resulting solid was dried under vacuum at ambient temperature for 3 days.Crystalline Compound A Form 1 was obtained with 1-butanol, 2-propanol, acetone, acetonitrile, benzyl alcohol, dichloromethane, dimethyl sulfoxide, ethanol, ethyl acetate, isopropyl acetate, methanol, methyl ethyl ketone, methyl isobutyl ketone, tert-butyl methyl ether, tetrahydrofuran, toluene, Tween 80, tert-butyl methyl ether / water (2:98 v / v%), acetonitrile / 1-butanol / tert-butyl methyl ether (25:25:50 v / v%), Tween 80 / propylene glycol / benzyl alcohol (14:81:5 w / w%), and methanol / water (40:60 v / v%) solutions.

[0163] Example 3: Crash-cooling preparation of crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride Form 1 (Compound A Form 1) The solution obtained in Example 2 was quenched to 6°C. After 4 days, crystalline Compound A was obtained with ethanol solution. The remaining solution was quenched to -18°C. After 48 hours, crystalline Compound A was obtained with 1-butanol, 2-propanol, acetonitrile, Tween 80 / propylene glycol / benzyl alcohol (14:81:5 w / w%), methanol / water (40:60 v / v%), and methanol / water (80:20 v / v%) solutions. The remaining solution was treated with tert-butyl methyl ether. After 18 hours, crystalline Compound A Form 1 was obtained with benzyl alcohol and dimethyl sulfoxide solutions.

[0164] Example 4: Evaporative preparation of crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride Form 1 (Compound A Form 1) The solution obtained in Example 2 was added to an open vial at room temperature. After 4 days, crystalline Compound A Form 1 was obtained with 1-butanol, 2-propanol, acetonitrile, methanol, acetonitrile / 1-butanol / tert-butyl methyl ether / water (2:2:2:94 v / v%), acetonitrile / 1-butanol / tert-butyl methyl ether (25:25:50 v / v%), Tween 80 / propylene glycol / benzyl alcohol (14:81:5 w / w%), methanol / water (40:60 v / v%), and methanol / water (80:00 v / v%) solutions.

[0165] Example 5: Antisolvent Preparation of Crystalline 5-(3,6-Dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium Chloride Form 1 (Compound A Form 1) The solution obtained in Example 2 was added to a vial and tert-butyl methyl ether was added in 50 μL aliquots at ambient temperature until precipitation was observed or a total of 1.8 mL of antisolvent was added. The solid was isolated by centrifugation. The remaining solution was cooled to 6° C. and stored for 72 hours, cooled to −18° C. and stored for 48 hours. Crystalline Compound A Form 1 was obtained with 1-butanol, benzyl alcohol, dimethyl sulfoxide, ethanol, methanol, acetonitrile / 1-butanol / tert-butyl methyl ether (25:25:50 v / v%), and methanol / water (80:00 v / v%) solutions.

[0166] Example 6: Preparation of crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride form 2 (Compound A form 2) from Compound A form 1 A known mass of 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride Form 1 (Compound A Form 1) was added to a tared open aluminum pan and loaded into a TA Instruments Discovery SDT 650 Auto-Simultaneous DSC and held at room temperature. The sample was then heated from 30° C. to 200° C. at a rate of 10° C. / min. The sample was held at 200° C. for 10 minutes and then cooled to 30° C. This process yielded crystalline Compound A Form 2.

[0167] Example 7: Preparation of crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride form 3 (Compound A form 3)

[0168] synthesis 3,6-Dibromocarbazole was dissolved in MeCN / MeTHF. (5-Bromopentyl)-trimethyl-ammonium bromide was added immediately. After 10 min of magnetic stirring, potassium carbonate was added. After stirring for another 10 min, the temperature was raised to 50° C. and the mixture was stirred for 4 h. After cooling to room temperature, the solution was transferred to a separatory funnel and water and dichloromethane were added. The solvent mixture was shaken and the lower phase was collected. The upper aqueous phase was extracted four times with 3:1 dichloromethane / methanol. The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated. A portion of the resulting 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (compound A) was subjected to bead milling (6 cycles at 6000 rpm for 60 s each, with 10 s rest between cycles). The ground and unground samples were placed in a crystallization dish, protected from dust, and exposed to air at 20-25% relative humidity and ambient temperature for 15 days. Both the ground and unground samples yielded crystalline Compound A Form 3.

[0169] Temperature Cycling

[0170] To a known mass of 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (compound A) was added water until a moving slurry was observed. The slurry was gradually heated until the compound dissolved at about 56° C. The solution was further heated to 85° C., rapidly cooled to 65° C., and then slowly cooled to 20° C. over 9 hours. The slurry was stirred at 140 RPM for 7 days. A lower stirring speed of 110 RPM was implemented for two additional heating / cooling cycles. The slurry was reheated to about 56° C. where a very thin slurry formed, aged for 1 hour, and cooled to 20° C. over 8 hours. The slurry was then cooled at 20° C. for 5 hours, where the solids were isolated by filtration through a polypropylene felt filter (2 microns) to obtain a wet cake. The cake was rinsed with water, washed twice with MTBE, and dried under vacuum for 1 hour. Drying was continued for an additional hour to obtain crystalline Compound A Form 3.

[0171] Example 8: X-ray Powder Diffraction (XRPD) The diffractometers listed below were used, but other types of diffractometers can also be used. Additionally, other wavelengths can be used and converted to Cu Kα. In some embodiments, synchrotron radiation X-ray powder diffraction (SR-XRPD) can be used to characterize the crystalline form.

[0172] "Characteristic peaks" are a subset of observed peaks, if any, that are used to distinguish one crystalline polymorph from another crystalline polymorph (polymorphs that are crystalline forms having the same chemical composition). Characteristic peaks are determined by assessing which observed peaks, if any, are present within ±0.2° 2-θ in one crystalline polymorph of a compound relative to all other known crystalline polymorphs of that compound.

[0173] XRPD analysis was performed on a PANalytical X'pert Pro equipped with a PIXcel detector (128 channels) and samples were scanned between 3 and 35°2θ. The material was gently ground (if necessary) to open any aggregates and loaded onto a multi-well plate with a Kapton or Mylar polymer film to support the sample. The multi-well plate was then placed into the diffractometer and analyzed using Cu K radiation (α1λ=1.54060 Å; α2λ=1.54443 A; βλ=1.39225 A; α1:α2 ratio=0.5) operated in transmission mode (step size 0.0130°2θ, step time 18.87 s) using a 40 kV / 40 mA generator setting. Data were visualized and images were generated using the HighScore Plus 4.7 desktop application (PANalytical, 2017).

[0174] A representative XRPD pattern obtained for crystalline Compound A Form 1 is shown in Figure 1. Representative XRPD peaks obtained for crystalline Compound A Form 1 are listed below.

[0175] [Table 1]

[0176] Representative XRPD peaks obtained for crystalline Compound A Form 1 in some embodiments are listed in Table 1-1.

[0177] [Table 2]

[0178] A representative XRPD pattern obtained for crystalline Compound A Form 2 is shown in Figure 4. Representative XRPD peaks obtained for crystalline Compound A Form 2 are listed in Table 2.

[0179] [Table 3]

[0180] A representative XRPD pattern obtained for crystalline Compound A Form 3 is shown in Figure 7. Representative XRPD peaks obtained for crystalline Compound A Form 3 are listed in Table 3. Table 3.

[0181] [Table 4]

[0182] Example 9: Thermogravimetric Analysis / Differential Scanning Calorimetry (TGA / DSC) 5-10 mg of material was added to a tared open aluminum pan and loaded into a TA Instruments Discovery SDT 650 Auto-Simultaneous DSC and held at room temperature. The sample was then heated at a rate of 10°C / min from 30°C to 400°C while the change in sample weight was recorded along with the heat flow response (DSC). Nitrogen was used as the sample purge gas at 200 cm3 / min. 3 A flow rate of 1000 rpm was used. The TGA pattern obtained for crystalline Compound A Form 1 is shown in FIG. 3, and the TGA pattern obtained for crystalline Compound A Form 2 is shown in FIG.

[0183] Example 10: Differential Scanning Calorimetry (DSC) 1-5 mg of material was weighed into an aluminum DSC pan and non-hermetically sealed with an aluminum lid. The sample pan was then loaded into a TA Instruments Discovery DSC 2500 Differential Scanning Calorimeter equipped with an RC90 cooler. The samples and controls were heated to 300 °C at a scan rate of 10 °C / min and the resulting heat flow response was monitored. The samples were re-cooled to 20 °C and then re-heated to 300 °C at 10 °C / min. Nitrogen was blown at 50 cm per minute. 3 It was used as a purge gas at a flow rate of 1000 mL / min. The DSC thermogram obtained for crystalline Compound A Form 1 is shown in FIG. 2. The DSC thermogram obtained for crystalline Compound A Form 2 is shown in FIG.

[0184] Example 11: Stability Study of Crystalline Compound A Form 1 Crystalline Compound A Form 1 was unchanged after 7 days of storage at room temperature, 7 days of storage at 40° C. / 75% RH, or 7 days of storage at 80° C. The results of crystalline Compound A Form 1 in accelerated stability studies are shown in Table 4. Purity was determined by HPLC analysis.

[0185] [Table 5]

[0186] Crystalline Compound A Form 1 remained unchanged after storage at 25° C. / 60% RH for 36 months or at 40° C. / 75% RH for 6 months. The results of crystalline Compound A Form 1 in long-term stability studies are shown in Table 5. Purity was determined by HPLC analysis.

[0187] [Table 6]

[0188] Example 12: Karl Fischer (KF) Coulometric Titration The water content of crystalline Compound A was determined using KF coulometric titration by either direct addition or liquid extraction.

[0189] direct addition

[0190] 10-20 mg of crystalline compound A was weighed into a vial. The solid was then manually introduced into the titration cell of a METTLER TOLEDO C30 Compact Titrator. The vial was back-weighed after the solid was added and the weight of the added solid was entered into the instrument. The titration started when the sample was completely dissolved in the cell. The water content was automatically calculated as a percentage by the instrument and the data was printed. The analysis was performed in duplicate.

[0191] liquid extraction

[0192] 10-20 mg of crystalline Compound A was weighed into a vial. 10-15 mL of Coulomat was extracted from the cell of a METTLER TOLEDO C30 Compact Titrator and added to the vial containing the sample. The solid was dissolved by shaking manually or using an ultrasonic bath. Once complete dissolution was achieved, the solution was poured back into the cell titrator and the weight of the sample added was entered into the instrument. The water content was automatically calculated as a percentage by the instrument and the data was printed. The analysis was performed in duplicate. The KF titration results obtained for crystalline Compound A are summarized in Table 6.

[0193] [Table 7]

[0194] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous modifications, changes, and substitutions will occur to those skilled in the art without departing from the invention. It is understood that various alternatives to the embodiments of the invention described herein may be utilized in practicing the invention. It is intended that the following claims define the scope of the invention, and that methods and structures within the scope of these claims and their equivalents are covered thereby.

[0195] The present disclosure is further illustrated in the following list of embodiments, which are provided for illustrative purposes only and are not intended to limit the present disclosure in any way.

[0196] Example 1: Crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A)

[0197] [ka] or a hydrate thereof, wherein the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride is (a) An X-ray powder diffraction pattern measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å, the X-ray powder diffraction pattern including peaks at 4.0±0.2°2-θ, 16.5±0.2°2-θ, and 15.5±0.2°2-θ; (b) an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å; (c) A differential scanning calorimetry (DSC) thermogram, i) an endotherm in the range of about 260-270°C, and ii) an endotherm in the range of about 175-195°C; A differential scanning calorimetry (DSC) thermogram, (d) A differential scanning calorimetry (DSC) thermogram, i) an endotherm with an onset of about 265° C. and a peak of about 266° C.; and ii) an endotherm with an onset of about 180° C. and a peak at about 190° C. A differential scanning calorimetry (DSC) thermogram, (e) A differential scanning calorimetry (DSC) thermogram substantially the same as that shown in FIG. (f) Thermogravimetric analysis (TGA) thermogram substantially the same as that shown in FIG. (g) XRPD unchanged after storage at 40° C. and 75% relative humidity (RH) for 7 days; (h) XRPD unchanged after storage at 80°C for 7 days; or (i) Crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride or a hydrate thereof, characterized by having a combination thereof.

[0198] Embodiment 2: The crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride or hydrate thereof of embodiment 1, characterized in that the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride or hydrate thereof has an X-ray powder diffraction pattern comprising peaks at 4.0±0.2 degrees 2-θ, 16.5±0.2 degrees 2-θ, and 15.5±0.2 degrees 2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0199] Embodiment 3: Crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride or a hydrate thereof, characterized in that the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride has an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0200] Embodiment 4: The crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride is i) an endotherm in the range of about 260-270 ° C; ii) an endotherm in the range of about 175 to 195 °C; 4. The crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride of any one of embodiments 1 to 3, or a hydrate thereof, characterized by a differential scanning calorimetry (DSC) thermogram comprising:

[0201] Embodiment 5: The crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride is i) an endotherm with an onset of about 265° C. and a peak of about 266° C. ii) an endotherm having an onset of about 180° C. and a peak at about 190° C. 5. The crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or a hydrate thereof, according to any one of embodiments 1 to 4, characterized by a differential scanning calorimetry (DSC) thermogram comprising:

[0202] Embodiment 6: The crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride of any one of embodiments 1 to 5, wherein the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride is characterized by a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in FIG. 2, or a hydrate thereof.

[0203] Example 7: The crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride according to any one of embodiments 1 to 6, wherein the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride is characterized by a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in FIG. 3, or a hydrate thereof.

[0204] Example 8: Crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A)

[0205] [ka] or a hydrate thereof, wherein the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride is (a) An X-ray powder diffraction pattern measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å, the X-ray powder diffraction pattern including peaks at 28.4±0.2°2-θ, 18.5±0.2°2-θ, and 12.1±0.2°2-θ; (b) an X-ray powder diffraction pattern substantially the same as that shown in FIG. 7, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å; or (c) A combination of these Crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or a hydrate thereof, characterized by having:

[0206] Embodiment 9: The crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride of embodiment 8, or a hydrate thereof, characterized in that the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride has an X-ray powder diffraction pattern including peaks at 28.4±0.2°2-θ, 18.5±0.2°2-θ, and 12.1±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0207] Embodiment 10: The crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride of embodiment 8 or 9, or a hydrate thereof, characterized in that the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride has an X-ray powder diffraction pattern substantially the same as that shown in FIG. 7, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0208] Embodiment 11: A pharmaceutical composition comprising crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or a hydrate thereof, as described in any one of embodiments 1 to 10, and at least one pharma- ceutically acceptable excipient.

[0209] Embodiment 12: The pharmaceutical composition of embodiment 11, wherein the pharmaceutical composition is formulated for administration to a mammal by parenteral administration.

[0210] Embodiment 13: A method of treating a disease or disorder in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or a hydrate thereof, as described in any one of embodiments 1 to 10, or a pharmaceutical composition as described in embodiment 11 or 12.

[0211] Embodiment 14: The method of embodiment 13, wherein the disease or disorder is a fat-related disorder.

[0212] Embodiment 15: The method of embodiment 14, wherein the fat-related disorder is obesity, abnormal fat distribution, diabetes, cardiovascular disease, obstructive sleep apnea, lipoma, cancer, osteoarthritis, an endocrine disorder, a reproductive disorder, a neurological disorder, a psychiatric disorder, a rheumatic disorder, or an orthopedic disorder.

[0213] Embodiment 16: The method of embodiment 14, wherein the fat-related disorder is cellulite, excess fat in various body areas, lipoma, lipotumor disease, disorders associated with fat accumulation, Dercam's disease, lipedema, or edema.

[0214] Embodiment 17: The method of embodiment 13, wherein the disease or disorder is fibrosis associated with a second disease or disorder.

[0215] Embodiment 18: The method of embodiment 17, wherein the second disease or disorder is pulmonary fibrosis, liver cirrhosis, endomyocardial fibrosis, old myocardial infarction, atrial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, carpal tunnel syndrome, arthrofibrosis, Crohn's disease, keloids, scleroderma, arthrofibrosis, Peyronie's disease, Dupuytren's contracture, or adhesive capsulitis.

[0216] Embodiment 19: The method of claim 13, wherein the disease or disorder is liposarcoma or a solid tumor.

[0217] Embodiment 20: The method of embodiment 13, wherein the disease or disorder is lipoma.

[0218] Embodiment 21: The method of embodiment 13, wherein the disease or disorder is angiolipoma.

[0219] Embodiment 22: Use of crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or a hydrate thereof, as defined in any one of embodiments 1 to 10, or a composition as defined in embodiment 11 or 12, in the manufacture of a medicament for treating a disease or disorder in a subject in need thereof.

[0220] Embodiment 23: The use according to embodiment 22, wherein said disease or disorder is a fat-related disorder.

[0221] Embodiment 24: The use according to embodiment 23, wherein said fat-related disorder is obesity, abnormal fat distribution, diabetes, cardiovascular disease, obstructive sleep apnea, lipoma, cancer, osteoarthritis, an endocrine disorder, a reproductive disorder, a neurological disorder, a psychiatric disorder, a rheumatic disorder, or an orthopedic disorder.

[0222] Embodiment 25: The use according to embodiment 23, wherein said fat-related disorder is cellulite, excess fat in various body areas, lipoma, lipo-tumor disease, disorders associated with fat accumulation, Dercam's disease, lipedema, or edema.

[0223] Embodiment 26: The use according to embodiment 22, wherein said disease or disorder is fibrosis associated with a second disease or disorder.

[0224] Embodiment 27: The use according to embodiment 26, wherein the second disease or disorder is pulmonary fibrosis, liver cirrhosis, endomyocardial fibrosis, old myocardial infarction, atrial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, carpal tunnel syndrome, arthrofibrosis, Crohn's disease, keloids, scleroderma, arthrofibrosis, Peyronie's disease, Dupuytren's contracture, or adhesive capsulitis.

[0225] Embodiment 28: The use according to embodiment 22, wherein said disease or disorder is liposarcoma or a solid tumor.

[0226] Embodiment 29: The use according to embodiment 22, wherein the disease or disorder is angiolipoma.

Claims

1. Crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A) 【Chemistry 1】 or a hydrate thereof, wherein the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride is (a) an X-ray powder diffraction pattern measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å, the X-ray powder diffraction pattern including peaks at 4.0±0.2° 2-θ, 16.5±0.2° 2-θ, and 15.5±0.2° 2-θ; (b) an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1 , measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å; (c) a differential scanning calorimetry (DSC) thermogram; i) an endotherm in the range of about 260-270° C.; ii) an endotherm in the range of about 175-195° C.; A differential scanning calorimetry (DSC) thermogram comprising: (d) A differential scanning calorimetry (DSC) thermogram, i) an endotherm with an onset of about 265° C. and a peak at about 266° C.; ii) an endotherm with an onset of about 180° C. and a peak at about 190° C. A differential scanning calorimetry (DSC) thermogram comprising: (e) A differential scanning calorimetry (DSC) thermogram substantially the same as that shown in FIG. (f) a thermogravimetric analysis (TGA) thermogram substantially the same as that shown in FIG. (g) XRPD unchanged after storage for 7 days at 40° C. and 75% relative humidity (RH); (h) XRPD unchanged after storage at 80° C. for 7 days; or (i) Combinations thereof Crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or a hydrate thereof, characterized by having the following formula:

2. 2. The crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or hydrate thereof, according to claim 1, characterized in that it has an X-ray powder diffraction pattern comprising peaks at 4.0±0.2°2-θ, 16.5±0.2°2-θ, and 15.5±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

3. 2. The crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or a hydrate thereof, according to claim 1, characterized in that the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride has an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

4. The crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride is i) an endotherm in the range of about 260-270° C.; ii) an endotherm in the range of about 175-195° C.; 2. The crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or a hydrate thereof, of claim 1, characterized by a differential scanning calorimetry (DSC) thermogram comprising:

5. The crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride is i) an endotherm with an onset of about 265° C. and a peak at about 266° C.; ii) an endotherm with an onset of about 180° C. and a peak at about 190° C.

2. The crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or a hydrate thereof, of claim 1, characterized by a differential scanning calorimetry (DSC) thermogram comprising:

6. 2. The crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or a hydrate thereof, according to claim 1, wherein the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride is characterized by a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in FIG.

7. 2. The crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or a hydrate thereof, according to claim 1, wherein the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride is characterized by a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in FIG.

8. Crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A) 【Chemistry 2】 or a hydrate thereof, wherein the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride is (a) an X-ray powder diffraction pattern measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å, comprising peaks at 28.4±0.2° 2-θ, 18.5±0.2° 2-θ, and 12.1±0.2° 2-θ; (b) an X-ray powder diffraction pattern substantially the same as that shown in FIG. 7, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å; or (c) Combinations thereof Crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or a hydrate thereof, characterized by having the following formula:

9. 9. The crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or a hydrate thereof, according to claim 8, characterized in that the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride has an X-ray powder diffraction pattern comprising peaks at 28.4±0.2°2-θ, 18.5±0.2°2-θ, and 12.1±0.2°2-θ, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

10. 9. The crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or a hydrate thereof, according to claim 8, characterized in that the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride has an X-ray powder diffraction pattern substantially the same as that shown in FIG. 7, measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

11. A pharmaceutical composition comprising the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride or a hydrate thereof according to claim 1 or 8, and at least one pharma- ceutically acceptable excipient.

12. 12. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition is formulated for administration to a mammal by parenteral administration.

13. Use of crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, or a hydrate thereof, according to claim 1 or 8 in the manufacture of a medicament for treating a disease or disorder in a subject in need of such treatment.

14. The use of claim 13, wherein the disease or disorder is a fat-related disease or disorder.

15. The use of claim 14, wherein the fat-related disease or disorder is obesity, abnormal fat distribution, diabetes, cardiovascular disease, obstructive sleep apnea, lipoma, cancer, osteoarthritis, endocrine disease, reproductive disease, neurological disease, psychiatric disease, rheumatic disease, or orthopedic disease.

16. The use of claim 14, wherein the fat-related disease or disorder is cellulite, excess fat in various body areas, lipoma, adipose tumor disease, disorders associated with fat accumulation, Dercam's disease, lipedema, or brown lipoma.

17. The use described in claim 13, wherein the disease or disorder is fibrosis associated with a second disease or disorder.

18. The use described in claim 17, wherein the second disease or disorder is pulmonary fibrosis, liver cirrhosis, endomyocardial fibrosis, old myocardial infarction, atrial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, carpal tunnel syndrome, arthrofibrosis, Crohn's disease, keloids, scleroderma, arthrofibrosis, Peyronie's disease, Dupuytren's contracture, or adhesive capsulitis.

19. The use of claim 13, wherein the disease or disorder is liposarcoma or a solid tumor.

20. The use of claim 13, wherein the disease or disorder is a lipoma.

21. The use described in claim 13, wherein the disease or disorder is angiolipoma.

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