Crystalline carbazole derivative and method for producing same

Abstract

Crystalline carbazole derivatives, pharmaceutical compositions thereof, and methods of treatment are provided herein.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 382,608, filed November 7, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Fat-related disorders present many aesthetic and health-related problems. Although advances have been made in recent years, there remains a need for new treatments for fat-related disorders. Summary of the Invention

[0003] In one embodiment, anhydrous crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A):

[0004] [ka] is provided herein, and the anhydrous crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride is (a) an X-ray powder diffraction pattern containing peaks at 3.0±0.2°2-θ, 22.3±0.2°2-θ, and 31.2±0.2°2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å; (b) an X-ray powder diffraction pattern substantially the same as that shown in Figure 8; or (c) A combination of these It is characterized as having

[0005] In one embodiment, 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A):

[0006] [ka] Provided herein is a mixture of anhydrous crystalline forms of

[0007] In some embodiments, the mixture comprises anhydrous crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride characterized as having an X-ray powder diffraction pattern comprising peaks at 3.0±0.2°2-θ, 4.8±0.2°2-θ, 22.3±0.2°2-θ, 24.8±0.2°2-θ, 26.5±0.2°2-θ, and 31.2±0.2°2-θ, as measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the anhydrous crystalline form of Compound A is formed by a process comprising exposing Compound A to an elevated temperature. In some embodiments, the anhydrous crystalline form of Compound A is formed by a process comprising drying Compound A to reduce the water content.

[0008] In one aspect, provided herein is a process for the preparation of anhydrous crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A), the process comprising reducing the moisture content in a sample of Compound A and maintaining the sample at a low relative humidity. In some embodiments, reducing the moisture content comprises heating the sample of Compound A. In some embodiments, the low relative humidity is less than about 30%.

[0009] In one aspect, provided herein is a process for the 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 process comprising exposing a sample of Compound A to a humid environment. In some embodiments, the sample of Compound A is an unstable crystalline form. In some embodiments, the sample of Compound A is anhydrous.

[0010] 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 explanation of the drawings]

[0011] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings. [Figure 1] 1 shows the X-ray powder diffraction (XRPD) pattern for Form 1 of crystalline Compound A. [Figure 2] 1 shows a differential scanning calorimetry (DSC) thermogram for crystalline Compound A Form 1. [Figure 3] 1 shows the thermogravimetric analysis (TGA) pattern for crystalline Compound A Form 1. [Figure 4] 1 shows the X-ray powder diffraction (XRPD) pattern for crystalline Form 2 of Compound A. [Figure 5] 1 shows a differential scanning calorimetry (DSC) thermogram for crystalline Compound A Form 2. [Figure 6] 1 shows the thermogravimetric analysis (TGA) pattern for crystalline Compound A Form 2. [Figure 7] 1 shows the X-ray powder diffraction (XRPD) pattern for crystalline Compound A Form 3. [Figure 8] 1 shows the X-ray powder diffraction (XRPD) pattern for crystalline Compound A Form 4. Invention Details

[0012] While small molecule inhibitors are often first evaluated for their activity when dissolved in solution, solid-state characteristics 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 directly affect 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. Therefore, polymorphism is often an important factor in routinely testing the "sameness" of drug formulations from various manufacturers. For example, polymorphism is evaluated in many multi-million, even multi-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 pharmaceutical polymorphs. The present disclosure addresses this need and provides related advantages as well.

[0013] Compound A As used herein, Compound A refers to

[0014] [ka] It refers to 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, having the chemical structure shown in

[0015] 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).

[0016] In some embodiments disclosed herein, Compound A is amorphous. In some embodiments disclosed herein, Compound A is crystalline.

[0017] I. Crystalline Form of Compound A Compound A exhibits polymorphism, and the crystalline forms of Compound A produced by 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, and other analytical methods such as Raman spectroscopy, 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).

[0018] XRPD: The crystalline forms of Compound A according to the present invention can be characterized by XRPD, such as those shown in Figures 1, 4, or 7. The relative intensities of XRPD peaks can vary depending on particle size, sample preparation technique, sample mounting procedure, and the particular instrument used. Furthermore, instrument variation and other factors can affect 2-theta values. Thus, XRPD peak assignments can vary, for example, by plus or minus about 0.2 degrees.

[0019] DSC: The crystalline form of Compound A according to the present invention can be identified by its characteristic DSC thermogram, such as that shown in Figure 2 or Figure 5. For DSC, it is known that the observed temperatures depend on the rate of change of temperature, as well as the sample preparation technique and the particular instrument used. Thus, the values ​​reported herein for DSC thermograms may vary, for example, by plus or minus about 4°C.

[0020] TGA: The crystalline form of Compound A of the present invention may also exhibit thermal behavior that differs from that of amorphous material or another polymorphic form. Thermal behavior can be measured in the laboratory by thermogravimetric analysis (TGA), which can be used to distinguish some polymorphic forms from other polymorphic forms. In one embodiment, the crystalline form of Compound A can be characterized by thermogravimetric analysis. Crystalline Compound A can be identified by its characteristic TGA thermogram, such as that shown in Figure 3 or Figure 6.

[0021] Crystalline forms of Compound A are useful for manufacturing medicinal preparations and can be obtained by a crystallization process. Semi-crystalline forms can also be obtained. In some embodiments, the semi-crystalline form of Compound A comprises 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 either by producing the desired compound (e.g., Compound A) in a reaction mixture and isolating the desired crystalline form from the reaction mixture, or by dissolving the raw compound in a solvent, optionally with heating, followed by crystallization / solidification of the product by cooling (including active cooling) and / or by adding an antisolvent over a period of time. Following crystallization or solidification, drying can be carried out under controlled conditions until the desired water content for the desired crystalline form is reached.

[0022] In various embodiments, crystalline Compound A disclosed herein is stable at room temperature. In some examples, crystalline Compound A is stable and can be stored at room temperature for extended periods of time without chemical degradation or change in crystalline form. In some examples, crystalline Compound A is stable and can be stored at room temperature for extended periods of time without significant chemical degradation or change in crystalline form. In some examples, crystalline Compound A is stable and can be stored at room temperature 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 is stable and can be stored at room temperature for more than about 7 days. In some examples, crystalline Compound A is stable and can be stored at room temperature for 10-20 days. In some examples, crystalline Compound A is stable and can be stored at room temperature for 10-15 days. In some examples, crystalline Compound A is stable and can be stored at room temperature for 15-20 days. In some examples, crystalline Compound A is stable and can be stored at room temperature for 10-12 days. In some examples, crystalline Compound A is stable and can be stored at room temperature for 12-14 days. In some examples, crystalline Compound A is stable and can be stored at room temperature for a period of 14 to 16 days. In some examples, crystalline Compound A is stable and can be stored at room temperature for a period of 16 to 18 days. In some examples, crystalline Compound A is stable and can be stored at room temperature for a period of 18 to 20 days. In some examples, crystalline Compound A is stable and 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, 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, crystalline Compound A is stable and 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 is stable and can be stored at room temperature for one year or more without chemical decomposition or chemical change in the crystalline form. In some embodiments, crystalline Compound A is stable and can be stored at room temperature for one year or more without significant chemical decomposition or chemical change in the crystalline form. In some embodiments, crystalline Compound A is stable and can be stored at room temperature for 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 is stable and can be stored at room temperature for one to two years without chemical decomposition or chemical change in the crystalline form. In some embodiments, crystalline Compound A is stable and can be stored at room temperature for one to two years without significant chemical decomposition or chemical change in the crystalline form. In some embodiments, crystalline Compound A is stable and can be stored at room temperature for two years or more. In some embodiments, crystalline Compound A is stable and can be stored at room temperature for at least 24 months, at least 30 months, or at least 36 months. In some embodiments, crystalline Compound A is stable and can be stored at room temperature for 36 months. In some embodiments, crystalline Compound A is stable and can be stored at room temperature for a period of 12 to 18 months, 14 to 20 months, 16 to 22 months, 18 to 24 months, 20 to 26 months, 22 to 38 months, or 24 to 40 months.

[0023] In various embodiments, the crystalline Compound A disclosed herein is stable at temperatures above room temperature and / or at high relative humidity (RH). In some examples, crystalline Compound A is stable and can be stored at about 40°C and about 75% RH for extended periods of time without chemical degradation or change in crystalline form. In some examples, crystalline Compound A is stable and can be stored at about 40°C and about 75% RH for extended periods of time without significant chemical degradation or change in crystalline form. In some examples, crystalline Compound A is stable and 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 is stable and can be stored at about 40°C and about 75% RH for more than about 7 days. In some examples, crystalline Compound A is stable and can 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 is stable and can 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.

[0024] In various embodiments, crystalline Compound A disclosed herein is stable at high temperatures. In some examples, crystalline Compound A is stable and can be stored at about 80°C for extended periods of time without chemical decomposition or change in crystalline form. In some examples, crystalline Compound A is stable and can be stored at about 80°C for extended periods of time without significant chemical decomposition or change in crystalline form. In some examples, crystalline Compound A is stable and can be stored at about 80°C 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 is stable and can be stored at about 80°C for at least about 7 days. In some examples, 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 is stable and 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.

[0025] Crystalline Compound A Form 1 FIG. 1 shows the X-ray powder diffraction (XRPD) pattern for crystalline Compound A Form 1.

[0026] FIG. 2 shows the differential scanning calorimetry (DSC) thermogram for crystalline Compound A Form 1.

[0027] FIG. 3 shows the thermogravimetric analysis (TGA) pattern for crystalline Compound A Form 1.

[0028] 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 compositions comprising crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride. In some embodiments, 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 containing peaks at 4.0±0.2°2-θ, 16.5±0.2°2-θ, and 15.5±0.2°2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å; (b) an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1 when measured using Cu Kα radiation having an X-ray wavelength of 1.54060 Å; (c) 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) 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 Figure 2; (f) Thermogravimetric analysis (TGA) thermogram substantially the same as that shown in Figure 3; (g) Unaltered XRPD after storage for 7 days at 40°C and 75% relative humidity (RH); (h) Unaltered XRPD after storage at 80°C for 7 days, or (i) A combination of these It is characterized as having

[0029] In some embodiments, Form 1 of crystalline Compound A is characterized as having substantially the same X-ray powder diffraction pattern as shown in FIG. 1, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0030] In some embodiments, Form 1 of crystalline Compound A is characterized as having an X-ray powder diffraction pattern comprising peaks at 4.0±0.2 degrees two-theta, 16.5±0.2 degrees two-theta, and 15.5±0.2 degrees two-theta, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, Form 1 of crystalline Compound A is characterized as having an X-ray powder diffraction pattern comprising peaks at 4.0±0.1 degrees two-theta, 16.5±0.1 degrees two-theta, and 15.5±0.1 degrees two-theta, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, Form 1 of crystalline Compound A is characterized as having an X-ray powder diffraction pattern comprising peaks at about 4.0°2-θ, about 16.5°2-θ, and about 15.5°2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0031] 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 degrees two-theta, 26.0±0.2 degrees two-theta, and 26.1±0.2 degrees two-theta, when 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 24.1±0.1 degrees two-theta, 26.0±0.1 degrees two-theta, and 26.1±0.1 degrees two-theta, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of Form 1 of crystalline Compound A further comprises at least one peak selected from about 24.1°2-θ, about 26.0°2-θ, and about 26.1°2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0032] 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 degrees two-theta, 23.8±0.2 degrees two-theta, and 26.5±0.2 degrees two-theta, when 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 degrees two-theta, 23.8±0.1 degrees two-theta, and 26.5±0.1 degrees two-theta, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of Form 1 of crystalline Compound A further comprises at least one peak selected from about 19.9°2-θ, about 23.8°2-θ, and about 26.5°2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0033] In some embodiments, the X-ray powder diffraction pattern of Form 1 of crystalline Compound A 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, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of Form 1 of crystalline Compound A 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, when 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, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of Form 1 of crystalline Compound A 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, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.In some embodiments, the X-ray powder diffraction pattern of Form 1 of crystalline Compound A 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, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of Form 1 of crystalline Compound A 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, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of Form 1 of crystalline Compound A 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, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of Form 1 of crystalline Compound A 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, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.In some embodiments, the X-ray powder diffraction pattern of Form 1 of crystalline Compound A comprises 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, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of Form 1 of crystalline Compound A comprises 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, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of Form 1 of crystalline Compound A comprises 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, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0034] In some embodiments, Form 1 of crystalline Compound A is characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in Figure 2. In some embodiments, Form 1 of crystalline Compound A 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, Form 1 of crystalline Compound A 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.

[0035] In some embodiments, crystalline Compound A Form 1 is characterized in a DSC thermogram by an endotherm in the range of about 260-270° C., e.g., 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 26-270° C. In some examples, crystalline Compound A Form 1 is characterized in a DSC thermogram by an endotherm at about 266° C.

[0036] In some embodiments, crystalline Compound A Form 1 is further characterized in a DSC thermogram 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 190-195° C. In some examples, crystalline Compound A Form 1 is further characterized in a DSC thermogram by an endotherm at about 190° C.

[0037] In some embodiments, Form 1 of crystalline Compound A is characterized by a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in Figure 3. In various embodiments, Form 1 of crystalline Compound A decomposes at temperatures greater than 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, Form 1 of crystalline Compound A decomposes at temperatures greater than about 250°C.

[0038] Crystalline Compound A Form 2 FIG. 4 shows the X-ray powder diffraction (XRPD) pattern for crystalline Compound A Form 2.

[0039] FIG. 5 shows a differential scanning calorimetry (DSC) thermogram for crystalline Compound A Form 2.

[0040] FIG. 6 shows the thermogravimetric analysis (TGA) pattern for crystalline Compound A Form 2.

[0041] 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 compositions comprising crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride. In some embodiments, crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride Form 2 (Compound A Form 2) is (a) an X-ray powder diffraction pattern containing peaks at 4.8±0.2° 2-θ, 26.5±0.2° 2-θ, and 24.8±0.2° 2-θ, when measured using Cu Kα radiation having an X-ray wavelength of 1.54060 Å; (b) an X-ray powder diffraction pattern substantially the same as that shown in FIG. 4 when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å; (c) i) A differential scanning calorimetry (DSC) thermogram containing an endotherm in the range of about 260-270°C. (d) i) a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 265°C and a peak at about 266°C; (e) A differential scanning calorimetry (DSC) thermogram substantially the same as that shown in Figure 5; (f) Thermogravimetric analysis (TGA) thermogram substantially the same as that shown in Figure 6; (g) Unaltered XRPD after storage at 80°C for 7 days, or (h) Combinations of these It is characterized as having

[0042] In some embodiments, crystalline Compound A Form 2 is characterized as having an X-ray powder diffraction pattern substantially the same as that shown in FIG.

[0043] In some embodiments, crystalline Compound A Form 2 is characterized as having an X-ray powder diffraction pattern comprising peaks at 4.8±0.2 degrees two-theta, 26.5±0.2 degrees two-theta, and 24.8±0.2 degrees two-theta, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, crystalline Compound A Form 2 is characterized as having an X-ray powder diffraction pattern comprising peaks at 4.8±0.1 degrees two-theta, 26.5±0.1 degrees two-theta, and 24.8±0.1 degrees two-theta, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, Form 2 of crystalline Compound A is characterized as having an X-ray powder diffraction pattern comprising peaks at about 4.8°2-θ, about 26.5°2-θ, and about 24.8°2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0044] 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 degrees two-theta, 17.9±0.2 degrees two-theta, and 21.0±0.2 degrees two-theta, when 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 further comprises at least one peak selected from 17.5±0.1 degrees two-theta, 17.9±0.1 degrees two-theta, and 21.0±0.1 degrees two-theta, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of Form 2 of crystalline Compound A further comprises at least one peak selected from about 17.5°2-θ, about 17.9°2-θ, and about 21.0°2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0045] 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 degrees two-theta, 25.5±0.2 degrees two-theta, and 20.4±0.2 degrees two-theta, when 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 further comprises at least one peak selected from 19.6±0.1 degrees two-theta, 25.5±0.1 degrees two-theta, and 20.4±0.1 degrees two-theta, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of Form 2 of crystalline Compound A further comprises at least one peak selected from about 19.6°2-θ, about 25.5°2-θ, and about 20.4°2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0046] 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, when 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, when 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, when 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, when 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°2-θ, when 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, when 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°2-θ, when 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°2-θ, when 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 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, when 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 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, when 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 peaks at about 4.8°2-θ, about 17.5°2-θ, about 17.9°2-θ, about 19.6°2-θ, about 20.4°2-θ, about 21.0°2-θ, about 24.8°2-θ, about 25.5°2-θ, and about 26.6°2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0047] In some embodiments, Form 2 of crystalline Compound A is characterized by a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in Figure 5. In some embodiments, Form 2 of crystalline Compound A is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 260-270°C. In some embodiments, Form 2 of crystalline Compound A 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.

[0048] In some embodiments, crystalline Compound A Form 2 is characterized in a DSC thermogram by an endotherm in the range of about 260-270° C., e.g., 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 268-270° C. In some embodiments, crystalline Compound A Form 2 is characterized in a DSC thermogram by an endotherm at about 266° C.

[0049] In some embodiments, crystalline Compound A Form 2 is characterized by a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in FIG.

[0050] In some embodiments, crystalline Compound A Form 1 is formed by exposing crystalline Compound A Form 2 to ambient conditions. In some embodiments, crystalline Compound A Form 1 is formed by exposing crystalline Compound A Form 2 to humid conditions. In some embodiments, the humid conditions include an RH greater than about 25%. In some embodiments, the humid conditions include an RH greater than about 30%. In some embodiments, the humid conditions include an RH greater than about 35%. In some embodiments, the humid conditions include an RH greater than about 40%. In some embodiments, the humid conditions include an RH greater than about 45%. In some embodiments, the humid conditions include an RH greater than about 50%. In some embodiments, the humid conditions include an RH greater than about 55%. In some embodiments, the humid conditions include an RH greater than about 60%. In some embodiments, the humid conditions include an RH greater than about 65%. In some embodiments, the humid conditions include an RH greater than about 70%. In some embodiments, the humid conditions include an RH greater than about 75%. In some embodiments, the wet condition comprises an RH greater than about 80%. In some embodiments, the wet condition comprises an RH of about 30% to about 70%. In some embodiments, the wet condition comprises an RH less than about 90%. In some embodiments, the wet condition comprises an RH less than about 80%. In some embodiments, the wet condition comprises an RH less than about 70%. In some embodiments, the wet condition comprises an RH less than about 60%. In some embodiments, the wet condition comprises an RH less than about 50%. In some embodiments, the wet condition comprises an RH less than about 40%. In some embodiments, the wet condition comprises an RH less than about 30%. In some embodiments, crystalline Compound A Form 1 is formed by a process comprising: (i) exposing crystalline Compound A Form 2 to a first humidity; and (ii) exposing the compound from step (i) to a second humidity. In some embodiments, the first humidity is greater than the second humidity. In some embodiments, the first humidity is greater than about 80% RH. In some embodiments, the first humidity is. Higher than about 90% RH.In some embodiments, the first humidity is about 80% to about 90% RH. In some embodiments, the second humidity is less than about 80% RH. In some embodiments, the second humidity is less than 70% RH. In some embodiments, the second humidity is about 30% to about 70% RH. In some embodiments, the forming further comprises allowing crystalline Form 2 of Compound A to stand at a temperature of about 15°C to about 80°C. In some embodiments, the temperature is about 20°C to about 80°C. In some embodiments, the temperature is about 20°C to about 75°C. In some embodiments, the temperature is about 25°C to about 80°C. In some embodiments, the temperature is about 25°C to about 75°C. In some embodiments, the temperature is about 25°C to about 70°C. In some embodiments, the temperature is about 25°C to about 65°C. In some embodiments, the temperature is about 20°C to about 60°C. In some embodiments, the temperature is greater than about 20°C. In some embodiments, the temperature is greater than about 25°C. In some embodiments, the temperature is greater than about 35°C. In some embodiments, the temperature is greater than about 50°C. In some embodiments, the temperature is greater than about 60°C. In some embodiments, the temperature is greater than about 70°C. In some embodiments, the temperature is less than about 80°C. In some embodiments, the temperature is less than about 70°C. In some embodiments, the temperature is less than about 65°C. In some embodiments, the temperature is less than about 55°C. In some embodiments, the temperature is less than about 45°C. In some embodiments, the temperature is less than about 35°C.

[0051] Crystalline Compound A Form 3 FIG. 7 shows the X-ray powder diffraction (XRPD) pattern for crystalline Form 3 of crystalline Compound A.

[0052] 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 compositions comprising crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride. In some embodiments, 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 containing peaks at 28.4±0.2°2-θ, 18.5±0.2°2-θ, and 12.1±0.2°2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å; (b) an X-ray powder diffraction pattern substantially the same as that shown in FIG. 7 when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å; or (c) A combination of these It is characterized as having

[0053] In some embodiments, crystalline Compound A Form 3 is characterized as having an X-ray powder diffraction pattern substantially the same as that shown in FIG.

[0054] In some embodiments, Form 3 of crystalline Compound A is characterized as having an X-ray powder diffraction pattern comprising peaks at 28.4±0.2 degrees two-theta, 18.5±0.2 degrees two-theta, and 12.1±0.2 degrees two-theta, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, Form 3 of crystalline Compound A is characterized as having an X-ray powder diffraction pattern comprising peaks at 28.4±0.1 degrees two-theta, 18.5±0.1 degrees two-theta, and 12.1±0.1 degrees two-theta, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, Form 3 of crystalline Compound A is characterized as having an X-ray powder diffraction pattern comprising peaks at about 28.4°2-θ, about 18.5°2-θ, and about 12.1°2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0055] 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 degrees two-theta, 31.7±0.2 degrees two-theta, and 23.3±0.2 degrees two-theta, when 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 further comprises at least one peak selected from 26.8±0.1 degrees two-theta, 31.7±0.1 degrees two-theta, and 23.3±0.1 degrees two-theta, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of Form 3 of crystalline Compound A further comprises at least one peak selected from about 26.8°2-θ, about 31.7°2-θ, and about 23.3°2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0056] 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 degrees two-theta, 30.8±0.2 degrees two-theta, and 21.8±0.2 degrees two-theta, when 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 further comprises at least one peak selected from 20.7±0.1 degrees two-theta, 30.8±0.1 degrees two-theta, and 21.8±0.1 degrees two-theta, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of Form 3 of crystalline Compound A further comprises at least one peak selected from about 20.7°2-θ, about 30.8°2-θ, and about 21.8°2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0057] 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, when 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, when 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, when 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, when 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 when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. The compound 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 when measured using Kα1 radiation. 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, when 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, when 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 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, when 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 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, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of Form 3 of crystalline Compound A comprises 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, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0058] Crystalline Compound A Form 4 FIG. 8 shows the X-ray powder diffraction (XRPD) pattern for crystalline Compound A Form 4.

[0059] 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 compositions comprising crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride. In some embodiments, crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride Form 4 (Compound A Form 4) is (a) an X-ray powder diffraction pattern containing peaks at 3.0±0.2°2-θ, 22.3±0.2°2-θ, and 31.2±0.2°2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å; (b) an X-ray powder diffraction pattern substantially the same as that shown in Figure 8; or (c) A combination of these It is characterized as having

[0060] In some embodiments, crystalline Compound A Form 4 is characterized as having an X-ray powder diffraction pattern substantially the same as that shown in FIG.

[0061] In some embodiments, Form 4 of crystalline Compound A is characterized as having an X-ray powder diffraction pattern comprising peaks at 3.0±0.2 degrees two-theta, 22.3±0.2 degrees two-theta, and 31.2±0.2 degrees two-theta, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, Form 4 of crystalline Compound A is characterized as having an X-ray powder diffraction pattern comprising peaks at 3.0±0.1 degrees two-theta, 22.3±0.1 degrees two-theta, and 31.2±0.1 degrees two-theta, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, Form 4 of crystalline Compound A is characterized as having an X-ray powder diffraction pattern comprising peaks at about 3.0°2-θ, about 22.3°2-θ, and about 31.2°2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0062] In some embodiments, Form 4 of crystalline Compound A is characterized as having an X-ray powder diffraction pattern comprising peaks at 4.0±0.2°2-θ, 5.0±0.2°2-θ, and 15.3±0.2°2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, Form 4 of crystalline Compound A is characterized as having an X-ray powder diffraction pattern comprising peaks at 4.0±0.1°2-θ, 5.0±0.1°2-θ, and 15.3±0.1°2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, Form 4 of crystalline Compound A is characterized as having an X-ray powder diffraction pattern comprising peaks at about 4.0°2-θ, about 5.0°2-θ, and about 15.3°2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0063] In some embodiments, the X-ray powder diffraction pattern of crystalline Compound A Form 4 further comprises at least one peak selected from 3.0±0.2 degrees two-theta, 25.6±0.2 degrees two-theta, and 31.2±0.2 degrees two-theta, when 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 4 further comprises at least one peak selected from 3.0±0.1 degrees two-theta, 25.6±0.1 degrees two-theta, and 31.2±0.1 degrees two-theta, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of Form 4 of crystalline Compound A further comprises at least one peak selected from about 3.0°2-θ, about 25.6°2-θ, and about 31.2°2-θ, when 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 4 further comprises at least one peak selected from 17.6±0.2 degrees two-theta, 20.6±0.2 degrees two-theta, and 22.3±0.2 degrees two-theta, when 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 4 further comprises at least one peak selected from 17.6±0.1 degrees two-theta, 20.6±0.1 degrees two-theta, and 22.3±0.1 degrees two-theta, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of Form 4 of crystalline Compound A further comprises at least one peak selected from about 17.6°2-θ, about 20.6°2-θ, and about 22.3°2-θ, when 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 Form 4 of crystalline Compound A comprises at least one peak selected from 3.0±0.2°2-θ, 4.0±0.2°2-θ, 5.0±0.2°2-θ, 15.3±0.2°2-θ, 17.6±0.2°2-θ, 20.6±0.2°2-θ, 22.3±0.2°2-θ, 25.6±0.2°2-θ, and 31.2±0.2°2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å. In some embodiments, the X-ray powder diffraction pattern of Form 4 of crystalline Compound A comprises at least two peaks selected from 3.0±0.2°2-θ, 4.0±0.2°2-θ, 5.0±0.2°2-θ, 15.3±0.2°2-θ, 17.6±0.2°2-θ, 20.6±0.2°2-θ, 22.3±0.2°2-θ, 25.6±0.2°2-θ, and 31.2±0.2°2-θ, when 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 4 comprises at least three peaks selected from 3.0±0.2°2-θ, 4.0±0.2°2-θ, 5.0±0.2°2-θ, 15.3±0.2°2-θ, 17.6±0.2°2-θ, 20.6±0.2°2-θ, 22.3±0.2°2-θ, 25.6±0.2°2-θ, and 31.2±0.2°2-θ, when 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 4 comprises at least four peaks selected from 3.0±0.2°2-θ, 4.0±0.2°2-θ, 5.0±0.2°2-θ, 15.3±0.2°2-θ, 17.6±0.2°2-θ, 20.6±0.2°2-θ, 22.3±0.2°2-θ, 25.6±0.2°2-θ, and 31.2±0.2°2-θ, when 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 4 comprises at least five peaks selected from 3.0±0.2°2-θ, 4.0±0.2°2-θ, 5.0±0.2°2-θ, 15.3±0.2°2-θ, 17.6±0.2°2-θ, 20.6±0.2°2-θ, 22.3±0.2°2-θ, 25.6±0.2°2-θ, and 31.2±0.2°2-θ, when 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 4 comprises at least six peaks selected from 3.0±0.2°2-θ, 4.0±0.2°2-θ, 5.0±0.2°2-θ, 15.3±0.2°2-θ, 17.6±0.2°2-θ, 20.6±0.2°2-θ, 22.3±0.2°2-θ, 25.6±0.2°2-θ, and 31.2±0.2°2-θ, when 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 4 comprises at least seven peaks selected from 3.0±0.2°2-θ, 4.0±0.2°2-θ, 5.0±0.2°2-θ, 15.3±0.2°2-θ, 17.6±0.2°2-θ, 20.6±0.2°2-θ, 22.3±0.2°2-θ, 25.6±0.2°2-θ, and 31.2±0.2°2-θ, when 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 4 comprises at least eight peaks selected from 3.0±0.2°2-θ, 4.0±0.2°2-θ, 5.0±0.2°2-θ, 15.3±0.2°2-θ, 17.6±0.2°2-θ, 20.6±0.2°2-θ, 22.3±0.2°2-θ, 25.6±0.2°2-θ, and 31.2±0.2°2-θ, when 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 4 comprises peaks at 3.0±0.2°2-θ, 4.0±0.2°2-θ, 5.0±0.2°2-θ, 15.3±0.2°2-θ, 17.6±0.2°2-θ, 20.6±0.2°2-θ, 22.3±0.2°2-θ, 25.6±0.2°2-θ, and 31.2±0.2°2-θ, when 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 4 comprises peaks at 3.0±0.1°2-θ, 4.0±0.1°2-θ, 5.0±0.1°2-θ, 15.3±0.1°2-θ, 17.6±0.1°2-θ, 20.6±0.1°2-θ, 22.3±0.1°2-θ, 25.6±0.1°2-θ, and 31.2±0.1°2-θ, when 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 4 comprises peaks at about 3.0°2-θ, about 4.0°2-θ, about 5.0°2-θ, about 15.3°2-θ, about 17.6°2-θ, about 20.6°2-θ, about 22.3°2-θ, about 25.6°2-θ, and about 31.2°2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0066] In some embodiments, crystalline Compound A Form 1 is formed by exposing crystalline Compound A Form 4 to humid conditions. In some embodiments, the humid condition comprises an RH greater than about 25%. In some embodiments, the humid condition comprises an RH greater than about 30%. In some embodiments, the humid condition comprises an RH greater than about 35%. In some embodiments, the humid condition comprises an RH greater than about 40%. In some embodiments, the humid condition comprises an RH greater than about 45%. In some embodiments, the humid condition comprises an RH greater than about 50%. In some embodiments, the humid condition comprises an RH greater than about 55%. In some embodiments, the humid condition comprises an RH greater than about 60%. In some embodiments, the humid condition comprises an RH greater than about 65%. In some embodiments, the humid condition comprises an RH greater than about 70%. In some embodiments, the humid condition comprises an RH greater than about 75%. In some embodiments, the humid condition comprises an RH greater than about 80%. In some embodiments, the humid condition comprises an RH between about 30% and about 70%. In some embodiments, the wet state comprises an RH of less than about 90%. In some embodiments, the wet state comprises an RH of less than about 80%. In some embodiments, the wet state comprises an RH of less than about 70%. In some embodiments, the wet state comprises an RH of less than about 60%. In some embodiments, the wet state comprises an RH of less than about 50%. In some embodiments, the wet state comprises an RH of less than about 40%. In some embodiments, the wet state comprises an RH of less than about 30%. In some embodiments, the forming further comprises allowing crystalline Form 4 of Compound A to stand at a temperature of about 15°C to about 80°C. In some embodiments, the temperature is about 20°C to about 80°C. In some embodiments, the temperature is about 20°C to about 75°C. In some embodiments, the temperature is about 25°C to about 80°C. In some embodiments, the temperature is about 25°C to about 75°C. In some embodiments, the temperature is about 25°C to about 70°C. In some embodiments, the temperature is about 25°C to about 65°C. In some embodiments, the temperature is from about 20°C to about 60°C. In some embodiments, the temperature is from about 25°C to about 40°C. In some embodiments, the temperature is greater than about 20°C.In some embodiments, the temperature is greater than about 25°C. In some embodiments, the temperature is greater than about 35°C. In some embodiments, the temperature is greater than about 50°C. In some embodiments, the temperature is greater than about 60°C. In some embodiments, the temperature is greater than about 70°C. In some embodiments, the temperature is less than about 80°C. In some embodiments, the temperature is less than about 70°C. In some embodiments, the temperature is less than about 65°C. In some embodiments, the temperature is less than about 55°C. In some embodiments, the temperature is less than about 45°C. In some embodiments, the temperature is less than about 35°C.

[0067] II. Methods for Making Compound A and Its Polymorphic Forms In one aspect, the present invention provides compound A:

[0068] [ka] The present invention provides a method for producing a crystalline form of

[0069] In some embodiments, Compound A is prepared according to the Examples herein.

[0070] Crystalline Compound A according to the present invention is not limited by the starting materials used to prepare Compound A.

[0071] In one aspect, the present invention relates to a method of making a crystalline form of Compound A, or a pharmaceutically acceptable salt and / or solvate thereof, either by isolating the desired crystalline form as a first solid form after synthesis of Compound A, or alternatively, by isolating the desired crystalline form as a transition from a previous solid form of Compound A. 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 desired form for the manufacture of a pharmaceutical formulation.

[0072] Isolation and purification of the chemical entities and chemical intermediates described herein, if desired, can be carried out by any suitable separation or purification procedure, such as filtration, extraction, crystallization, column chromatography, thin-layer chromatography, or thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be found by reference to the examples below. 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, 97% chemical purity, 98% chemical purity, 99% chemical purity, about 98% chemical purity, or about 100% chemical purity.

[0073] 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 to a chemical purity ranging from 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%.

[0074] In some embodiments, isolating the desired crystalline form of Compound A comprises crystallizing the crude reaction product from a single solvent system. In various embodiments, isolating the desired crystalline form of Compound A comprises crystallizing the crude product from binary, tertiary, or more solvent systems, collectively understood as multi-solvent systems.

[0075] In some embodiments, crystallization is carried out by producing the desired compound A in a reaction mixture and isolating the desired crystalline form from the reaction mixture. In some embodiments, a reaction mixture is formed by adding (5-bromopentyl)-trimethyl-ammonium bromide, dipotassium carbonate 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. In some embodiments, brine and HCl are also added to the reaction mixture. In some embodiments, brine and HCl are added to the reaction mixture after the reaction is complete.

[0076] Preparation of crystalline Compound A In some embodiments, crystalline Compound A is obtained from a solution formed by adding a solvent to Compound A. In some embodiments, the solvent is selected from 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, and combinations thereof.

[0077] In some embodiments, crystalline Compound A is obtained by temperature cycling a solution of Compound A. In some embodiments, temperature cycling comprises cycling temperatures from 0°C to 80°C, such as 0°C to 80°C, 0°C to 70°C, 0°C to 60°C, 0°C to 50°C, 5°C to 80°C, 5°C to 70°C, 5°C to 60°C, 5°C to 50°C, 10°C to 80°C, 10°C to 70°C, 10°C to 60°C, 10°C to 50°C, 15°C to 80°C, 15°C to 70°C, 15°C to 60°C, 15°C to 50°C, 20°C to 80°C, 20°C to 70°C, 20°C to 60°C, or 20°C to 50°C. In some embodiments, temperature cycling comprises cycling temperatures from 5°C to 50°C. In some embodiments, the temperature cycle includes hold periods of 0.5 to 10 hours at the lower and higher temperatures, such as 0.5 to 10 hours, 0.5 to 8 hours, 0.5 to 6 hours, 0.5 to 4 hours, 0.5 to 2 hours, 1 to 10 hours, 1 to 8 hours, 1 to 6 hours, 1 to 4 hours, 1 to 2 hours, 2 to 10 hours, 0.5 to 10 hours, 2 to 8 hours, 2 to 6 hours, 2 to 4 hours, 4 to 10 hours, 4 to 8 hours, 4 to 6 hours, 6 to 10 hours, 6 to 8 hours, or 8 to 10 hours. In some embodiments, the temperature cycle includes hold periods of 1 hour at the lower and higher temperatures. In some embodiments, the temperature cycle further includes the addition of an anti-solvent. In some embodiments, the anti-solvent is tert-butyl methyl ether.

[0078] 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 of 0°C to 10°C, such as 0°C to 10°C, 0°C to 8°C, 0°C to 6°C, 0°C to 4°C, 0°C to 2°C, 1°C to 10°C, 1°C to 8°C, 1°C to 6°C, 1°C to 4°C, 1°C to 2°C, 2°C to 10°C, 2°C to 8°C, 2°C to 6°C, 2°C to 4°C, 4°C to 10°C, 4°C to 8°C, 4°C to 6°C, 6°C to 10°C, 6°C to 8°C, or 8°C to 10°C. In some embodiments, crash cooling comprises rapidly cooling the solution to a temperature of 6°C. In some embodiments, crash cooling the solution at temperatures ranging from 0°C to -20°C, 0°C to -18°C, 0°C to -16°C, 0°C to -14°C, 0°C to -12°C, 0°C to -10°C, 0°C to -8°C, 0°C to -6°C, 0°C to -4°C, 0°C to -2°C, -2°C to -20°C, -2°C to -18°C, -2°C to -16°C, -2°C to -14°C, -2℃~-12℃, -2℃~-10℃, -2℃~-8℃, -2℃~-6℃, -2℃~-4℃, -4℃~-20℃, -4℃~-18℃, -4℃~-16℃, -4℃~-14℃, -4℃~-12℃, -4℃~-10℃, -4℃~-8℃, -4℃~-6℃, -6℃~-20℃, -6℃~-18℃, -6℃~-16 °C, -6°C to -14°C, -6°C to -12°C, -6°C to -10°C, -6°C to -8°C, -8°C to -20°C, -8°C to -18°C, -8°C to -16°C, -8°C to -14°C, -8°C to -12°C, -8°C to -10°C, -10°C to -20°C, -10°C to -18°C, -10°C to -16°C, -10°C to -14°C, -10°C to - The crash-cooling method may further comprise rapidly cooling the solution to a temperature of 0°C to -20°C, such as 12°C, -12°C to -20°C, -12°C to -18°C, -12°C to -16°C, -12°C to -14°C, -14°C to -20°C, -14°C to -18°C, -14°C to -16°C, -16°C to -20°C, -16°C to -18°C, or -18°C to -20°C. In some embodiments, the crash-cooling method may further comprise rapidly cooling the solution to a temperature of -18°C. In some embodiments, the crash-cooling method may further comprise 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, hi some embodiments, the anti-solvent is tert-butyl methyl ether.

[0079] In various embodiments, the crystallization further comprises filtering the resulting solution containing crystalline Compound A crystals. In some embodiments, the crystallization optionally comprises washing the resulting crystals with a solvent, e.g., a recrystallization solvent, one or more times. In some embodiments, the crystallization optionally comprises drying the resulting crystals under vacuum, e.g., at a temperature of about 20-30°C.

[0080] In some embodiments, the chemical purity of crystalline Compound A is greater than 60%, 70%, 80%, 90%, 95%, or 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.

[0081] 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 characterized as being hydrated and having 1 to 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 about 1 to about 10% water content (w / w%). In some embodiments, crystalline Compound A comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% water content (w / w%). In some embodiments, crystalline Compound A comprises a water content (w / w%) of 2 to about 8%. In some embodiments, crystalline Compound A comprises a water content (w / w%) of 3 to about 6%. In some embodiments, 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.

[0082] III. Additional Definitions As used herein, "active agent" is used to refer to a chemical substance that has biological activity. In certain embodiments, an "active agent" is a compound that has pharmaceutical utility.

[0083] 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. The change can be an increase or 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 in turn 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 to increase or decrease target activity, or by increasing or decreasing (directly or indirectly) the amount of target present in a cell or organism.

[0084] 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, delay of disease progression, or prevention of disease.

[0085] "Treating" or "treatment" encompasses administration of Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, to a mammalian subject, particularly a human subject, in need of such administration, and includes prophylactic treatment to (i) halt the progression of clinical symptoms of the disease, (ii) bring about regression of clinical symptoms of the disease, and / or (iii) prevent the onset of the disease.

[0086] As used herein, a "pharmaceutically 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 response) commensurate with a reasonable benefit / risk ratio.

[0087] "Pharmaceutically acceptable salts" include salts with inorganic acids, such as hydrochlorides, carbonates, phosphates, hydrogen phosphates, diphosphates, hydrobromides, sulfates, sulfinates, nitrates, and the like; salts with organic acids, such as malate, malonate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, gluconate, methanesulfonate, tris(hydroxymethyl-aminomethane), p-toluenesulfonate, priopionate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearic acid, oxalate, pamoate, and alkanoates, such as acetate, HO2C-(CH2) n and salts with —COH, where n is 0 to 4. Other salts include sulfates, metasulfonates, chlorides, bromides, trifluoroacetates, picrates, sorbates, benzilates, salicylates, nitrates, phthalates, or morpholines.

[0088] As used herein, "subject" refers to a mammal that has been or is the object of treatment, observation, or experiment. The methods described herein can be useful in both human therapy and veterinary applications. In some embodiments, the subject is a human.

[0089] The term "mammal" is intended to have its standard meaning and includes, for example, humans, dogs, cats, sheep, and cattle.

[0090] The compounds disclosed herein may be present in different isotopically enriched forms, e.g., 2 H, 3 H, 11 C. 13 C, and / or 14It can be used in an isotopic form enriched in C content. In one particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared 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 can improve the efficacy of drugs and increase the duration of action.

[0091] Deuterium-substituted compounds can be 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.

[0092] In one aspect, a compound having the structure

[0093] [ka] A compound having the formula: During the ceremony, 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.

[0094] A "solvate" is formed by the interaction of a solvent and a compound. The term "compound" is intended to include solvates of the compound. Similarly, "pharmaceutically acceptable salts" includes solvates of pharmaceutically acceptable salts. 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.

[0095] Pharmaceutically acceptable forms of the compounds described herein include pharmaceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures thereof.

[0096] 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.

[0097] A "non-covalent complex" is formed by the interaction of a compound with another molecule, and no covalent bond is formed between the compound and the molecule. For example, complex formation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding). Such non-covalent complexes are included in the term "compound." Similarly, pharmaceutically acceptable salts include "non-covalent complexes" of pharmaceutically acceptable salts.

[0098] 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 and specific embodiments therein are intended to be included.

[0099] The term "about," when referring to a number or numerical range, means that the referenced number or numerical range is approximate within experimental variability (or within statistical experimental error); thus, the number or numerical range may vary, for example, by 1% to 15% of the stated number or numerical range. In some examples of numerical ranges, "about" means ±10%.

[0100] As used herein, "significant" refers to any detectable change that is statistically significant (p<0.05) in a standard parametric test of statistical significance, such as Student's T-test.

[0101] IV. How to use In another aspect, provided herein is a method of treating a disease or disorder in a subject in need thereof, the method 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.

[0102] 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, adipose accumulation-related disorder, Dercum's disease, lipedema, or hibernoma. 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 a lipotumor disease. In some embodiments, the adipose-related disorder is adipose accumulation-related disorder. In some embodiments, the fat-related disorder is Dercum's disease. In some embodiments, the fat-related disorder is cellulite. In some embodiments, the fat-related disorder is brown lipoma.

[0103] In some embodiments, the disease or disorder is fibrosis associated with a second disease or disorder, hi 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.

[0104] 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 a solid tumor.

[0105] In some embodiments, the disease or disorder is angiolipoma.

[0106] 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 or a hydrate thereof provided herein, or a pharmaceutical composition provided herein, in the manufacture of a medicament for the treatment of a disease or disorder in a subject in need thereof.

[0107] 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 disorder, reproductive disorder, neurological disorder, psychiatric disorder, rheumatic disease, or orthopedic disorder. In some embodiments, the adipose-related disorder is cellulite, excess fat in various body regions, lipoma, lipotumor disease, a disorder associated with adipose accumulation, Dercum's disease, lipedema, or brown lipoma. 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 a lipotumor disease. In some embodiments, the adipose-related disorder is a disorder associated with adipose accumulation. In some embodiments, the adipose-related disorder is Dercum's disease. In some embodiments, the adipose-related disorder is lipedema. In some embodiments, the adipose-related disorder is brown lipoma.

[0108] 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, previous 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.

[0109] 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 a solid tumor.

[0110] In some embodiments, the disease or disorder is angiolipoma.

[0111] 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 methods also contemplate the use of subtherapeutic amounts of crystalline Compound A to treat the intended condition.

[0112] The amount of crystalline Compound A administered may vary depending on the intended use (in vitro or in vivo), or the subject and condition being treated, e.g., the subject's weight and age, the severity of the condition, the mode of administration, etc., which can be readily determined by one skilled in the art.

[0113] Measuring the biological effect of crystalline Compound A can include performing 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.

[0114] Subjects being treated with crystalline Compound A can be monitored to determine the effectiveness of treatment, and the treatment regimen can be adjusted based on the subject's physiological response to treatment. For example, if the inhibition of the 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 it is determined that the treatment is effective. The method can include maintaining, tapering, reducing, or stopping the amount of compound administered in the treatment if it is determined that the treatment is effective. The method can include increasing the amount of compound administered in the treatment if it is determined that the treatment is ineffective. Alternatively, the method can include stopping the treatment if it is determined that the treatment is ineffective. In some embodiments, treatment with crystalline Compound A is discontinued if the inhibition of the biological effect is above or below a threshold, such as a lack of response or an adverse reaction. The biological effect can be a change in any of various physiological indicators.

[0115] V. Compositions and Formulations The present disclosure provides compositions, including pharmaceutical compositions, comprising the crystalline form(s) of the present invention.

[0116] In some embodiments, crystalline Compound A is formulated into a pharmaceutical composition. In specific embodiments, 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 the active compound / crystalline active compound into a medicament-usable preparation. The appropriate formulation depends on the selected route of administration. Any pharmaceutically acceptable techniques, carriers, and excipients may be used as appropriate to formulate the pharmaceutical compositions 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, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams and Wilkins 1999).

[0117] Provided herein are pharmaceutical compositions comprising crystalline Compound A and a pharmaceutically acceptable diluent, excipient, or carrier. In certain embodiments, crystalline Compound A is administered as a pharmaceutical composition in which crystalline Compound A is mixed with other active ingredients, such as in combination therapy. All combinations of active substances described in the combination therapy section below and throughout this disclosure are encompassed herein. In specific embodiments, the pharmaceutical composition comprises crystalline Compound A. In some embodiments, crystalline Compound A is crystalline Form 1. In some embodiments, crystalline Compound A is crystalline Form 2. In some embodiments, crystalline Compound A is crystalline Form 3. In some embodiments, crystalline Compound A is crystalline Form 4. In some embodiments, crystalline Compound A is a mixture of crystalline Form 1 and crystalline Form 2. In some embodiments, crystalline Compound A is a mixture of crystalline Form 1 and crystalline Form 3. In some embodiments, crystalline Compound A is a mixture of crystalline Form 1 and crystalline Form 4. In some embodiments, crystalline Compound A is a mixture of crystalline Form 2 and crystalline Form 3. In some embodiments, crystalline Compound A is a mixture of crystalline Form 1 and crystalline Form 4. In some embodiments, crystalline Compound A is a mixture of crystalline Form 2 and crystalline Form 3. In some embodiments, crystalline Compound A is a mixture of crystalline Form 2 and crystalline Form 4. In some embodiments, crystalline Compound A is a mixture of crystalline Form 3 and crystalline Form 4. In some embodiments, crystalline Compound A is a mixture of crystalline Form 1, crystalline Form 2, and crystalline Form 3. In some embodiments, crystalline Compound A is a mixture of crystalline Form 1, crystalline Form 2, and crystalline Form 4. In some embodiments, crystalline Compound A is a mixture of crystalline Form 1, crystalline Form 3, and crystalline Form 4. In some embodiments, crystalline Compound A is a mixture of crystalline Form 2, crystalline Form 3, and crystalline Form 4. In some embodiments, crystalline Compound A is a mixture of crystalline Form 1, crystalline Form 2, crystalline Form 3, and crystalline Form 4.

[0118] Pharmaceutical composition, as used herein, refers to a mixture of crystalline 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 crystalline Compound A to an organism. In some embodiments, in practicing the methods of treatment or use provided herein, a therapeutically effective amount of crystalline Compound A is administered in a pharmaceutical composition to a mammal having the disease or disorder to be treated. In specific embodiments, 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. Crystalline Compound A described herein is used alone or as a component of a mixture in combination with one or more therapeutic agents.

[0119] In one embodiment, crystalline Compound A is formulated in an aqueous solution. In specific embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank's solution, Ringer's solution, or physiological saline buffer. In other embodiments, crystalline Compound A is formulated for transmucosal administration. In certain embodiments, transmucosal formulations include a penetrant appropriate for the barrier to be permeated. In yet other embodiments, where crystalline Compound A described herein is formulated for parenteral injection, 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 includes 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%).

[0120] In another embodiment, crystalline Compound A described herein is formulated for oral administration. Crystalline Compound A is formulated by combining crystalline Compound A with, for example, a pharmaceutically acceptable carrier or excipient. In various embodiments, crystalline Compound A described herein is formulated into oral dosage forms, including, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like.

[0121] In certain embodiments, pharmaceutical preparations for oral use are prepared by mixing one or more solid excipients with crystalline Compound A described herein, optionally grinding the resulting mixture, and optionally adding suitable excipients, followed by processing the granular mixture to obtain tablets or dragee cores.Suitable excipients are fillers, such as sugars including lactose, sucrose, mannitol, or sorbitol, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or other cellulose preparations such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.In certain embodiments, disintegrants are optionally added.Disintegrants include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate.

[0122] In one embodiment, dosage forms such as dragee cores and tablets are provided with one or more suitable coatings.In certain embodiments, concentrated sugar solutions are used to coat dosage forms.The sugar solutions optionally contain additional components such as, for example, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.Dyes and / or pigments are also optionally added to the coating for identification purposes.In addition, dyes and / or pigments are optionally used to characterize different combinations of active compound doses.

[0123] In certain embodiments, the therapeutically effective amount of crystalline Compound A described herein is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. In certain embodiments, the push-fit capsules contain the active ingredient in a mixture 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, 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. In addition, stabilizers are optionally added.

[0124] In other embodiments, the crystalline Compound A described herein is formulated in a therapeutically effective amount 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 Compound A described herein is formulated for parenteral injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, the formulation for injection is provided in a unit dosage form (e.g., an ampule) or in a multi-dose container. Optionally, a preservative is added to the injection formulation. In still other embodiments, the pharmaceutical composition of crystalline Compound A is formulated in a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in an oily or aqueous vehicle. The parenteral injection formulation optionally contains a formulatory agent, such as a suspending agent, a stabilizing agent, and / or a dispersing agent. In specific embodiments, the pharmaceutical formulation for parenteral administration comprises an aqueous solution of the active crystalline Compound A in water-soluble form. In some embodiments, the pharmaceutical formulation for parenteral administration comprises propylene glycol. In some embodiments, pharmaceutical formulations for parenteral administration contain propylene glycol and water. In further embodiments, suspensions of active crystalline Compound A are prepared as suitable oily injection suspensions. Lipophilic solvents or vehicles suitable 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 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 crystalline Compound A, allowing for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form, which is then reconstituted with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0125] In yet another embodiment, crystalline Compound A is administered topically.Crystalline Compound A described herein is formulated into various topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments.Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancers, buffers and preservatives.

[0126] In yet other embodiments, crystalline Compound A is formulated for transdermal administration. In certain embodiments, transdermal formulations use 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 crystalline Compound A is achieved by means such as iontophoretic patches. In certain embodiments, transdermal patches provide controlled delivery of crystalline Compound A. In specific embodiments, the absorption rate is slowed by using rate-controlling membranes or by entrapment of the compound within a polymer matrix or gel. In alternative embodiments, absorption enhancers are used to increase absorption. Absorption enhancers or carriers include absorbable pharmaceutically acceptable solvents that aid in passage through the skin. For example, in one embodiment, the transdermal device is in the form of a bandage that includes a backing member, a reservoir containing the compound, optionally with a carrier, and optionally a rate-controlling 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.

[0127] In other embodiments, crystalline 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 pharmaceutical composition of crystalline Compound A is conveniently delivered in the form of aerosol spray presentation from a pressurized pack or nebulizer, using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas).In specific embodiments, the dosage unit of the pressurized aerosol is determined by providing a valve for delivering a metered amount.In certain embodiments, by way of example only, capsules and cartridges such as gelatin for use in inhalers or insufflators are formulated to contain a powder mixture of the compound and a suitable powder base, such as lactose or starch.

[0128] In yet another embodiment, crystalline Compound A is formulated into rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas containing a conventional suppository base such as cocoa butter or other glycerides, and a synthetic polymer such as polyvinylpyrrolidone or PEG. In suppository forms 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.

[0129] In certain embodiments, pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries that facilitate the processing of active crystalline Compound A into pharmaceutically usable preparations.Suitable formulations depend on the selected route of administration.Any pharmaceutically acceptable technology, carrier, and excipient are optionally used appropriately.Pharmaceutical compositions containing crystalline Compound A are prepared in a conventional manner, for example, by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, encapsulating, or compressing processes.

[0130] The pharmaceutical composition comprises at least one pharmaceutically acceptable carrier, diluent, or excipient, and the crystalline Compound A described herein as an active ingredient. The active ingredient is in free acid or free base form, or in a pharmaceutically acceptable salt form. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Furthermore, the compounds described herein include unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. The solvated forms of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical composition optionally contains other medicinal or pharmaceutical agents, carriers, adjuvants such as preservatives, stabilizers, wetting agents, or emulsifiers, solution enhancers, salts for adjusting osmotic pressure, buffers, and / or other therapeutically valuable substances.

[0131] Methods for preparing compositions containing crystalline Compound A described herein include formulating crystalline Compound A with one or more inert pharmaceutically 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 compounds 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 solution or suspension in liquid prior to 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.

[0132] In some embodiments, the pharmaceutical composition comprising crystalline Compound A is illustratively in the form of a liquid, where the drug is in solution, in suspension, or both. Typically, 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.

[0133] In certain embodiments, useful aqueous suspensions contain one or more polymers as suspending agents.Useful polymers include water-soluble polymers such as cellulose polymers, water-insoluble polymers such as hydroxypropylmethylcellulose, and cross-linked carboxyl-containing polymers.Some pharmaceutical compositions described herein include mucoadhesive polymers selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0134] Useful pharmaceutical compositions also optionally include a solubilizing agent to aid in the solubility of crystalline Compound A. The term "solubilizing agent" generally includes agents that result in the formation of a micellar or true solution of the drug. Certain acceptable nonionic surfactants, such as polysorbate 80, are useful as solubilizing agents, as are ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

[0135] In addition, useful pharmaceutical compositions optionally contain one or more pH adjusters or buffers, 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 tris-hydroxymethylaminomethane, and buffers such as citric acid / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0136] In addition, useful compositions also optionally contain one or more salts in an amount necessary to bring the osmolality of the composition into an acceptable range. Such salts include those having 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.

[0137] Other useful pharmaceutical compositions optionally contain one or more preservatives to 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.

[0138] Still other useful compositions contain one or more surfactants to enhance 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 alkylphenyl ethers, such as Octoxynol 10 and Octoxynol 40.

[0139] Still other useful compositions include one or more antioxidants to enhance chemical stability where needed. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0140] In certain embodiments, the aqueous suspension composition is packaged in single-dose non-reclosable containers. Alternatively, multi-dose reclosable containers are used, typically including a preservative in the composition.

[0141] In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are used. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also used. In further embodiments, the crystalline forms described herein are delivered using a sustained release system, such as a semipermeable matrix 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 form for several weeks to over 100 days. Depending on the chemical nature and biological stability of the therapeutic reagent, additional strategies for protein stabilization are employed.

[0142] 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.

[0143] VI. Route of Administration Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, subcutaneous, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. Further, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0144] In certain embodiments, crystalline Compound A is administered locally rather than systemically, e.g., by injecting crystalline Compound A directly into an organ, often in a depot or sustained-release formulation. In specific embodiments, long-acting formulations are 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, e.g., in a liposome coated with an organ-specific antibody. In such embodiments, the liposome is targeted to and selectively taken up by the organ. In still other embodiments, crystalline Compound A is provided in the form of a rapid-release formulation, an extended-release formulation, or an intermediate-release formulation. In still other embodiments, crystalline Compound A is administered locally. In some embodiments, crystalline Compound A is administered subcutaneously.

[0145] VII. Kits / Products (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, package, or container that is compartmentalized to receive one or more containers, such as vials, tubes, etc., and each of the containers contains one of the separate elements used in the methods described herein.Suitable containers include, for example, bottles, vials, syringes, and test tubes.The containers are formed from various materials, such as glass or plastic.

[0146] 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 material suitable for the selected formulation and the intended mode of administration and treatment. For example, the container(s) optionally contain the crystalline Compound A described herein, optionally in a composition or in combination with another drug disclosed herein. The container(s) optionally have a sterile access port (e.g., the container is an intravenous solution bag or vial with a stopper that can be penetrated by a hypodermic injection needle). Such kits optionally contain the compound together with an identifying description or label or instructions for its use in the methods described herein.

[0147] The kits described herein may include one or more of the crystalline forms provided in this disclosure and a pharmaceutically acceptable excipient, carrier, diluent, solution, or buffer solution for reconstituting a pharmaceutical crystalline form suitable for administration to an individual. The diluent, solution, or buffer solution may include, for example, water for injection, saline, or another suitable isotonic buffer solution. In some embodiments, the pharmaceutically acceptable excipient, carrier, diluent, solution, or buffer is propylene glycol, polyoxyl hydrogenated castor oil, ethanol, glycerol, sorbitol, mannitol, benzyl alcohol, lauryl glucoside, ammonium lauryl sulfate, sodium lauryl sulfate, sodium laureth sulfate, sodium myreth sulfate, docusate, perfluorooctanesulfonate, perfluorobutanesulfonate, sodium stearate, sodium lauroyl sarcosinate, sodium lauroyl sarcosinate, sodium lauroyl sarcosinate, sodium lauroyl sarcosinate, sodium laureth sulfate, sodium myreth sulfate, sodium laureth sulfate, sodium laureth sulfate, sodium laureth sulfate, sodium laureth sulfate, sodium lauroyl sarcosinate ... sarcosinate, perfluorononanoate, perfluorooctanoate, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride, dimethyldioctadecylammonium chloride, dimethyldioctadecylammonium bromide, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate, cocamidopropyl hydroxysultainehydroxysultaine, cocamidopropyl betaine, phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, sphingomyelin, octaethylene glycol monododecyl ether, pentaethylene glycol monododecyl ether, nonaethylene glycol, polyethylene glycol nonyl phenyl ether, 2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethanol, polyoxyl-35 castor oil, polyethoxylated tallow amine, cocamide monoethanolamine, cocamide diethanolamine, glycerol monostearate, glycerol distearate, glycerol tristearate, glycerol monolaurate, glycerol dilaurate, glycerol trilaurate, sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, decyl glucosideglucoside, lauryl glucoside, octyl glucoside, lauryldimethylamine oxide, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, nonadecylic acid, arachidic acid, heneisocylic acid, behenic acid, tricosylic acid, lignoceric acid, pentacosylic acid, cerotic acid, carboseric acid, montanic acid, nonacosylic acid, melissic acid, hentriacosylic acid, lacterolic acid, psyllic acid acid, gedic acid, ceroplastic acid, hexatriacontylic acid, heptatriacontylic acid, octatriacontylic acid, nonatriacontylic acid, tetratriacontylic acid, crotonic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, gadolic acid, eicosenoic acid, erucic acid, neuronic acid, linoleic acid, eicosadienoic acid, docosadienoic acid, linolenic acid, pinolenic acid, eleostearic acid, meadic acid acid), dihomo-γ-linolenic acid, eicosatrienoic acid, stearidonic acid, arachidonic acid, eicosatetraenoic acid, adrenic acid, phospopentaenoic acid, eicosapentaenoic acid, ozubondo acid, sardine acid, tetracosanolpentaenoic acid, cervonic acid, herring acidThe soluble fiber may include one or more of the following: arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, vitamin E, ascorbyl palmitate, butylated hydroxytoluene, triethyl citrate, citric acid, or combinations thereof. In some embodiments, the pharmaceutically acceptable excipient, carrier, diluent, solution, or buffer is propylene glycol, polyoxyl hydrogenated castor oil, ethanol, glycerol, sorbitol, mannitol, benzyl alcohol, lauryl glucoside, ammonium lauryl sulfate, sodium lauryl sulfate, sodium laureth sulfate, sodium myreth sulfate, sodium stearate, sodium lauroyl sarcosinate ...sarcosinate), benzalkonium chloride, benzethonium chloride, phosphatidylcholine, sphingomyelin, 2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethanol, polyoxyl-35 castor oil, glycerol monostearate, glycerol distearate, glycerol tristearate, glycerol monolaurate, glycerol dilaurate, glycerol trilaurate, sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 , lauric acid, tridecylic acid, myristic acid, palmitic acid, stearic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, ellagic acid, vaccenic acid, gadoleic acid, arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, vitamin E, ascorbyl palmitate, butylated hydroxytoluene, triethyl citrate, citric acid, or combinations thereof. In some embodiments, the pharmaceutically acceptable excipient, carrier, diluent, solution, or buffer may include one or more of ethanol, glycerol, propylene glycol, sorbitol, mannitol, benzyl alcohol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or combinations thereof. In some embodiments, the pharmaceutically acceptable excipient, carrier, diluent, solution, or buffer may include polysorbate 80, propylene glycol, benzyl alcohol, and water for injection. The pharmaceutically acceptable excipient, carrier, diluent, solution, or buffer may be provided in the same or separate containers. In some embodiments, the pharmaceutically acceptable excipient, carrier, diluent, solution, or buffer may be provided in the same container. In some embodiments, the pharmaceutically acceptable excipient, carrier, diluent, solution, or buffer may be provided in separate containers.

[0148] For example, a kit typically includes one or more additional containers, each containing one or more of various materials (e.g., reagents, optionally in concentrated form, and / or devices) desirable from a commercial and user perspective for use of the compounds described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes, carriers, packages, containers, vials, and / or tube labels listing the contents and / or instructions for use, as well as package inserts with the instructions. A set of instructions for use is also typically included. A label is optionally on or associated with a container. For example, a label is on a container when letters, numbers, or other characters forming the label are attached, molded, or etched into the container itself, and a label is associated with a container when the label is present in a receptacle or carrier that holds the container, e.g., as a package insert. Additionally, a label is used to indicate that the contents are to be used for a particular therapeutic application. Furthermore, a label indicates directions for using the contents, such as in the methods described herein. In certain embodiments, pharmaceutical compositions are provided in a pack or dispenser device containing one or more unit dosage forms containing a compound provided herein. The pack, for example, comprises metal or plastic foil, such as a blister pack. Alternatively, the pack or dispenser device is accompanied by instructions for administration. Alternatively, the pack or dispenser has associated therewith a notice on the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, the notice reflecting approval by the agency of the drug form for human or veterinary administration. Such notice, for example, is labeling approved by the US Food and Drug Administration for prescription drugs, or an approved package insert. In some embodiments, a composition containing a polymorph of Compound A formulated in a compatible pharmaceutical carrier is prepared, placed in an appropriate container, and labeled for treatment of an indicated disease.

[0149]

[0010] In some embodiments, disclosed herein are kits comprising crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A) and one or more pharmaceutically acceptable excipients. In some embodiments, the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A) is anhydrous. In some embodiments, the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A) is hydrated. In some embodiments, the crystalline Compound A is crystalline Compound A Form 1. In some embodiments, the crystalline Compound A is crystalline Compound A Form 2. In some embodiments, the crystalline Compound A is crystalline Compound A Form 3. In some embodiments, the crystalline Compound A is crystalline Compound A Form 4. In some embodiments, Compound A is Compound A Form 1. In some embodiments, crystalline Compound A is a mixture of crystalline Form 1 and crystalline Form 2. In some embodiments, crystalline Compound A is a mixture of crystalline Form 1 and crystalline Form 3. In some embodiments, crystalline Compound A is a mixture of crystalline Form 1 and crystalline Form 4. In some embodiments, crystalline Compound A is a mixture of crystalline Form 2 and crystalline Form 3. In some embodiments, crystalline Compound A is a mixture of crystalline Form 2 and crystalline Form 4. In some embodiments, crystalline Compound A is a mixture of crystalline Form 3 and crystalline Form 4. In some embodiments, crystalline Compound A is a mixture of crystalline Form 1, crystalline Form 2, and crystalline Form 3. In some embodiments, crystalline Compound A is a mixture of crystalline Form 1, crystalline Form 2, and crystalline Form 4. In some embodiments, crystalline Compound A is a mixture of crystalline Form 1, crystalline Form 3, and crystalline Form 4. In some embodiments, crystalline Compound A is a mixture of crystalline Form 2, crystalline Form 3, and crystalline Form 4. In some embodiments, crystalline Compound A is a mixture of crystalline Form 1, crystalline Form 2, crystalline Form 3, and crystalline Form 4.

[0150] In some embodiments, provided herein is a kit comprising crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A) and one or more pharmaceutically acceptable excipients for use in treating a disease or disorder. In some embodiments, the disease or disorder is an adipose-related disease or disorder, a fibrosis-related disease or disorder, liposarcoma, a solid tumor, or an angiolipoma. 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, an endocrine disorder, a reproductive disorder, a neurological disorder, a psychiatric disorder, a rheumatic disease, or an orthopedic disorder. In some embodiments, the adipose-related disorder is cellulite, excess fat in various body regions, lipoma, a lipoma, a lipomatous disease, a disorder associated with adipose accumulation, Dercum's disease, lipedema, or brown lipoma. In some embodiments, the fat-related disorder is cellulite. In some embodiments, the fat-related disorder is excess fat in various body regions. In some embodiments, the fat-related disorder is lipoma. In some embodiments, the fat-related disorder is adipose tumor disease. In some embodiments, the fat-related disorder is a disorder associated with fat accumulation. In some embodiments, the fat-related disorder is Dercum's disease. In some embodiments, the fat-related disorder is cellulite. In some embodiments, the fat-related disorder is lipedema. In some embodiments, the fat-related disorder is brown lipoma. 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, previous 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. 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 a solid tumor.In some embodiments, the disease or disorder is angiolipoma. [Example]

[0151] The following examples will serve to more fully illustrate the manner of using the present invention. These examples are offered for illustrative purposes and do not serve to limit the true scope of this invention.

[0152] 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. Pat. No. 9,447,040, which are incorporated by reference for such synthesis. In some embodiments, Compound A is prepared as described herein.

[0153] 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 in one portion. After 10 minutes of magnetic stirring, potassium carbonate (1.40 g, 10 mM) was added. After stirring for an additional 10 minutes, the temperature was raised to 50°C and the mixture was stirred for 4 hours. 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). 1 H 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+,symmetric 2Br triplet) and 452,454,456(M+H + , symmetric 2Br triplet).

[0154] Example 2: Temperature Cycling Preparation of Crystalline 5-(3,6-Dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium Chloride Form 1 (Form 1 of Compound A) A known mass of 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (compound A) was dissolved in a 0.5 mL aliquot of a 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 ( A solvent selected from the group consisting of 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%) was added until a mobile slurry was observed. The reaction mixture was maintained at 50°C with stirring during the solvent addition, followed by a 1-hour hold time between 5°C and 50°C, as well as temperature cycling at 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 the total volume reached 1.8 mL. The reaction mixture was then allowed 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.

[0155] 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 rapidly cooled to 6°C. After 4 days, crystalline Compound A was obtained with an ethanol solution. The remaining solution was rapidly cooled to -18°C. After 48 hours, crystalline Form 1 of 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 a benzyl alcohol and dimethyl sulfoxide solution.

[0156] 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.

[0157] Example 5: Antisolvent Addition 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 until a total of 1.8 mL of antisolvent had been added. The solid was isolated by centrifugation. The remaining solution was cooled to 6° C. and stored for 72 hours, then 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.

[0158] 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 pre-tared open aluminum pan, 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 before being cooled to 30°C. This process yielded crystalline Compound A (Form 2).

[0159] 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) synthesis

[0160] 3,6-Dibromocarbazole was dissolved in MeCN / MeTHF. (5-Bromopentyl)-trimethyl-ammonium bromide was added in one portion. After 10 minutes of magnetic stirring, potassium carbonate was added. After stirring for an additional 10 minutes, the temperature was raised to 50°C and the mixture was stirred for 4 hours. 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 (6000 rpm, six cycles of 60 seconds each, with a 10-second pause between cycles). The ground and unground samples were placed in crystallization dishes, 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).

[0161] Temperature cycling

[0162] To a known mass of 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A), water was added until a mobile slurry was observed. The slurry was gradually heated until the compound dissolved at approximately 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 approximately 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, whereupon the solid was isolated by filtration through a polypropylene felt filter (2 micron) to yield 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 give crystalline Compound A (Form 3).

[0163] Example 8: Preparation of crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride Form 4 (Compound A Form 4) from Compound A A known mass of 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride was dried until the moisture content reached ≦1% (w / w). The dried sample was stored under low humidity conditions. This process yielded crystalline Compound A (Form 4).

[0164] Example 9: Preparation of crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride Form 1 (Compound A Form 1) from Compound A Form 2 5-(3,6-Dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride Form 2 (Form 2 of Compound A) of known mass was analyzed by variable humidity X-ray powder diffraction (VH-XRPD) on a Philips X'Pert Pro Multipurpose diffractometer equipped with a humidity chamber. The sample was scanned between 4 and 35.99°2θ using Cu K radiation (αλ = 1.54060 Å; α = 1.54443 Å; β = 1.39225 Å; α:α ratio = 0.5) operating in Bragg-Brentano geometry (step size 0.008°2θ) using a 40 kV / 40 mA generator setting. Measurements were performed from 7 to 90% RH, and XRPD scans were collected at each humidity step. VH-XRPD analysis was performed during the absorption phase from ambient humidity to 90% RH, the desorption phase from 90% RH to 7% RH, and the second absorption phase from 20% to 40% RH. Crystalline Form 1 of Compound A was observed during the desorption phase from 90% RH to 20% RH and during the second absorption phase at 40% RH.

[0165] Example 10: Preparation of crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride Form 1 (Compound A Form 1) from Compound A Form 4 A known mass of 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride Form 4 (Form 4 of Compound A) was converted to crystalline Form 1 of Compound A after standing at 25°C and 40°C and >30% RH.

[0166] Example 11: X-ray powder diffraction (XRPD) The following diffractometer was used, although 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.

[0167] "Characteristic peaks," to the extent that they exist, are a subset of observed peaks used to distinguish one crystalline polymorph from another (a polymorph that is a crystalline form having the same chemical composition). Characteristic peaks are determined by evaluating which observed peaks, if any, are present in a crystalline polymorph of a compound relative to all other known crystalline polymorphs of that compound, within ±0.2° 2-θ.

[0168] XRPD analysis was performed on a PANalytical X'pert Pro equipped with a PIXcel detector (128 channels), and samples were scanned from 3 to 35°2θ. The material was gently ground (if necessary) to release any aggregates and loaded onto a multiwell plate with a Kapton or Mylar polymer film to support the sample. The multiwell plate was then placed in the diffractometer and analyzed using Cu K radiation (α1λ = 1.54060 Å; α2λ = 1.54443 Å; βλ = 1.39225 Å; α1:α2 ratio = 0.5) operating 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).

[0169] 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 in Table 1.

[0170] [Table 1] In some embodiments, representative XRPD peaks obtained for crystalline Compound A (Form 1) are listed in Table 1-1.

[0171] [Table 2]

[0172] 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.

[0173] [Table 3]

[0174] 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.

[0175] [Table 4] *Where 1 is the peak with the strongest signal intensity and 30 is the peak with the weakest signal intensity.

[0176] A representative XRPD pattern obtained for crystalline Compound A (Form 4) is shown in Figure 8. Representative XRPD peaks obtained for crystalline Compound A (Form 4) are listed in Table 4.

[0177] [Table 5] *Of the representative peaks listed, 1 is the peak with the strongest signal intensity and 10 is the peak with the weakest signal intensity.

[0178] Example 12: Thermogravimetric Analysis / Differential Scanning Calorimetry (TGA / DSC) 5-10 mg of material was added to a pre-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 to 400°C at a rate of 10°C / min, during which 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 kJ / min was used. The TGA pattern obtained for crystalline Compound A (Form 1) is shown in Figure 3, and the TGA pattern obtained for crystalline Compound A (Form 2) is shown in Figure 6.

[0179] Example 13: 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 condenser. The sample and reference were heated to 300°C at a scan rate of 10°C / min, and the resulting heat flow response was monitored. The sample was re-cooled to 20°C and then reheated again at 10°C / min to 300°C. Nitrogen was used as the purge gas at 50 cm3 / min. 3 A flow rate of 1000 kJ / min was used. The DSC thermogram obtained for crystalline Compound A (Form 1) is shown in Figure 2. The DSC thermogram obtained for crystalline Compound A (Form 2) is shown in Figure 5.

[0180] Example 14: Stability Study of Crystalline Compound A Form 1 Crystalline Compound A (Form 1) remained 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 5. Purity was determined by HPLC analysis.

[0181] [Table 6]

[0182] Crystalline Compound A (Form 1) remained unchanged after 36 months of storage at 25°C / 60% RH or 6 months of storage at 40°C / 75% RH. The results of crystalline Compound A (Form 1) in long-term stability studies are shown in Table 6. Purity was determined by HPLC analysis.

[0183] [Table 7]

[0184] Example 15: 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.

[0185] Direct Addition 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. After the solid was added, the vial was back-weighed and the weight of the added solid was placed in the instrument. The titration began 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. Analyses were performed in duplicate.

[0186] liquid extraction 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 solids were dissolved by manual shaking or using an ultrasonic bath. When complete dissolution was achieved, the solution was injected back into the cell titrator, and the weight of the added sample was added to the instrument. The water content was automatically calculated by the instrument as a percentage, and the data was printed. Analyses were performed in duplicate.

[0187] The KF titration results obtained for crystalline Compound A are summarized in Table 7.

[0188] [Table 8]

[0189] 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 variations, 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 employed 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 be covered thereby.

[0190] The disclosure of the present application is further illustrated in the following list of embodiments, which are provided for illustrative purposes only and are not intended to limit the disclosure in any way.

[0191] Embodiment 1: Crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A):

[0192] [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 containing peaks at 4.0±0.2°2-θ, 16.5±0.2°2-θ, and 15.5±0.2°2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å; (b) an X-ray powder diffraction pattern substantially the same as that shown in Figure 1 when measured using Cu Kα radiation at an X-ray wavelength of 1.54060 Å; (c) 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) 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 Figure 2; (f) Thermogravimetric analysis (TGA) thermogram substantially the same as that shown in Figure 3; (g) Unaltered XRPD after storage for 7 days at 40°C and 75% relative humidity (RH); (h) Unaltered XRPD after storage at 80°C for 7 days, or (i) A combination of these 1. Crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride or a hydrate thereof, characterized as having

[0193] 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 as having an X-ray powder diffraction pattern comprising peaks at 4.0±0.2 degrees two-theta, 16.5±0.2 degrees two-theta, and 15.5±0.2 degrees two-theta, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0194] Embodiment 3: The crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride or hydrate thereof of embodiment 1 or 2, wherein the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride is characterized as having substantially the same X-ray powder diffraction pattern as shown in FIG. 1 , when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0195] 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, and ii) an endotherm in the range of about 175-195°C 4. The crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride or hydrate thereof of any one of embodiments 1-3, characterized by a differential scanning calorimetry (DSC) thermogram comprising:

[0196] 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, and ii) an endotherm with 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 hydrate thereof of any one of embodiments 1-4, characterized by a differential scanning calorimetry (DSC) thermogram comprising:

[0197] Embodiment 6: The crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride or hydrate thereof of any one of embodiments 1-5, 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 the same as that shown in FIG. 2 .

[0198] Embodiment 7: The crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride or hydrate thereof of any one of Embodiments 1-6, 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 the same as that shown in FIG. 3.

[0199] Embodiment 8: The crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A):

[0200] [ka] or its hydrate, crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride is (a) an X-ray powder diffraction pattern containing peaks at 28.4±0.2°2-θ, 18.5±0.2°2-θ, and 12.1±0.2°2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å; (b) an X-ray powder diffraction pattern substantially the same as that shown in FIG. 7 when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å; or (c) A combination of these 1. Crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride or a hydrate thereof, characterized as having

[0201] Embodiment 9: The crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride or a hydrate thereof of embodiment 8, wherein the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride is characterized as having an X-ray powder diffraction pattern comprising peaks at 28.4±0.2 degrees two-theta, 18.5±0.2 degrees two-theta, and 12.1±0.2 degrees two-theta, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0202] Embodiment 10: The crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride or hydrate thereof of embodiment 8 or 9, wherein the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride is characterized as having substantially the same X-ray powder diffraction pattern as shown in FIG. 7, when measured using Cu Kα1 radiation at an X-ray wavelength of 1.54060 Å.

[0203] 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 according to any one of embodiments 1 to 10, and at least one pharmaceutically acceptable excipient.

[0204] Embodiment 12: The pharmaceutical composition of embodiment 11, wherein the pharmaceutical composition is formulated for administration to a mammal by parenteral administration.

[0205] Embodiment 13: 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 as described in any one of embodiments 1 to 10, or the pharmaceutical composition of embodiment 11 or 12.

[0206] Embodiment 14: The method of embodiment 13, wherein the disease or disorder is a fat-related disorder.

[0207] 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.

[0208] Embodiment 16: The method of embodiment 14, wherein the fat-related disorder is cellulite, excess fat in various body regions, lipoma, lipomatous disease, a disorder associated with fat accumulation, Dercum's disease, lipedema, or brown lipoma.

[0209] Embodiment 17: The method of embodiment 13, wherein the disease or disorder is fibrosis associated with a second disease or disorder.

[0210] 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, keloid, scleroderma, arthrofibrosis, Peyronie's disease, Dupuytren's contracture, or adhesive capsulitis.

[0211] Embodiment 19: The method of claim 13, wherein the disease or disorder is liposarcoma or a solid tumor.

[0212] Embodiment 20: The method of embodiment 13, wherein the disease or disorder is lipoma.

[0213] Embodiment 21: The method of embodiment 13, wherein the disease or disorder is angiolipoma.

[0214] Embodiment 22: Use of crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride or a hydrate thereof of any one of embodiments 1 to 10, or a pharmaceutical composition of embodiment 11 or 12, in the manufacture of a medicament for the treatment of a disease or disorder in a subject in need thereof.

[0215] Embodiment 23: The use of embodiment 22, wherein the disease or disorder is a fat-related disorder.

[0216] Embodiment 24: The use of embodiment 23, 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.

[0217] Embodiment 25: The use of embodiment 23, wherein said fat-related disorder is cellulite, excess fat in various body areas, lipoma, lipomatous disease, disorders associated with fat accumulation, Dercum's disease, lipedema, or brown lipoma.

[0218] Embodiment 26: The use of embodiment 22, wherein the disease or disorder is fibrosis associated with a second disease or disorder.

[0219] Embodiment 27: The use of 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, keloid, scleroderma, arthrofibrosis, Peyronie's disease, Dupuytren's contracture, or adhesive capsulitis.

[0220] Embodiment 28: The use of embodiment 22, wherein the disease or disorder is liposarcoma or a solid tumor.

[0221] Embodiment 29: The use of embodiment 22, wherein the disease or disorder is angiolipoma.

[0222] Embodiment 30: Anhydrous crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A):

[0223] [ka] The anhydrous crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride is (a) an X-ray powder diffraction pattern containing peaks at 3.0±0.2°2-θ, 22.3±0.2°2-θ, and 31.2±0.2°2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å; (b) an X-ray powder diffraction pattern substantially the same as that shown in Figure 8; or (c) A combination of these Anhydrous crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, characterized as having

[0224] Embodiment 31: Anhydrous crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride according to embodiment 30, characterized as having an X-ray powder diffraction pattern comprising peaks at 3.0±0.2 degrees two-theta, 22.3±0.2 degrees two-theta, and 31.2±0.2 degrees two-theta, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0225] Embodiment 32: The anhydrous crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride of embodiment 30 or embodiment 31, wherein the anhydrous crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride is characterized as having substantially the same X-ray powder diffraction pattern as shown in FIG. 8, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0226] Embodiment 33: 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (compound A):

[0227] [ka] A mixture of anhydrous crystalline forms of.

[0228] Embodiment 34: The mixture of Example 33, wherein the mixture comprises anhydrous crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, characterized as having an X-ray powder diffraction pattern comprising peaks at 3.0±0.2 degrees two-theta, 4.8±0.2 degrees two-theta, 22.3±0.2 degrees two-theta, 24.8±0.2 degrees two-theta, 26.5±0.2 degrees two-theta, and 31.2±0.2 degrees two-theta, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0229] Embodiment 35: The mixture of embodiment 33 or embodiment 34, wherein the anhydrous crystalline form of Compound A is formed by a process comprising exposing Compound A to an elevated temperature.

[0230] Embodiment 36: The mixture of embodiment 35, wherein the elevated temperature is greater than about 90°C.

[0231] Embodiment 37: The mixture of embodiment 35, wherein the elevated temperature is greater than about 100°C.

[0232] Embodiment 38: The mixture of embodiment 35, wherein the elevated temperature is greater than about 150°C.

[0233] Embodiment 39: The mixture of embodiment 35, wherein the elevated temperature is greater than about 200°C.

[0234] Embodiment 40: The mixture of any one of embodiments 33-39, wherein the anhydrous crystalline form of Compound A is formed by a process comprising drying Compound A to a lower moisture content.

[0235] Embodiment 41: The mixture of embodiment 40, wherein the moisture content is less than about 5% (w / w).

[0236] Embodiment 42: The mixture of embodiment 40, wherein the moisture content is less than about 2.5% (w / w).

[0237] Embodiment 43: The mixture of embodiment 40, wherein the moisture content is less than about 1% (w / w).

[0238] Embodiment 44: A process for the preparation of anhydrous crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A), the process comprising reducing the moisture content in a sample of Compound A and maintaining the sample at a low relative humidity.

[0239] Embodiment 45: The process of embodiment 44, wherein reducing the moisture content comprises heating the sample of compound A.

[0240] Embodiment 46: The process of embodiment 44 or 45, wherein reducing the moisture content comprises heating the sample of Compound A to a temperature greater than about 90°C.

[0241] Embodiment 47: The process of embodiment 44 or 45, wherein reducing the moisture content comprises heating the sample of compound A to a temperature greater than about 100° C.

[0242] Embodiment 48: The process of embodiment 44 or 45, wherein reducing the moisture content comprises heating the sample of compound A to a temperature greater than about 150°C.

[0243] Embodiment 49: The process of embodiment 44 or 45, wherein reducing the moisture content comprises heating the sample of compound A to a temperature greater than about 200° C.

[0244] Embodiment 50: The process of any one of embodiments 44 to 49, wherein the low relative humidity is less than about 30%.

[0245] Embodiment 51: The process of any one of embodiments 44 to 49, wherein the low relative humidity is less than about 20%.

[0246] Embodiment 52: The process of any one of embodiments 44 to 49, wherein the low relative humidity is less than about 10%.

[0247] Embodiment 53: The process of any one of embodiments 44 to 49, wherein the moisture content in the sample is reduced to less than about 5% (w / w).

[0248] Embodiment 54: The process of any one of embodiments 44 to 49, wherein the moisture content in the sample is reduced to less than about 2.5% (w / w).

[0249] Embodiment 55: The process of any one of embodiments 44 to 49, wherein the moisture content in the sample is reduced to less than about 1% (w / w).

[0250] Embodiment 56: A process for the 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 process comprising exposing a sample of Compound A to a humid environment.

[0251] Embodiment 57: The process of embodiment 56, wherein said sample of Compound A is in an unstable crystalline form.

[0252] Embodiment 58: The process of embodiment 56 or 57, wherein said sample of Compound A is anhydrous.

[0253] Embodiment 59: The sample of Compound A is anhydrous, and (a) an X-ray powder diffraction pattern containing peaks at 3.0±0.2°2-θ, 22.3±0.2°2-θ, and 31.2±0.2°2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å; (b) an X-ray powder diffraction pattern substantially the same as that shown in Figure 8; or (c) A combination of these 59. The process of embodiment 58, characterized as having:

[0254] Embodiment 60: Compound A of the above sample is anhydrous, and (a) an X-ray powder diffraction pattern containing peaks at 4.8±0.2° 2-θ, 26.5±0.2° 2-θ, and 24.8±0.2° 2-θ, when measured using Cu Kα radiation having an X-ray wavelength of 1.54060 Å; (b) an X-ray powder diffraction pattern substantially the same as that shown in FIG. 4 when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å; or (c) A combination of these 59. The process of embodiment 58, characterized as having:

[0255] Embodiment 61 The process of embodiment 58, wherein the sample of compound A comprises a mixture of anhydrous crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride.

[0256] Embodiment 62: The process of embodiment 61, wherein the mixture of anhydrous crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride is characterized as having an X-ray powder diffraction pattern comprising peaks at 3.0±0.2°2-θ, 4.8±0.2°2-θ, 22.3±0.2°2-θ, 24.8±0.2°2-θ, 26.5±0.2°2-θ, and 31.2±0.2°2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

[0257] Embodiment 63: The process of any one of embodiments 56 to 62, wherein the humid environment comprises a relative humidity of greater than about 30%.

[0258] Embodiment 64: The process of any one of embodiments 56 to 62, wherein the humid environment comprises a relative humidity of greater than about 40%.

[0259] Embodiment 65: The process of any one of embodiments 56 to 62, wherein the humid environment comprises a relative humidity of greater than about 50%.

[0260] Embodiment 66: The process of any one of embodiments 56 to 62, wherein the humid environment comprises a relative humidity of greater than about 60%.

[0261] Embodiment 67: The process of any one of embodiments 56 to 62, wherein the humid environment comprises a relative humidity of greater than about 70%.

[0262] Embodiment 68: The process of any one of embodiments 56 to 62, wherein the humid environment comprises a relative humidity of about 30% to about 70%.

[0263] Embodiment 69: The process of any one of embodiments 56 to 68, wherein the humid environment further comprises a temperature of about 15°C to about 50°C.

[0264] Embodiment 70: The process of any one of embodiments 56 to 68, wherein the humid environment further comprises a temperature of about 15°C to about 40°C.

[0265] Embodiment 71: The process of any one of embodiments 56 to 68, wherein the humid environment further comprises a temperature of about 20°C to about 40°C.

Claims

1. Anhydrous crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A): 【Chemistry 1】 The anhydrous crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride is (a) an X-ray powder diffraction pattern comprising peaks at 3.0±0.2° 2-θ, 22.3±0.2° 2-θ, and 31.2±0.2° 2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å; (b) an X-ray powder diffraction pattern substantially the same as that shown in Figure 8; or (c) Combinations of these Anhydrous crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride, characterized as having

2. 2. The anhydrous crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride of claim 1, characterized as having an X-ray powder diffraction pattern comprising peaks at 3.0±0.2 degrees two-theta, 22.3±0.2 degrees two-theta, and 31.2±0.2 degrees two-theta, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

3. 2. The anhydrous crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride of claim 1, wherein the anhydrous crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride is characterized as having substantially the same X-ray powder diffraction pattern as shown in FIG. 8 when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

4. 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A): 【Chemistry 2】 A mixture of anhydrous crystalline forms of.

5. 5. The mixture of claim 4, wherein the mixture comprises anhydrous crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride characterized as having an X-ray powder diffraction pattern comprising peaks at 3.0±0.2 degrees two-theta, 4.8±0.2 degrees two-theta, 22.3±0.2 degrees two-theta, 24.8±0.2 degrees two-theta, 26.5±0.2 degrees two-theta, and 31.2±0.2 degrees two-theta, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

6. 5. The mixture of claim 4, wherein the anhydrous crystalline form of Compound A is formed by a process comprising exposing Compound A to an elevated temperature.

7. 7. The mixture of claim 6, wherein the elevated temperature is greater than about 90°C.

8. 7. The mixture of claim 6, wherein the elevated temperature is greater than about 100°C.

9. 7. The mixture of claim 6, wherein the elevated temperature is greater than about 150°C.

10. 7. The mixture of claim 6, wherein the elevated temperature is greater than about 200°C.

11. 5. The mixture of claim 4, wherein the anhydrous crystalline form of Compound A is formed by a process comprising drying Compound A to a lower moisture content.

12. 12. The mixture of claim 11, wherein the moisture content is less than about 5% (w / w).

13. 12. The mixture of claim 11, wherein the moisture content is less than about 2.5% (w / w).

14. 12. The mixture of claim 11, wherein the moisture content is less than about 1% (w / w).

15. 1. A process for the preparation of anhydrous crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A), the process comprising reducing the moisture content in a sample of Compound A and maintaining the sample at a low relative humidity.

16. 16. The process of claim 15, wherein reducing the moisture content comprises heating the sample of Compound A.

17. 16. The process of claim 15, wherein reducing the moisture content comprises heating the sample of Compound A to a temperature greater than about 90°C.

18. 16. The process of claim 15, wherein reducing the moisture content comprises heating the sample of Compound A to a temperature greater than about 100°C.

19. 16. The process of claim 15, wherein reducing the moisture content comprises heating a sample of Compound A to a temperature greater than about 150°C.

20. 16. The process of claim 15, wherein reducing the moisture content comprises heating the sample of Compound A to a temperature greater than about 200°C.

21. 16. The process of claim 15, wherein the low relative humidity is less than about 30%.

22. 16. The process of claim 15, wherein the low relative humidity is less than about 20%.

23. 16. The process of claim 15, wherein the low relative humidity is less than about 10%.

24. 16. The process of claim 15, wherein the moisture content in the sample is reduced to less than about 5% (w / w).

25. 16. The process of claim 15, wherein the moisture content in the sample is reduced to less than about 2.5% (w / w).

26. 16. The process of claim 15, wherein the moisture content in the sample is reduced to less than about 1% (w / w).

27. 1. A process for the preparation of crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride Form 1 (Compound A Form 1), said process comprising exposing a sample of Compound A to a humid environment.

28. 28. The process of claim 27, wherein the sample of Compound A is in an unstable crystalline form.

29. 28. The process of claim 27, wherein the sample of Compound A is anhydrous.

30. the sample of Compound A is anhydrous; and (a) an X-ray powder diffraction pattern comprising peaks at 3.0±0.2° 2-θ, 22.3±0.2° 2-θ, and 31.2±0.2° 2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å; (b) an X-ray powder diffraction pattern substantially the same as that shown in Figure 8; or (c) Combinations of these 30. The process of claim 29, characterized as having:

31. said sample of Compound A is anhydrous; and (a) an X-ray powder diffraction pattern comprising peaks at 4.8±0.2° 2-θ, 26.5±0.2° 2-θ, and 24.8±0.2° 2-θ, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å; (b) an X-ray powder diffraction pattern substantially the same as that shown in FIG. 4 when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å; or (c) Combinations of these 30. The process of claim 29, characterized as having:

32. 30. The process of claim 29, wherein the sample of Compound A comprises a mixture of anhydrous crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride.

33. 33. The process of claim 32, wherein the mixture of anhydrous crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride is characterized as having an X-ray powder diffraction pattern comprising peaks at 3.0±0.2 degrees two-theta, 4.8±0.2 degrees two-theta, 22.3±0.2 degrees two-theta, 24.8±0.2 degrees two-theta, 26.5±0.2 degrees two-theta, and 31.2±0.2 degrees two-theta, when measured using Cu Kα1 radiation having an X-ray wavelength of 1.54060 Å.

34. 28. The process of claim 27, wherein the humid environment comprises a relative humidity of greater than about 30%.

35. 28. The process of claim 27, wherein the humid environment comprises a relative humidity of greater than about 40%.

36. 28. The process of claim 27, wherein the humid environment comprises a relative humidity of greater than about 50%.

37. 28. The process of claim 27, wherein the humid environment comprises a relative humidity of greater than about 60%.

38. 28. The process of claim 27, wherein the humid environment comprises a relative humidity of greater than about 70%.

39. 28. The process of claim 27, wherein the humid environment comprises a relative humidity of about 30% to about 70%.

40. 28. The process of claim 27, wherein the humid environment further comprises a temperature of about 15°C to about 50°C.

41. 28. The process of claim 27, wherein the humid environment further comprises a temperature of about 15°C to about 40°C.

42. 28. The process of claim 27, wherein the humid environment further comprises a temperature of about 20°C to about 40°C.

43. A kit comprising crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A) and one or more pharmaceutically acceptable excipients.

44. 44. The kit of claim 43, wherein the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A) is anhydrous.

45. 44. The kit of claim 43, wherein the crystalline 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride (Compound A) is hydrated.

46. 46. ​​The kit of any one of claims 43 to 45 for use in the treatment of a disease or disorder.

47. 47. The kit of claim 46, wherein the disease or disorder is an adipose-related disease or disorder, a fibrosis-related disease or disorder, a liposarcoma, a solid tumor, or an angiolipoma.

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