Polymorphism of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone and its salts

Abstract

The present invention encompasses polymorphs of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone and its salts. These polymorphs are characterized by their X-ray diffraction patterns and DSC thermograms, among other methods. The polymorphs are used in the preparation of pharmaceutical compositions and products.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to U.S. Provisional Application No. 63 / 336,193, filed April 28, 2022, and U.S. Provisional Application No. 63 / 336,198, filed April 28, 2022, which are incorporated herein by reference. [Background technology]

[0002] The discovery of novel polymorphs can help alleviate limitations in preclinical or clinical studies, as well as in pharmaceutical manufacturing processes, due to drugs with poor or limited solubility, which is often a challenge in drug development. Polymorphs can provide stable, easily manipulated forms of drugs that can facilitate processing and administration. However, given the wide variety of novel polymorphic forms that a compound or its pharma-ceutically acceptable salts or solvates can exhibit, finding a suitable polymorph can be a time-consuming and challenging task. With the availability of multiple polymorphs to choose from, the physicochemical properties of a compound can be tailored by selecting a polymorph that facilitates the manufacture of a commercial drug product from that compound. Improvements in physicochemical properties can be achieved by modifying the physical form of a given compound. Common physical forms include amorphous (non-crystalline forms lacking long-range order) or crystalline (ordered arrangement of molecules in a packing array) polymorphs. It is possible to screen for polymorphs of an unmodified compound or its solvates, salts, hydrates, etc., without losing pharmaceutical activity. The latter three physical forms differ in chemical composition, and therefore, technically, they are pseudopolymorphs. Once a polymorph or pseudopolymorph is established, the alternative forms can also be characterized to identify the form with the preferred properties. Properties that vary across different polymorphic forms include thermodynamic properties such as melting point and sublimation temperature, vapor pressure, enthalpy, entropy, heat capacity, free energy, chemical potential, and solubility; kinetic properties such as dissolution rate, solid reaction rate, physical / chemical stability, nucleation / crystal growth rate; packing properties such as molar volume and density, conductivity (electrical or thermal), refractive index, particle morphology, hygroscopicity, or color; surface properties such as surface free energy or interfacial tension; or mechanical properties such as hardness, tensile strength, compressibility, and tableting, handling, filtration, flow, and blending.

[0003] The most important properties during drug discovery and development include solubility, dissolution rate, bioavailability, and physical / chemical stability. Other favorable differences in physicochemical properties may include higher melting points, more favorable powder properties, etc., which may result from using the optimal polymorph for formulations with, for example, higher storage stability at higher temperatures and / or higher relative humidity, or easier or cheaper manufacturing and / or distribution procedures. In many known cases, several polymorphs exist and can crystallize simultaneously. However, systems tend to move toward a thermodynamically equilibrated state. In other words, the metastable forms in any system will eventually be converted to the most stable form. Therefore, solid dosage forms should use the most stable dosage form to avoid changes in their physicochemical properties. However, the path to the final state depends on the kinetics and other factors that require extensive testing of all discovered metastable forms, and their specific conditions that trigger the process of interconversion to other, more thermodynamically stable forms.

[0004] In some cases, certain stable crystalline polymorphs are discovered first because the energy barrier for nucleation of these less stable polymorphs is relatively low compared to the most stable form. However, much later, these polymorphs may be discovered to be converted into the most thermodynamically stable polymorph. The conversion of the less stable form to the most stable form at ambient conditions may be too slow a process for commercial use, but the process of obtaining the pure most thermodynamically stable polymorph can be accelerated by adding a small amount of the most stable polymorph during the crystallization process. This type of process, known as crystal seeding or seeding, removes the relatively high energy barrier for nucleation of the most stable polymorph, resulting in a direct and rapid process for the pure preparation of the most thermodynamically stable polymorph.

[0005] Polymorphs are discovered by recrystallization from a single solvent or mixture of solvents, heating to induce a transition (e.g., a monotropic polymorph does not change into another form over the entire temperature range), slurry experiments, and other methods known to those skilled in the art. The most thermodynamically stable polymorphic form is required for formulation of an active pharmaceutical ingredient (API) because the less stable form is prone to conversion to the thermodynamically stable form, for example, during compression or storage, causing intolerable shifts in the properties of the drug product over time, which may result in withdrawal of the drug product by the FDA.

[0006] Tubulin inhibitors have shown high efficacy and have been approved by the FDA for the treatment of various cancers. New tubulin inhibitors that bind to the colchicine binding site have shown great potential as therapeutic agents. However, none of these colchicine binding site inhibitors have been approved for oncological or virological indications, although colchicine has been approved for anti-inflammatory applications such as gout and familial Mediterranean fever (FMF). [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone is one such tubulin inhibitor compound with therapeutic applications in cancer (WO2012 / 027481), viral infections such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (WO2021 / 203100) and influenza (PCT / US23 / 17943), and anti-inflammatory diseases such as acute respiratory distress syndrome (ARDS) (WO2022 / 216308). The compounds and their activity were disclosed in PCT publications WO2010 / 74776, WO2011 / 109059, WO2012 / 027481, WO2021 / 203100, and WO2022 / 216308, which are incorporated by reference herein.

[0007] The creation of stable polymorphic forms of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone or a pharma- ceutically acceptable salt or solvate thereof would be advantageous, at a minimum, in the synthesis, handling, and formulation of the compound. Summary of the Invention [Means for solving the problem]

[0008] One embodiment of the present invention encompasses the crystalline polymorphic Form A of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized by an XRD pattern substantially as shown in Figure 35. In one aspect of this embodiment, Form A is characterized by an XRD pattern having peaks at about 9.6, 12.0, 19.2, 23.6, and 24.4 2θ±0.2 2θ. In another aspect of this embodiment, Form A is characterized by an XRD pattern having peaks at about 16.3, 18.1, and 28.9 2θ±0.2 2θ.

[0009] One embodiment of the present invention encompasses the crystalline polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride known as Form B (in Example 3), which is characterized by an XRD pattern having peaks at 9.5, 12.1, 18.0, 18.9, and 23.0 2θ±0.2 2θ. The crystalline polymorphic form B of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride may be further characterized by an XRD pattern substantially as shown in FIG. Alternatively, the crystalline polymorphic form B of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone may be further characterized by XRD peaks at 19.2, 28.5, 29.5, and 31.8 2θ±0.2 2θ. The crystalline polymorphic form B of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride is prepared similarly to Example 3.

[0010] Another embodiment of the present invention is a crystalline polymorphic Form C of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized by an XRD pattern substantially as shown in FIG. H In one aspect of this embodiment, Form C H In another aspect of this embodiment, Form C is characterized by an XRD pattern having peaks at about 5.1, 13.1, 16.6, 22.5, and 25.7 2θ±0.2 2θ. H is characterized by an XRD pattern having peaks at about 10.3, 18.0, 23.7, 28.7, and 29.7 2θ±0.2 2θ.

[0011] Another embodiment of the invention is directed to a crystalline polymorphic form D of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized by an XRD pattern substantially as shown in Figure 25. In one aspect of this embodiment, form D is characterized by an XRD pattern having peaks at about 9.4, 15.1, 17.3, 22.1, and 23.2 2θ±0.2 2θ. In another aspect of this embodiment, form D is characterized by an XRD pattern having peaks at about 10.5, 18.1, 22.8, 24.8, and 30.3 2θ±0.2 2θ.

[0012] Another embodiment of the present invention encompasses the crystalline polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride known as Form E, which is characterized by an X-ray powder diffraction (XRD) pattern having peaks at 9.4, 17.3, 22.1, 23.4, and 24.8 2θ±0.2 2θ. The crystalline polymorphic form E of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride may be further characterized by an XRD pattern substantially as shown in FIG. Alternatively, the crystalline polymorphic form E of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride may be further characterized by XRD peaks at 12.9, 15.0, 18.1, 21.0, and 30.3 2θ±0.2 2θ. The crystalline polymorphic form E of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was formed by the process described in Examples 4 and 5. One embodiment relates to a process for making form E. In one aspect of this embodiment, form E was made by recrystallization from 2-propanol, 1-propanol / 1-dioxane mixture, or ethanol. In one aspect of this embodiment, Form E is made by recrystallization of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride salt, which is added to 2-propanol at saturation concentration at 25° C., heated to 45-50° C. to dissolve the solids, and recrystallized at ambient temperature under 1.5 psi N 2The solid form was formed by rapid evaporation under a stream of water to produce solid form E. In another aspect of this embodiment, form E was made by recrystallization of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, which was added at saturation concentration to a 1-propanol / 1-dioxane mixture at 25° C. and the solvent was allowed to slowly evaporate at ambient temperature to produce solid form E. In another embodiment, form E was made by recrystallization of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, which was added at saturation concentration to ethanol at 25° C. and heated to 45-50° C. to dissolve any solids, and then evaporating at 1.5 psi N at 40° C. 2 The solvent was evaporated rapidly under reflux to produce solid Form E.

[0013] Yet another embodiment of the present invention encompasses a crystalline polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride known as Form E1, which is characterized by an X-ray powder diffraction (XRD) pattern having peaks at 9.4, 17.3, 22.1, 23.4, and 24.8 2θ±0.2 2θ. The crystalline polymorphic Form E1 of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride may be further characterized by an XRD pattern substantially as shown in FIG. Alternatively, the crystalline polymorphic form E1 of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride may be further characterized by XRD peaks at 13.0, 15.1, 18.1, 20.9, and 24.8 2θ±0.2 2θ. The crystalline polymorphic form E1 of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was formed by the process described in Examples 4 and 5. One embodiment is directed to a process for making form E1. In one aspect of this embodiment, form E1 was made by recrystallization from 2-propanol / dichloromethane or 2-propanol / trichloromethane. In one aspect of this embodiment, Form E1 is made by recrystallization of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride salt, which is added at saturation concentration to a 2-propanol / dichloromethane binary solvent mixture at 25° C., heated to 45-50° C. to dissolve the solid, and cooled to 1.5 psi N at 40° C. 2 In another aspect of this embodiment, Form E1 was made by recrystallization of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride salt, which was added at saturation concentration to a 2-propanol / trichloromethane binary solvent mixture at 25° C., heated to 45-50° C. to dissolve the solid, and then recrystallized under 1.5 psi N at 40° C. 2Rapid evaporation under stream yielded solid form E1.

[0014] Another embodiment of the present invention is Form F H The present invention encompasses a crystalline polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride known as crystalline polymorphic form F of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized by an X-ray powder diffraction (XRD) pattern with peaks at 9.06, 10.4, 18.85, 25.48, and 27.97 2θ±0.2 2θ. H may be further characterized by XRD peaks at 12.9, 20.9, and 26.14 2θ±0.2 2θ. Alternatively, crystalline polymorphic form F of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride may be H The crystalline polymorphic form F of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride may be further characterized by an XRD pattern substantially as shown in Figure 38. H has a differential scanning calorimetry (DSC) thermogram exhibiting a larger split endotherm with an onset of about 90.8° C. and a peak maximum of 99.7° C., substantially as shown in FIG.

[0015] In another embodiment, the present invention relates to Form G H The present invention encompasses a crystalline polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, known as [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized by an X-ray powder diffraction (XRD) pattern with peaks at 11.8, 14.5, 16.8, 23.1, and 28.5 2θ±0.2 2θ. Hmay be further characterized by XRD peaks at 10.4, 22.3, 24.7, and 25.3 2θ±0.2 2θ. Alternatively, crystalline polymorphic form G of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride may be H can be further characterized by an XRD pattern substantially as shown in Figure 40. Crystalline polymorphic Form G of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride H has a thermogravimetric analysis (TGA) thermogram with an average weight loss of 4.8% at 150° C. (FIG. 41). H has a differential scanning calorimetry (DSC) thermogram with two endotherms with extrapolated onsets of 140.5° C. and 246.5° C. (FIG. 42).

[0016] In yet another embodiment, the present invention encompasses a crystalline polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride known as Form H, which is characterized by an X-ray powder diffraction (XRD) pattern with peaks at 11.8, 20.1, 23.6, 25.0, and 26.5 2θ±0.2 2θ. The crystalline polymorphic form H of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride may be further characterized by XRD peaks at 8.6, 12.5, 18.6, 21.2, and 28.1 2θ±0.2 2θ. Alternatively, the crystalline polymorphic form H of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride may be further characterized by an XRD pattern substantially as shown in Figure 43. The crystalline polymorphic form H of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride has a thermogravimetric analysis (TGA) thermogram with an average weight loss of 0.03% at 150°C as shown in Figure 44. The crystalline polymorphic form H of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride has a differential scanning calorimetry (DSC) thermogram with a melting endotherm with an onset of 247.5° C. and a peak maximum of 250.1° C., as shown in FIG. 45. In one embodiment, form H was made under ambient conditions. In some embodiments, form H was made from form E under ambient conditions. In some embodiments, form H was made from form E1 under ambient conditions. In some embodiments, form H was made from other polymorphic forms under ambient conditions. In one embodiment, form H was made by one of two competitive slurry experiments in which forms E and H were slurried in 2-butanol or 2-propanol for 1 day. In these embodiments, the samples were not further dried prior to X-ray analysis to avoid possible desolvation or physical changes after isolation.In one embodiment, the process of making form H included co-incubating form E and form H in 2-butanol for 1 day. In this embodiment, form E and form H were added to pure 2-butanol until saturation, the resulting suspension was stirred at ambient temperature for 1 day, the solid was vacuum filtered, and analyzed by XRD to determine the resulting form as form H. In another embodiment, the process of making form H included co-incubating form E and form H in 2-propanol for 1 day. In this embodiment, form E and form H were added to pure 2-propanol until saturation, the resulting suspension was stirred at ambient temperature for 1 day, the solid was vacuum filtered, and analyzed by XRD to determine the resulting form as form H.

[0017] In one embodiment, the present invention encompasses a crystalline polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride known as Form I, which is characterized by an X-ray powder diffraction (XRD) pattern with peaks at 10.0, 10.6, 16.6, 23.7, and 25.7 2θ±0.2 2θ. The crystalline polymorphic Form I of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride may be further characterized by XRD peaks at 11.8, 15.9, 26.7, and 27.6 2θ±0.2 2θ. Alternatively, the crystalline polymorphic Form I of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride may be further characterized by an XRD pattern substantially as shown in FIG.

[0018] In another embodiment, the present invention provides at least polymorphic Forms A, B, C, and D, characterized by the X-ray powder diffraction (XRD) patterns described herein and shown in FIG. H , Form D, Form E, Form E1, Form F H , form G HThe hydrochloride salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone is characterized by Forms H, H, and I.

[0019] One embodiment of the present invention encompasses a crystalline form of the free base of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone, known as Form II, which is characterized by an X-ray powder diffraction (XRD) pattern with peaks at 10.8, 15.3, 15.9, 18.6, and 25.9 2θ±0.2 2θ. The crystalline polymorphic Form II of the free base of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone may be further characterized by an XRD pattern substantially as shown in FIG. Alternatively, the crystalline polymorphic Form II of the free base of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone may be further characterized by XRD peaks at 14.4, 17.8, 20.0, 24.7, and 26.8 2θ±0.2 2θ.

[0020] Another embodiment of the present invention encompasses a crystalline polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride characterized by an X-ray powder diffraction (XRD) pattern having peaks at 10.8, 13.3, 21.5, 23.1, and 35.2 2θ±0.2 2θ. This crystalline polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride may be further characterized by an XRD pattern substantially as shown in FIG. Alternatively, this crystalline polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride may be further characterized by XRD peaks at 10.5, 14.1, 16.1, and 26.2 2θ±0.2 2θ. This crystalline polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was prepared according to Examples 1 and 2.

[0021] Yet another embodiment of the present invention encompasses a crystalline polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone mesylate characterized by an X-ray powder diffraction (XRD) pattern having peaks at 8.3, 9.9, 10.9, 17.5, and 19.9 2θ±0.2 2θ. The crystalline polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone mesylate may be further characterized by an XRD pattern substantially as shown in FIG. Alternatively, the crystalline polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone mesylate may be further characterized by XRD peaks at 12.1, 18.8, 21.9, 24.5, and 28.2 2θ±0.2 2θ. This crystalline polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone mesylate was prepared according to Examples 1 and 2.

[0022] In another embodiment of the present invention, the polymorphs of the present invention are used to treat a disease. Some of these embodiments include the use of the polymorphs of the present invention for the treatment of cancer. In some of these embodiments, the cancer is cancer of the prostate, breast, skin, or other organs, as known by those skilled in the art. Some of these embodiments include the use of the polymorphs of the present invention for the treatment of a viral infection. In some of these embodiments, the viral infection is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or influenza. Some of these embodiments include the use of the polymorphs of the present invention for the treatment of an inflammatory disease. In some of these embodiments, the inflammatory disease affects the lungs. In other of these embodiments, the inflammatory disease is an infection. In some embodiments, the inflammatory disease causes acute respiratory distress syndrome (ARDS). In some of these embodiments, the use of the polymorphs of the present invention for a disease includes any one of Form E, Form E1, or Form H of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride. [Brief description of the drawings]

[0023] [Figure 1] FIG. 1 shows the X-ray powder diffraction (XRD) pattern of polymorphic crystalline Form II (Form II) of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone free base. [Diagram 2] 1 shows a differential scanning calorimetry (DSC) thermogram of Form II. [Diagram 3] 1 shows a thermogravimetric analysis (TGA) thermogram of Form II. [Figure 4]Similar X-ray powder diffraction (XRD) patterns, which are the same as Form II in FIG. 1 , were obtained for the [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone free base samples slurried in acetone (top spectrum), THF (second spectrum below), and toluene (third spectrum below), indicating that the XRD pattern of Form II represents a stable form of the free base of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone. [Diagram 5] 1 shows the XRD pattern of a polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, showing that the salt form was crystalline. This unnamed crystalline polymorphic form of the hydrochloride salt was produced by the process of Example 1 or 2 (small scale synthesis and scale-up of the hydrochloride salt). [Figure 6] 1 shows a DSC profile of an unnamed crystalline form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride produced by the process of Examples 1 or 2, which exhibited multiple thermal events prior to the final melting onset endotherm at about 211.9° C. [Figure 7] 1 shows the TGA profile of an unnamed crystalline form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride produced by the process of Examples 1 or 2, which exhibited a progressive weight loss from 25° C. to 110° C. with a weight loss of approximately 0.54% to 4.1%. [Figure 8A] Shown is Dynamic Vapor Sorption (DVS) data for an unnamed crystalline form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride produced by the process of Examples 1 or 2, which exhibited non-stoichiometric uptake of water as a hydrate in a complex that can form above 30-40% relative humidity (RH). [Figure 8B]A DVS is shown with an upper line for adsorption and a lower line for desorption. [Figure 9] 1 shows the XRD pattern of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone citrate produced by the process of Examples 1 or 2, indicating a poorly ordered crystalline solid. [Figure 10] 1 shows a DSC profile of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone citrate salt of Example 1 or 2, which shows a small exothermic transition at about 130° C., followed immediately by a broad melting onset endotherm at about 184.5° C. [Figure 11] 1 shows a TGA profile of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone citrate salt of Example 1 or 2, which showed a weight loss of about 0.38% to 1.13% from 25° C. to 125° C., followed by decomposition. [Figure 12] 1 shows the XRD pattern of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone phosphate produced by the process of Examples 1 or 2, with the crystallinity exhibiting preferred grain orientation. [Figure 13] 1 shows a DSC profile for [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone phosphate salt of Example 1 or 2, which exhibited a loss of volatiles at about 149° C.-152° C., followed immediately by an exothermic recrystallization at 158.7° C., an onset endotherm of melting at about 216° C.-219° C., followed by decomposition. [Figure 14] 1 shows the TGA profile of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone phosphate salt of Example 1 or 2, which showed a continuous weight loss with a weight loss of about 2.6% to 2.88%, likely due to loss of volatiles from 25° C. to 100° C. followed by further decomposition. [Figure 15]1 shows the XRD pattern of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone mesylate produced by the process of Example 1 or 2, showing a crystalline solid. [Figure 16] The DSC profile pattern of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone mesylate of Example 1 or 2 shows a fairly sharp melting onset endotherm with an extrapolated onset temperature of about 254°C to 265°C and a peak temperature of about 261°C to 268°C. [Figure 17] 1 shows a TGA profile of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone mesylate of Example 1 or 2, which showed a weight loss of 0.51% from about 25° C. to 120-150° C., followed by decomposition. [Figure 18] FIG. 1 shows the XRD pattern of polymorphic form B of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride prepared via recrystallization from a methanol / acetonitrile binary solvent mixture (form B) as described in Example 3. [Figure 19] 1 shows a TGA thermogram of Form B which exhibited an average weight loss of less than 0.05% at 150° C. [Figure 20] 1 shows a DSC thermogram of Form B, which exhibited a sharp melting onset endotherm with an average onset of about 247.4° C. [Figure 21] 1 shows the solid-state Fourier transform infrared (FT-IR) spectrum of Form B. [Figure 22] FIG. 1 shows the XRD pattern of polymorphic form CH of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, which was a hydrate, prepared as described in Example 6 (Form CH). [Figure 23] 1 shows the TGA thermogram of form CH. [Figure 24] 1 shows a DSC thermogram of form CH. [Diagram 25] 1 shows the XRD pattern of polymorphic form D of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride (Form D) made by the non-competitive slurry process described in Example 4. [Figure 26] 1 shows the TGA thermogram of Form D. [Figure 27] 1 shows a DSC thermogram of Form D. [Figure 28] 1 shows the solid state FTIR spectrum of Form D. [Figure 29] FIG. 1 shows the XRD pattern of polymorphic form E of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride (Form E) produced as a result of multiple processes described in Examples 3 and 5. [Diagram 30] FIG. 1 shows the XRD pattern of polymorphic form E1 of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, produced as a result of multiple processes described in Examples 3-5 (Form E1). [Diagram 31] 1 shows a TGA thermogram of Form E which exhibited a weight loss of about 0.66% at 150° C. [Diagram 32] 1 shows a DSC thermogram of Form E, which exhibits an onset melting endotherm at about 239.6° C., followed immediately by a large broad decomposition. [Diagram 33] 1 shows the solid state FTIR spectrum of Form E. [Diagram 34] 1 shows a DSC thermogram of Form E1, which exhibits an onset melting endotherm at about 243.2° C., followed immediately by a large broad decomposition. [Diagram 35] FIG. 1 shows the XRD pattern of polymorphic form A of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride (Form A), prepared via recrystallization from 1-propanol / nitromethane as described in Example 3. [Diagram 36] FIG. 1 shows a TGA thermogram of Form A which was free of volatiles and had a weight loss of about 0.04% from 25° C. to 150° C. [Figure 37] 1 shows a DSC thermogram of Form A exhibiting a melting onset endotherm with an average onset of about 250.3° C. [Figure 38] 1 shows the XRD pattern of polymorphic form FH of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride (Form FH) prepared according to Example 6. [Figure 39] 1 shows a DSC thermogram of form FH which exhibited a larger split endotherm with an onset of about 90.8° C. and peak maxima at 99.7° C. and 119.6° C. The Karl Fischer (KF) water content was 14% by weight. [Diagram 40] 1 shows the XRD pattern of polymorphic form GH of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride (Form GH) prepared according to Example 6. [Diagram 41] 1 shows the TGA thermogram of form GH. [Diagram 42] 1 shows a DSC thermogram of form GH. [Diagram 43] FIG. 1 shows the XRD pattern of polymorphic form H of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride prepared according to Examples 5 and 6 (Form H). [Diagram 44] 1 shows a TGA thermogram of Form H of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride. [Diagram 45] 1 shows a DSC thermogram of Form H. [Figure 46] 1 shows the XRD diffraction pattern of polymorphic Form I (Form I) of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride prepared according to Example 6. [Figure 47] 1 shows an overlay of the XRD diffraction patterns of Forms A, B, CH, D, E, FH, GH, H, and I. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Polymorphism is the ability of a chemical substance to exist in different three-dimensional arrangements in the solid state. Different polymorphic forms of a compound may have different physicochemical properties. [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone is a tubulin inhibitor compound with therapeutic applications in the treatment of cancer, viral infections such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza, and anti-inflammatory diseases such as acute respiratory distress syndrome (ARDS). The present invention is directed to the synthesis (method or process of making) and compositions of matter of stable polymorphic forms of the compound [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone and its pharma-ceutically acceptable salts and solvates, and methods of their use. In particular, the characterization of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride and its hydrates is emphasized. Without being limited by theory, it is believed that a stable polymorphic form is useful for obtaining a generally pure compound during transport and formulation of the compound. The most desirable form is the most thermodynamically stable polymorphic form. To determine the most thermodynamically stable compound and its polymorphs, samples of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone free base, as well as its pharma- ceutically acceptable salts, solvates, and hydrates, were synthesized by the methods described herein and characterized using X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and other methods described herein. Moreover, one of skill in the art would know that these compounds and their novel polymorphs may have advantages in terms of their use to treat cancer, viral infections, and inflammatory diseases, such as increasing the solubility or bioavailability of the API, or increasing the stability of pharmaceutical products containing the API.

[0025] Characterization of the free base of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone (Example 1): The process of making the crystalline polymorphic form II of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone free base (Form II) was carried out by recrystallization of the amorphous form of the free base (Form I) (Figure 1). Other processes for making Form II of the free base included non-competitive single solvent slurry experiments carried out by the process described in Example 4 using the amorphous form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone free base (Form I). Excess amounts of the free base (Form I) were slurried in methanol, ethanol, acetone, acetonitrile, ethyl acetate, THF or toluene. The suspension was slurried at ambient temperature for several days. The solids were collected by filtration and analyzed by XRD. Samples slurried in acetone, THF, and toluene produced Form II of the free base, as shown by the overlay of XRD spectra from these experiments (Figure 4). Figure 1 shows the X-ray powder diffraction (XRD) pattern of Form II of the free base. Form II of the free base was characterized by an XRD pattern with peaks at approximately 10.8, 15.3, 15.9, 18.6, and 25.9 2θ±0.2 2θ.

[0026] Form II of the free base was further characterized by an XRD pattern with peaks at 14.4, 17.8, 20.0, 24.7, and 26.8 2θ±0.2 2θ.

[0027] As shown in FIG. 2, the DSC thermogram of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone free base Form II exhibited a sharp melting endotherm with an extrapolated onset temperature of 205.2° C. and a peak temperature of 208.7° C. The DSC showed an enthalpy value of 103.9 J / g. The small endothermic drop observed at 190° C. may indicate a phase transformation. The TGA thermogram showed that [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone free base Form II had a loss of about 0.2% by weight at 150° C. and continued to lose weight as shown in FIG. 3. As mentioned above, samples of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone free base of Form I slurried in acetone, THF, or toluene (as described in Example 4) produced XRD patterns similar to Figure 1, which indicated that the XRD pattern of Form II represents a stable form of the free base (Figure 4). This also indicates that the slurry process of making Form II of the free base from amorphous Form I of the free base can be accomplished alternatively using acetone, THF, or toluene.

[0028] Salt Screening of the Free Base [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone (Example 1): A salt screening study was conducted to identify suitable polymorphic salts formed by reaction with [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone free base from a library of salt-forming acids. Initially, salt characterization was performed on a small scale (40 mg) with four salts believed to produce the desired polymorph. Small scale synthesis and characterization was performed as described in Example 1. The preferred salts were the hydrochloride, citrate, phosphate, and mesylate salts of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone. Each salt was scaled up and analyzed for crystallinity, thermal properties, water solubility, and hygroscopicity. All polymorphs or salts were contemplated for processability, therapeutic applications, and other factors. Scale-up salt synthesis is described in Example 2 and Table 1 (Example 2).

[0029] Scale-up of hydrochloride, citrate, phosphate, and mesylate salts (Example 2): The monohydrochloride (HCl), citrate, monophosphate (phosphate), and mesylate polymorphic salts were selected for scale-up. The salts were prepared on a 200-500 mg scale to facilitate additional testing and to determine reproducibility. A typical procedure is found in Table 1 of Example 2. Solids were collected by evaporation at ambient conditions with a nitrogen purge at approximately 2 psi. All solids produced the same XRD patterns as seen in prior small-scale experiments and were reproducible.

[0030] A salt screening study was conducted to identify suitable polymorphic salts formed by reacting a library of salt-forming acids with [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone free base as described in Examples 1 and 2. Initially, salt characterization was performed on a small scale (40 mg) with four salts believed to produce the desired polymorphs. Small scale synthesis and characterization was performed as described in Example 1. The preferred salts from Example 1 were the hydrochloride, citrate, phosphate, and mesylate salts of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone. Each salt was scaled up and analyzed for crystallinity, thermal properties, water solubility, and hygroscopicity. All polymorphs or salts were contemplated for processability, therapeutic applications, and other factors. Scale-up salt synthesis is described in this example and in Table 1.

[0031] One embodiment of the present invention is directed to the hydrochloride salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone. Another embodiment of the present invention is directed to any of the polymorphs of the hydrochloride salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone, as characterized herein. The polymorphic forms of the hydrochloride salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone were differentiated by X-ray powder diffraction (XRD) spectroscopy and further characterized by DSC, TGA, DVS, and other methods described herein. Some embodiments of the present invention encompass processes by which specific polymorphs may be synthesized. In some embodiments, the polymorph of interest may be synthesized by one or more of a recrystallization process or a non-competitive or competitive slurry process as described herein for each polymorph. In another embodiment of the present invention, the particular polymorph is used in a pharmaceutical product used to treat a disease. In some embodiments, the particular polymorph is used in a pharmaceutical product used for the treatment of cancer. In some embodiments, the cancer is prostate cancer, breast cancer, skin cancer such as melanoma, or cancer of other organs, as known by those skilled in the art. In some embodiments, the particular polymorph is used in a pharmaceutical product used to treat a viral infection. In some embodiments, the viral infection is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or influenza. In some embodiments, the particular polymorph is used in a pharmaceutical product used to treat an inflammatory disease. In some embodiments, the inflammatory disease affects the lungs. In some embodiments, the inflammatory disease is an infectious disease. In some embodiments, the inflammatory disease is causing acute respiratory distress syndrome (ARDS).

[0032] As used herein, a "pharmaceutical product" refers to a therapeutically effective amount of a particular polymorph of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride in combination with various excipients, such as suitable diluents, preservatives, solubilizers, emulsifiers, adjuvants and / or carriers.

[0033] One embodiment of the present invention is directed to a polymorph of the hydrochloride salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone, characterized by an XRD pattern substantially as shown in Figure 5. In another embodiment, this crystalline polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was characterized by an XRD pattern having peaks at about 10.8, 13.3, 21.5, 23.1, and 35.2 2θ±0.2 2θ. In another embodiment, this crystalline polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was further characterized by an XRD pattern having peaks at 10.5, 14.1, 16.1, and 26.2 2θ±0.2 2θ.

[0034] Another embodiment of the present invention is directed to a crystalline polymorphic form A of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized by an XRD pattern substantially as shown in Figure 35. In one aspect of this embodiment, form A was characterized by an XRD pattern having peaks at about 9.6, 12.0, 19.2, 23.6, and 24.4 2θ±0.2 2θ. In another aspect of this embodiment, form A was characterized by an XRD pattern having peaks at about 16.3, 18.1, and 28.9 2θ±0.2 2θ. One embodiment relates to a process for making form A. In one aspect of this embodiment, form A was made by recrystallization from a 1-propanol / nitromethane binary solvent mixture. In another aspect of this embodiment, Form A is made from [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride by adding the salt at saturation concentration to 1-propanol / nitromethane at 25° C., heating to 45-50° C. to dissolve the solid, and then evaporating at 1.5 psi N at 40° C. 2 The solid form A was produced by rapid evaporation under a stream of water. In another embodiment of the present invention, form A is used in a pharmaceutical product used to treat a disease. Some of these embodiments include the use of form A in a pharmaceutical product used to treat cancer. In some of these embodiments, the cancer is cancer of the prostate, breast, skin, or other organs, as known by those skilled in the art. Some of these embodiments include the use of form A in a pharmaceutical product used to treat a viral infection. In some of these embodiments, the viral infection is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or influenza. Some of these embodiments include the use of form A in a pharmaceutical product used to treat an inflammatory disease. In some of these embodiments, the inflammatory disease affects the lungs. In other of these embodiments, the inflammatory disease is an infectious disease. In some embodiments, the inflammatory disease is causing acute respiratory distress syndrome (ARDS).

[0035] Another embodiment of the present invention is directed to a crystalline polymorphic form B of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized by an XRD pattern substantially as shown in Figure 18. In one aspect of this embodiment, form B was characterized by an XRD pattern having peaks at about 9.5, 12.1, 18.0, 18.9, and 23.0 2θ±0.2 2θ. In another aspect of this embodiment, form B was characterized by an XRD pattern having peaks at about 19.2, 28.5, 29.5, and 31.8 2θ±0.2 2θ. One embodiment relates to the preparation of form B. In one aspect of this embodiment, form B was made by recrystallization from a methanol / acetonitrile binary solvent mixture. In another aspect of this embodiment, Form B is made from [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride by adding the salt at saturation in methanol / acetonitrile at 25° C., heating to 45-50° C. to dissolve the solid, and then evaporating at 1.5 psi N at 40° C. 2 The solid form B was obtained by rapid evaporation under a stream of water. In another aspect of this embodiment, form B can be obtained by condensing the solid form C in ethyl acetate. H and Form B. In this embodiment, Form B was prepared by competitive slurry with excess Form C. Hand Form B to pure ethyl acetate until saturated, the resulting suspension was stirred at ambient temperature for about 2 weeks, the solid was vacuum filtered and analyzed by XRD to determine the resulting form as Form B. In another embodiment of the present invention, Form B is used in a pharmaceutical product used to treat a disease. Some of these embodiments include the use of Form B in a pharmaceutical product used to treat cancer. In some of these embodiments, the cancer is cancer of the prostate, breast, skin, or other organs, as known by those skilled in the art. Some of these embodiments include the use of Form B in a pharmaceutical product used to treat a viral infection. In some of these embodiments, the viral infection is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or influenza. Some of these embodiments include the use of Form B in a pharmaceutical product used to treat an inflammatory disease. In some of these embodiments, the inflammatory disease affects the lungs. In other of these embodiments, the inflammatory disease is an infectious disease. In some embodiments, the inflammatory disease is causing acute respiratory distress syndrome (ARDS).

[0036] Another embodiment of the present invention is a crystalline polymorphic Form C of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized by an XRD pattern substantially as shown in FIG. H In one aspect of this embodiment, Form C H In another aspect of this embodiment, Form C is characterized by an XRD pattern having peaks at about 5.1, 13.1, 16.6, 22.5, and 25.7 2θ±0.2 2θ. H was characterized by an XRD pattern having peaks at about 10.3, 18.0, 23.7, 28.7, and 29.7 2θ±0.2 2θ. In another embodiment of the present invention, Form C H is used in medicines used to treat diseases. Some of these embodiments include the use of form C in medicines used to treat cancer. HIn some of these embodiments, the cancer is a cancer of the prostate, breast, skin, or other organ, as known by those skilled in the art. Some of these embodiments include the use of Form C in a medicament for use in the treatment of a viral infection. H In some of these embodiments, the viral infection is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or influenza. Some of these embodiments include the use of Form C in a medicament for use in the treatment of an inflammatory disease. H In some of these embodiments, the inflammatory disease affects the lungs. In other of these embodiments, the inflammatory disease is an infection. In some embodiments, the inflammatory disease causes acute respiratory distress syndrome (ARDS).

[0037] Another embodiment of the present invention is directed to a crystalline polymorphic form D of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized by an XRD pattern substantially as shown in Figure 25. In one aspect of this embodiment, form D was characterized by an XRD pattern having peaks at about 9.4, 15.1, 17.3, 22.1, and 23.2 2θ±0.2 2θ. In another aspect of this embodiment, form D was characterized by an XRD pattern having peaks at about 10.5, 18.1, 22.8, 24.8, and 30.3 2θ±0 2 2θ. An embodiment is directed to the preparation of form D. In one aspect of this embodiment, form D was made by a non-competitive slurry experiment in which form B was slurried in either non-aqueous solvent acetone or acetonitrile for 14 days. In one embodiment, the process for making Form D included non-competitive slurrying of Form B in acetone for 14 days. In this embodiment, excess Form B was added to pure acetone until saturation, the resulting suspension was stirred at ambient temperature for 14 days, the solid was vacuum filtered, and analyzed by XRD to determine the resulting form as Form D. In another embodiment, the process for making Form D included non-competitive slurrying of Form B in acetonitrile for 14 days. In this embodiment, excess Form B was added to pure acetonitrile until saturation, the resulting suspension was stirred at ambient temperature for 14 days, the solid was vacuum filtered, and analyzed by XRD to determine the resulting form as Form D. In another embodiment of the invention, Form D is used in a medicine used to treat disease. Some of these embodiments encompass the use of Form D in a medicine used to treat cancer. In some of these embodiments, the cancer is a cancer of the prostate, breast, skin, or other organs, as known by those skilled in the art. Some of these embodiments encompass the use of Form D in a medicine used to treat viral infections. In some of these embodiments, the viral infection is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or influenza. Some of these embodiments encompass the use of Form D in a medicament used to treat an inflammatory disease.In some of these embodiments, the inflammatory disease affects the lungs. In other of these embodiments, the inflammatory disease is an infection. In some embodiments, the inflammatory disease causes acute respiratory distress syndrome (ARDS).

[0038] Another embodiment of the present invention is directed to a crystalline polymorphic form E of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized by an XRD pattern substantially as shown in Figure 29. In one aspect of this embodiment, form E was characterized by an XRD pattern having peaks at about 9.4, 17.3, 22.1, 23.4, and 24.8 2θ ± 0.2 2θ. In another aspect of this embodiment, form E was characterized by an XRD pattern having peaks at about 12.9, 15.0, 18.1, 21.0, and 30.3 2θ ± 0.2 2θ. The two diffraction patterns of form E and form E1 appear very similar, except for minor differences between the two patterns in the 10-12° 2θ region.

[0039] One embodiment relates to the preparation of Form E. In one aspect of this embodiment, Form E was made by recrystallization from 2-propanol, 1-propanol / 1-dioxane mixture, or ethanol. In one aspect of this embodiment, Form E was made by recrystallization of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, which was added to 2-propanol at saturation concentration at 25° C., heated to 45-50° C. to dissolve the solids, and recrystallized in 1.5 psi N at ambient temperature. 2The solid form was formed by rapid evaporation under a stream of water to produce solid form E. In another aspect of this embodiment, form E was made by recrystallization of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, which was added at saturation concentration to a 1-propanol / 1-dioxane mixture at 25° C. and the solvent was allowed to slowly evaporate at ambient temperature to produce solid form E. In another embodiment, form E was made by recrystallization of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, which was added at saturation concentration to ethanol at 25° C. and heated to 45-50° C. to dissolve any solids, and then evaporating at 1.5 psi N at 40° C. 2The solvent was evaporated rapidly under running water to produce Form E. In one embodiment, Form E was made by competitive slurry experiments, where a binary combination of Form A, Form B, and Form D were slurried in 1-propanol for about 2 weeks. In one aspect of this embodiment, the process to make Form E included co-incubating Form B and Form D in 1-propanol for about 2 weeks. In this aspect of the embodiment, Form B and Form D were added to pure 1-propanol until saturated, the resulting suspension was stirred at ambient temperature for about 2 weeks, the solids were vacuum filtered, and analyzed by XRD to determine the resulting form as Form E. In another embodiment, the process to make Form E included co-incubating Form A and Form B in 1-propanol for about 2 weeks. In this aspect of the embodiment, Form A and Form B were added to pure 1-propanol until saturated, the resulting suspension was stirred at ambient temperature for about 2 weeks, the solid was vacuum filtered, and analyzed by XRD to determine the resulting form as Form E. In another embodiment of the present invention, Form E is used in a pharmaceutical product used to treat a disease. Some of these embodiments include the use of Form E in a pharmaceutical product used to treat cancer. In some of these embodiments, the cancer is cancer of the prostate, breast, skin, or other organs, as known by those skilled in the art. Some of these embodiments include the use of Form E in a pharmaceutical product used to treat a viral infection. In some of these embodiments, the viral infection is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or influenza. Some of these embodiments include the use of Form E in a pharmaceutical product used to treat an inflammatory disease. In some of these embodiments, the inflammatory disease affects the lungs. In other of these embodiments, the inflammatory disease is an infectious disease. In some embodiments, the inflammatory disease is causing acute respiratory distress syndrome (ARDS).

[0040] Another embodiment of the present invention is directed to crystalline polymorphic Form E1 of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized by an XRD pattern substantially as shown in Figure 30. In one aspect of this embodiment, Form E1 was characterized by an XRD pattern having peaks at about 9.4, 10.9, 17.3, 22.1, and 23.2 2θ ± 0.2 2θ. In another aspect of this embodiment, Form E1 was characterized by an XRD pattern having peaks at about 13.0, 15.1, 18.1, 20.9, and 24.8 2θ ± 0.2 2θ. The two diffraction patterns of Form E and Form E1 appear very similar, except for minor differences between the two patterns in the 10-12° 2θ region.

[0041] One embodiment is directed to the preparation of Form E1. In one aspect of this embodiment, Form E1 was made by recrystallization from 2-propanol / dichloromethane or 2-propanol / trichloromethane. In one aspect of this embodiment, Form E1 was made by recrystallization of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride salt, which was added at saturation concentration to a 2-propanol / dichloromethane binary solvent mixture at 25° C., heated to 45-50° C. to dissolve the solids, and recrystallized at 1.5 psi N at 40° C. 2 In another aspect of this embodiment, Form E1 was made by recrystallization of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride salt, which was added at saturation concentration to a 2-propanol / trichloromethane binary solvent mixture at 25° C., heated to 45-50° C. to dissolve the solid, and then recrystallized under 1.5 psi N at 40° C. 2 Rapid evaporation under stream yielded solid form E1.

[0042] One embodiment is directed to the preparation of Form E1. In one aspect of this embodiment, the process to make Form E1 included non-competitive slurrying of Form B in any one of five binary solvent mixtures including ethanol / toluene, acetonitrile (ACN) / acetone, ethanol / acetonitrile, 1-propanol / ethyl acetate (EtOAc) or 2-propanol / tetrahydrofuran (THF) for 11 days. In these embodiments, the samples were not further dried prior to X-ray analysis to avoid possible desolvation or physical changes after isolation. In this embodiment, the process to make Form E1 included non-competitive slurrying of Form B in a non-aqueous binary solvent system of ethanol / toluene for 11 days. In this embodiment, excess Form B was added to the ethanol / toluene mixture until saturation, the resulting suspension was stirred at ambient temperature for 11 days, and the solid was vacuum filtered and analyzed by XRD to determine the resulting form as Form E1. In another embodiment, the process for making Form E1 included non-competitive slurrying of Form B in a non-aqueous binary solvent system of acetonitrile (ACN) / acetone for 11 days. In this embodiment, excess Form B was added to an acetonitrile (ACN) / acetone mixture until saturation, the resulting suspension was stirred at ambient temperature for 11 days, the solid was vacuum filtered, and analyzed by XRD to determine the resulting form as Form E1. In another embodiment, the process for making Form E1 included non-competitive slurrying of Form B in a non-aqueous binary solvent system of ethanol / acetonitrile for 11 days. In this embodiment, excess Form B was added to an ethanol / acetonitrile mixture until saturation, the resulting suspension was stirred at ambient temperature for 11 days, the solid was vacuum filtered, and analyzed by XRD to determine the resulting form as Form E1. In another embodiment, the process for making Form E1 included non-competitive slurrying of Form B in a non-aqueous binary solvent system of 1-propanol / ethyl acetate (EtOAc) for 11 days. In this embodiment, excess Form B was added to a 1-propanol / ethyl acetate (EtOAc) mixture until saturation, the resulting suspension was stirred at ambient temperature for 11 days, the solid was vacuum filtered and analyzed by XRD, and the resulting form was determined as Form E1.In another embodiment, the process for making Form E1 involved non-competitive slurrying of Form B in a non-aqueous binary solvent system of 2-propanol / tetrahydrofuran (THF) for 11 days. In this embodiment, excess Form B was added to the 2-propanol / tetrahydrofuran (THF) mixture until saturation, the resulting suspension was stirred at ambient temperature for 11 days, and the solid was vacuum filtered and analyzed by XRD to determine the form obtained as Form E1.

[0043] In one embodiment, Form E1 is a mixture of Form A, Form B, Form C H The binary combination of Forms E, D, and E was prepared by any one of four competitive slurry experiments in which the binary combination of Forms E, D, and E was slurried in 1-propanol for approximately two weeks. In these embodiments, the samples were not further dried prior to X-ray analysis to avoid possible desolvation or physical changes after isolation. In one embodiment, the process to make Form E1 includes Forms C, D, and E. H and Form B were co-incubated in 1-propanol for about two weeks. Hand Form B were added to pure 1-propanol until saturated, the resulting suspension was stirred at ambient temperature for about 2 weeks, the solids were vacuum filtered, and analyzed by XRD to determine the resulting form as Form E1. In another embodiment, the process for making Form E1 included co-incubating Form A and Form D in 1-propanol for about 2 weeks. In this embodiment, Form A and Form D were added to pure 1-propanol until saturated, the resulting suspension was stirred at ambient temperature for about 2 weeks, the solids were vacuum filtered, and analyzed by XRD to determine the resulting form as Form E1. In another embodiment, the process for making Form E1 included co-incubating Form B and Form E in 1-propanol for about 2 weeks. In this embodiment, Form B and Form E were added to pure 1-propanol until saturated, the resulting suspension was stirred at ambient temperature for about 2 weeks, the solids were vacuum filtered, and analyzed by XRD to determine the resulting form as Form E1. In another embodiment, the process of making Form E1 included co-incubating Form D and Form E in 1-propanol for about 2 weeks. In this embodiment, Form D and Form E were added to pure 1-propanol until saturation, the resulting suspension was stirred at ambient temperature for about 2 weeks, the solid was vacuum filtered, and analyzed by XRD to determine the resulting form as Form E1. In another embodiment of the present invention, Form E1 is used in a medicine used to treat a disease. Some of these embodiments include the use of Form E1 in a medicine used to treat cancer. In some of these embodiments, the cancer is cancer of the prostate, breast, skin, or other organs, as known by those skilled in the art. Some of these embodiments include the use of Form E1 in a medicine used to treat a viral infection. In some of these embodiments, the viral infection is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or influenza. Some of these embodiments include the use of Form E1 in a medicine used to treat an inflammatory disease. In some of these embodiments, the inflammatory disease affects the lungs. In other of these embodiments, the inflammatory disease is an infectious disease.In some embodiments, the inflammatory disease causes acute respiratory distress syndrome (ARDS).

[0044] Another embodiment of the present invention is a crystalline polymorphic Form F of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized by an XRD pattern substantially as shown in FIG. H In one aspect of this embodiment, form F H In another aspect of this embodiment, Form F is characterized by an XRD pattern having peaks at about 9.06, 10.4, 18.85, 25.48, and 27.97 2θ±0.2 2θ. H was characterized by an XRD pattern with peaks at about 12.9, 20.9, and 26.14 2θ±0.2 2θ. One embodiment is form F from form E or form E1 stored at ambient conditions. H In another embodiment of the present invention, the preparation of Form F H is used in medicaments used to treat diseases. Some of these embodiments include the use of form F in medicaments used to treat cancer. H In some of these embodiments, the cancer is a cancer of the prostate, breast, skin, or other organ, as known by those skilled in the art. Some of these embodiments include the use of Form F in a medicament for use in the treatment of a viral infection. H In some of these embodiments, the viral infection is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or influenza. Some of these embodiments include the use of form F in a medicament for use in the treatment of an inflammatory disease. H In some of these embodiments, the inflammatory disease affects the lungs. In other of these embodiments, the inflammatory disease is an infection. In some embodiments, the inflammatory disease causes acute respiratory distress syndrome (ARDS).

[0045] Another embodiment of the present invention is a crystalline polymorphic Form G of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized by an XRD pattern substantially as shown in FIG. H In one aspect of this embodiment, Form G H In another aspect of this embodiment, Form G is characterized by an XRD pattern having peaks at about 11.8, 14.5, 16.8, 23.1, and 28.5 2θ±0.2 2θ. H was characterized by an XRD pattern with peaks at about 10.4, 22.3, 24.7, and 25.3 2θ±0.2 2θ. One embodiment is form G from form E or form E1 stored at ambient conditions. H In another embodiment of the present invention, the preparation of Form G H is used in medicines used to treat diseases. Some of these embodiments include the use of form G in medicines used to treat cancer. H In some of these embodiments, the cancer is a cancer of the prostate, breast, skin, or other organ, as known by those skilled in the art. Some of these embodiments include the use of form G in a medicament for use in the treatment of a viral infection. H In some of these embodiments, the viral infection is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or influenza. Some of these embodiments include the use of form G in a medicament for use in the treatment of an inflammatory disease. H In some of these embodiments, the inflammatory disease affects the lungs. In other of these embodiments, the inflammatory disease is an infection. In some embodiments, the inflammatory disease causes acute respiratory distress syndrome (ARDS).

[0046] Another embodiment of the present invention is directed to a crystalline polymorphic form H of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized by an XRD pattern substantially as shown in Figure 43. In one aspect of this embodiment, form H was characterized by an XRD pattern having peaks at about 11.8, 20.1, 23.6, 25.0, and 26.5 2θ±0.2 2θ. In another aspect of this embodiment, form H was characterized by an XRD pattern having peaks at about 8.6, 12.5, 18.6, 21.2, and 28.1 2θ±0.2 2θ. An embodiment is directed to the preparation of form H from form E stored at ambient conditions. Another embodiment is directed to the preparation of form H from form E1 stored at ambient conditions. Another embodiment is directed to the preparation of Form H from any polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride stored at ambient conditions. In one embodiment, the conversion of Form E, Form E1, or any other polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride occurs at ambient conditions in the absence of any Form H seed crystals.

[0047] In one embodiment, form H is prepared by one of two competitive slurry experiments in which form E and form H were slurried in 2-butanol or 2-propanol for 1 day. In these embodiments, the samples were not further dried prior to X-ray analysis to avoid possible desolvation or physical changes after isolation. In one embodiment, the process to make form H included co-incubating form E and form H in 2-butanol for 1 day. In this embodiment, form E and form H were added to pure 2-butanol until saturation, the resulting suspension was stirred at ambient temperature for 1 day, the solid was vacuum filtered, and analyzed by XRD to determine the resulting form as form H. In another embodiment, the process to make form H included co-incubating form E and form H in 2-propanol for 1 day. In this embodiment, form E and form H were added to pure 2-propanol until saturation, the resulting suspension was stirred at ambient temperature for 1 day, the solid was vacuum filtered, and analyzed by XRD to determine the resulting form as form H. In one embodiment, a process for making substantially pure form H included the synthesis of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride from intermediate C-5 in the presence of trace amounts of form H (Example 7). In another embodiment, a process for making substantially pure form H included the conversion of form E to form H in the presence of trace amounts of form H seed crystals. In some embodiments, kilogram-scale quantities of form H can be made from crude [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride in any polymorphic form in the presence of gram amounts of form H seed crystals. In some embodiments, form H seed crystals are added to crude [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride slurried in ethanol and ethyl acetate.

[0048] In another embodiment of the present invention, form H is used in a medicine used to treat a disease. Some of these embodiments include the use of form H in a medicine used to treat cancer. In some of these embodiments, the cancer is cancer of the prostate, breast, skin, or other organs, as known by those skilled in the art. Some of these embodiments include the use of form H in a medicine used to treat a viral infection. In some of these embodiments, the viral infection is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) I or influenza. Some of these embodiments include the use of form H in a medicine used to treat an inflammatory disease. In some of these embodiments, the inflammatory disease affects the lungs. In other of these embodiments, the inflammatory disease is an infectious disease. In some embodiments, the inflammatory disease is causing acute respiratory distress syndrome (ARDS).

[0049] Another embodiment of the present invention is directed to crystalline polymorphic Form I of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized by an XRD pattern substantially as shown in FIG. 46. In one aspect of this embodiment, Form I of the HCl salt was characterized by an XRD pattern having peaks at about 10.0, 10.6, 16.6, 23.7, and 25.7 2θ±0.2 2θ. In another aspect of this embodiment, Form I of the HCl salt was characterized by an XRD pattern having peaks at about 11.8, 15.9, 26.7, and 27.6 2θ±0.2 2θ. In another embodiment of the present invention, Form I of the HCl salt is used in a medicament used to treat a disease. Some of these embodiments encompass the use of Form I of the HCl salt in a medicament used to treat a cancer. In some of these embodiments, the cancer is a cancer of the prostate, breast, skin, or other organ, as known by those skilled in the art. Some of these embodiments include the use of Form I of the HCl salt in a medicine used to treat a viral infection. In some of these embodiments, the viral infection is Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) I or influenza. Some of these embodiments include the use of Form I of the HCl salt in a medicine used to treat an inflammatory disease. In some of these embodiments, the inflammatory disease affects the lungs. In other of these embodiments, the inflammatory disease is an infectious disease. In some embodiments, the inflammatory disease is causing acute respiratory distress syndrome (ARDS).

[0050] One embodiment of the present invention is directed to a mesylate salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone. Another embodiment of the present invention is directed to a polymorph of the mesylate salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone, as characterized herein. In one embodiment, the crystalline polymorph of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone mesylate salt is characterized by an XRD pattern substantially as shown in FIG. 15. In one aspect of this embodiment, the crystalline polymorph of the mesylate salt was characterized by an XRD pattern having peaks at about 8.3, 9.9, 10.9, 17.5, and 19.9 2θ±0.2 2θ. In another aspect of this embodiment, the crystalline polymorph of the mesylate salt was characterized by an XRD pattern having peaks at about 12.1, 18.8, 21.9, 24.5, and 28.2 2θ±0.2 2θ.

[0051] One embodiment of the present invention is directed to a phosphate salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone. Another embodiment of the present invention is directed to a polymorph of the phosphate salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone, as characterized herein. In one embodiment, the crystalline polymorph of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone phosphate is characterized by an XRD pattern substantially as shown in FIG. 12. In one aspect of this embodiment, the crystalline polymorph of the phosphate salt was characterized by an XRD pattern having peaks at about 5.7, 9.3, 12.4, 12.6, and 18.8 2θ±0.2 2θ. In another aspect of this embodiment, the crystalline polymorph of the Phosphate Salt was characterized by an XRD pattern having peaks at about 9.7, 10.9, 11.6, and 20.7 2θ±0.2 2θ.

[0052] One embodiment of the present invention is directed to a citrate salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone. Another embodiment of the present invention is directed to a polymorph of the citrate salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone, as characterized herein. In one embodiment, the crystalline polymorph of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone citrate salt is characterized by an XRD pattern substantially as shown in FIG. 9. In one aspect of this embodiment, the crystalline polymorph of the citrate salt was characterized by an XRD pattern having peaks at about 9.7, 10.7, 15.1, 15.6, and 22.1 2θ±0.2 2θ. In another aspect of this embodiment, the crystalline polymorph of the Citrate Salt was characterized by an XRD pattern having peaks at about 18.6, 19.2, 26.4, and 27.1 2θ±0.2 2θ.

[0053] Since hydrochloric acid (HCl) is a class I salt-forming acid, [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was synthesized to provide a class I salt with lower safety risks compared to other salt forms. Class I salts form physiologically ubiquitous ions or occur as intermediate metabolites in biochemical pathways, allowing for unrestricted use. [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride formed in Example 2 was crystalline, polymorphic, and had good solubility in unbuffered water (less than 1 mg / mL). This unnamed polymorph of the hydrochloride salt also showed evidence of possible hydrate formation at about 30-40% RH (relative humidity), especially at about 50% RH.

[0054] The XRD pattern of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride formed in Example 2 indicated that the compound was crystalline, as shown in Figure 5. This unnamed crystalline polymorph is consistent with the other polymorphic forms (Forms A, B, C, D, E, F, F, G, H) of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride characterized herein. H , D, E, E1, F H , G H , H, and I). The crystalline polymorph of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride formed in Example 2 was characterized by an XRD pattern with peaks at about 10.8, 13.3, 21.5, 23.1, and 35.2 2θ±0.2 2θ. The crystalline polymorph of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride formed in Example 2 was further characterized by an XRD pattern with peaks at 10.5, 14.1, 16.1, and 26.2 2θ±0.2 2θ. The DSC profile exhibited multiple thermal events before the final melting onset endotherm at about 235.7° C., as shown in FIG. 6. The TGA profile showed a continuous loss in weight with a weight loss of about 0.54% to 4.1% from 25 °C to 110 °C, as shown in Figure 7. Hygroscopicity was determined by dynamic vapor sorption (DVS). The DVS data exhibited non-stoichiometric uptake of water as hydrates that may form above 30-40% RH in the composite, with a total adsorption of about 8.8 wt% to 14.9 wt% water at 90% RH, as shown in Figure 8.

[0055] [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone citrate had moderate crystallinity and good solubility (approximately 1 mg / mL) in unbuffered water. [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone citrate was polymorphic and showed evidence of possible dihydrate formation at approximately 30-40% RH, especially at 60% RH (data not shown). The XRD pattern of a small scale citrate salt (synthesized according to Example 1) showed a poorly ordered crystalline solid, as shown in Figure 9. The crystalline [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone citrate was characterized by an XRD pattern with peaks at about 9.7, 10.7, 15.1, 15.6, and 22.1 2θ±0.2 2θ. The crystalline [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone citrate was further characterized by an XRD pattern with peaks at 18.6, 19.2, 26.4, and 27.1 2θ±0.2 2θ. The DSC profile showed a small exothermic transition at about 130° C., followed immediately by a broad melting onset endotherm at about 184.5° C., as shown in FIG. 10. The TGA profile showed a weight loss of about 0.38% to 1.13% from 25° C. to 125° C., followed by decomposition, which is shown graphically in FIG.

[0056] [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone phosphate synthesized according to Example 1 exhibited good crystallinity and good solubility (less than 1 mg / mL) in unbuffered water. The XRD pattern of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone phosphate showed crystallinity with preferred grain orientation as shown in Figure 12. The crystalline polymorph of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone phosphate was characterized by an XRD pattern with peaks at about 5.7, 9.3, 12.4, 12.6, and 18.8 2θ±0.2 2θ. The crystalline polymorph of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone phosphate was further characterized by an XRD pattern with peaks at 9.7, 10.9, 11.6, and 20.7 2θ±0.2 2θ. The DSC profile exhibited a loss of volatiles from about 149° C. to 153° C., followed immediately by an exothermic recrystallization at 158.7° C., an onset of melting endotherm at about 216° C. to 219° C., followed by decomposition, as shown in FIG. 13. The TGA profile exhibited a loss of volatiles from 25° C. to 100° C., followed by a continuous loss in weight with a weight loss of about 2.6% to 2.88% due to further decomposition, as shown in FIG. 14.

[0057] [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone mesylate was highly crystalline and had good solubility (less than 1 mg / mL) in unbuffered water. The XRD pattern of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone mesylate synthesized according to Example 1 exhibited a crystalline solid as shown in Figure 15. The crystalline polymorph of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone mesylate was characterized by an XRD pattern with peaks at about 8.3, 9.9, 10.9, 17.5, and 19.9 2θ±0.2 2θ. The crystalline polymorph of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone mesylate was further characterized by an XRD pattern with peaks at 12.1, 18.8, 21.9, 24.5, and 28.2 2θ±0.2 2θ. The DSC profile showed a fairly sharp melting onset endotherm with an extrapolated onset temperature at about 254°C-265°C, a peak temperature at about 261°C-268°C, and an enthalpy value of about 96.7 J / g-128.5 J / g, as shown in FIG. 16. The TGA profile showed a weight loss of 0.51% from about 25°C to 120-150°C, followed by decomposition, as shown in FIG. 17. The following examples are presented to more fully illustrate preferred embodiments of the invention. However, they should not be construed as limiting the broad scope of the invention. EXAMPLES

[0058] Differential Scanning Calorimetry (DSC)

[0059] DSC data was collected on a TA Instruments DSC. Typically, samples ranging in mass from 1 to 10 mg were crimped in aluminum sample pans and scanned at 10° C. / min from 25° C. to about 250° C. or 300° C. with a nitrogen purge of 50 mL / min.

[0060] Proton nuclear magnetic resonance spectroscopy (1 H-NMR)

[0061] Samples were prepared by dissolving 1–10 mg of active pharmaceutical ingredient (API) in deuterated chloroform containing 0.05% (v / v) tetramethylsilane (TMS). Spectra were collected at ambient temperature on a Bruker 400 MHz NMR spectrometer.

[0062] X-ray powder diffraction (XRD)

[0063] Solids produced from the recrystallization panels, slurry experiments, and other means were analyzed by powder XRD. All XRD screening data was collected using a two-dimensional detection system to mitigate preferential grain effects. The two-dimensional detector is integrated along concentric Debye cones, which helps reduce pattern variability. If bright spots appear in the conical rings, it indicates a strong preferential grain effect and can cause considerable variability in the observed diffraction pattern. Some samples of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone HCl salt tended to show mild preferential grain effects, but overall [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone HCl did not appear to be affected by severe preferential grain effects. This resulted in XRD data with low variability for samples of a given polymorphic form. X-ray powder diffraction (XRD) patterns were obtained using a Bruker D8 Discovery diffractometer equipped with an XYZ stage, a laser video microscope for positioning, and a Vantec 500 (Photon) detector. The collection time was nominally 120 seconds. A CuKα radiation 1.5406 Å source operated at 40 kV and 40 mA was used to irradiate the samples. The X-ray optics consisted of a Goebel mirror coupled with a 0.5 mm pinhole collimator. A theta-theta continuous scan was used with a sample-detector distance of 30 cm, which resulted in an effective 2θ range of 4 to 40°2θ. Samples were mounted on low background quartz plates.

[0064] Hygroscopicity - Dynamic Vapor Sorption (DVS)

[0065] DVS is a gravimetric technique that measures how fast and how much of a solvent (water) is absorbed into a sample. The relative humidity or vapor concentration surrounding the sample is changed while the change in mass of the sample is measured. A vapor sorption isotherm shows the equilibrium amount of vapor absorbed as a function of relative humidity. The mass values ​​at each relative humidity step are used to generate the isotherm. The isotherm is separated into two components: sorption for increasing humidity steps and desorption for decreasing humidity steps. Plots of the kinetic data are also used to show the change in mass and humidity as a function of time.

[0066] Samples were analyzed using a TA Q5000 automated dynamic vapor sorption analyzer. Samples were dried at above ambient temperature for a period of time and then cooled to 25 °C with a dry nitrogen purge until no mass loss at 0% RH (relative humidity). Samples were then subjected to 0-90% RH in 10% RH steps and returned to 10% RH at 25 °C.

[0067] Thermogravimetric analysis (TGA)

[0068] Solids produced from recrystallization panels, slurry experiments, and other means were analyzed by TGA. TGA is an analytical test that determines the mass of volatile material lost as the temperature of a sample is increased. Conditions for TGA were as specified where TGA values ​​are reported herein. If not specified, the default conditions were as follows: sample size 5-20 mg (or appropriate size), temperature range: 25°C-150°C, heating rate: 10°C / min, purge gas: nitrogen; and replicates: single analysis.

[0069] Solid-state Fourier transform infrared spectroscopy (FT-IR)

[0070] Solids produced from recrystallization panels, slurry experiments, and other means were analyzed by this procedure of Fourier transform infrared spectroscopy (FT-IR). FT-IR is a qualitative chemical analysis tool that helps determine the presence of specific functional groups and verify the identity of a test sample by comparison with a reference sample. Depending on the offering, this test method was used to identify or characterize polymorphic substances by infrared spectroscopy. Samples submitted for confirmation of identity were analyzed by comparison of the sample spectrum with the reference spectrum. If the FT-IR spectrum matches that of the reference material, the material was positively identified. If the number, relative intensity, and wavenumber (cm-1) of observed vibrational bands match between the spectra, the spectra are considered to match. If differences appeared in the IR spectra of the analyte and standard that could be attributed to hydration, the sample was dissolved in equal portions of the test substance and standard in an equal volume of an appropriate solvent, the solution was evaporated to dryness under the same conditions in a similar container, and the test was repeated on the residue. The equipment used in this method was a Thermo Scientific Nicolet iS20 FTIR spectrometer equipped with Thermo Scientific's OMNIC™ software and compatible FTIR accessories for use with the spectrometer (as needed), including: (1) an attenuated total reflectance (ATR) attachment (e.g., Harrick SplitPea™ internal reflection nanosampler, Thermo Scientific Smart™ iTX), (2) a transmittance sample holder accessory (for use with KBr plates, removable KBr liquid cells, KBr pellets, disposable PTFE cards, etc.), (3) a pellet die and press (as needed), (4) a vacuum oven or desiccator (as needed), or (5) a forced air drying oven (as needed). The following reagents, supplies, media, and solutions were used as needed: (1) KBr plates (if required), (2) removable KBr liquid cell (if required), (3) KBr powder, spectroscopy / IR grade (if required), (4) disposable PTFE cards (if required), (5) suitable solvent for dissolving samples (if required), and (6) general lab equipment (spatulas, mortar and pestle, vials, flasks, etc.).In general, the physical properties of the sample and the purpose of the test dictated the particular approach and instrument accessories used to collect FTIR spectra. Liquid samples were applied directly to a KBr plate or window, applied to a disposable PTFE card, or collected using a removable liquid cell. Solid samples were analyzed with an ATR accessory or mixed with KBr (sample-KBr ratio approximately 1:100), pressed into pellets, and analyzed. Alternatively, samples may be dissolved in a suitable solvent and spectra collected using a removable liquid cell.

[0071] Karl Fischer titration (KF)

[0072] Solids produced from recrystallization panels, slurry experiments, and other means were analyzed by this procedure to determine water content. Samples were weighed on an analytical balance capable of weighing to 0.1 mg and then tested on a Karl Fischer apparatus suitable for coulometric and quantitative titrations. The Karl Fischer apparatus was calibrated using deionized (DI) water or a certified water standard prior to analyzing the test samples. Similarly, the calibration of the analytical balance was verified prior to weighing the samples. Samples were added directly to the vessel solution. If this was not possible, the sample was dissolved in a suitable solvent and then injected, and a solvent blank was also analyzed.

[0073] Hot Stage Microscopy

[0074] A Linkam hot stage accessory was used in conjunction with the microscope. Specimens were mounted on microscope slides with cover slips. Samples were heated from room temperature to melting using a Linkam TMS94 temperature control and Linksys 32 data capture software system. Observations such as possible phase changes, melting, recrystallization, decomposition, etc. were recorded.

[0075] Visual Solubility

[0076] A milligram-sized amount of each sample was placed in a vial. A certain amount of solvent was added and the vial was stirred for several minutes, after which it was visually inspected for remaining solids. Solvent was added gradually until the solids had dissolved, or a maximum volume of solvent was added and the experiment was terminated.

[0077] Example 1: Polymorphic characterization of the free base; and small-scale salt synthesis

[0078] The amorphous form of the free base, known as Form I of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone, served as the source material for polymorph screening of the free base. The polymorphs of the free base were screened by recrystallization and solvent slurry methods as described in Examples 3 and 4. The process of making the crystalline polymorphic Form II of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone free base (Form II) was carried out by recrystallization of the amorphous form of the free base (Form I) (Figure 1). Other processes that yielded Form II of the free base included non-competitive single solvent slurry experiments carried out by the process described in Example 4 using the amorphous form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone free base (Form I). Excess amounts of the free base (Form I) were slurried in methanol, ethanol, acetone, acetonitrile, ethyl acetate, tetrahydrofuran (THF) or toluene. The suspensions were slurried at ambient temperature for several days. Solids were collected by filtration and analyzed by X-ray powder diffraction (XRD). Samples slurried in acetone, THF and toluene produced Form II of the free base as shown by the overlay of the XRD spectra from these experiments as shown in FIG. 4. FIG. 1 shows the XRD pattern of Form II of the free base from recrystallization. Form II of the free base was characterized by an XRD pattern with peaks at about 10.8, 15.3, 15.9, 18.6, and 25.9 2θ±0.2 2θ. Form II of the free base was further characterized by an XRD pattern with peaks at 14.4, 17.8, 20.0, 24.7, and 26.8 2θ±0.2 2θ.

[0079] As shown in FIG. 2, the DSC of Form II of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone free base showed a sharp melting endotherm with an extrapolated onset temperature of 205.2° C. and a peak temperature of 208.7° C. The DSC showed an enthalpy value of 103.9 J / g. The small endothermic drop observed at 190° C. may indicate a phase transformation. Thermogravimetric analysis (TGA) thermograms showed that Form II of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone free base had a loss of about 0.2% by weight at 150° C. and continued to lose weight as shown in FIG. 3. As mentioned above, samples of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone free base of Form I slurried in acetone, THF, and / or toluene (following the method of Example 4) produced XRD patterns similar to Figure 1, which indicated that the XRD pattern of Form II represents a stable form of the free base (Figure 4). This also indicated that the solvent slurry process of making Form II of the free base from amorphous Form I of the free base could alternatively be accomplished using acetone, THF, or toluene.

[0080] Small scale polymorphic salt synthesis: A typical experiment to synthesize polymorphic salts was carried out as follows. The free base of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone was dissolved in methanol (approximately 5 mL), a salt-forming acid solution (0.1 mmol / mL in methanol) was added, and the solution was mixed. The ratio of free base to acid was approximately 1-1.1 molar ratio. Samples were crystallized under a nitrogen purge (approximately 1 psi) at ambient temperature. Isolated samples were examined by XRD. At least hydrochloric, citric, phosphoric, and methanesulfonate salt-forming acids were used to generate the (mono)hydrochloride, citrate, (mono)phosphate, and mesylate salts. These same salts were scaled up for further characterization as required to ensure that the XRD patterns as well as DSC, TGA, and DVS outputs were reproducible.

[0081] Example 2: Scaling up of polymorphic salt synthesis and characterization of the scaled up salts

[0082] The monohydrochloride (referred to elsewhere herein as HCl or hydrochloride), citrate, monophosphate (referred to elsewhere herein as phosphate), and mesylate (ester of methanesulfonic acid) polymorphic salts were selected for scale-up. To facilitate additional testing and to determine reproducibility, salts were prepared on a 200-500 mg scale. A typical procedure is found in Table 1. Solids were recovered by evaporation at ambient conditions with a nitrogen purge at approximately 2 psi. All solids produced the same XRD patterns as seen in prior small-scale experiments and were reproducible.

[0083] [Table 1]

[0084] A salt screening study was conducted to identify suitable polymorphic salts formed by reaction with [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone free base from a library of salt-forming acids as described in Examples 1 and 2. Initially, salt characterization was performed on a small scale (40 mg) with four salts believed to produce the desired polymorph. Small scale synthesis and characterization was performed as described in Example 1. The preferred salts from Example 1 were the hydrochloride, citrate, phosphate, and mesylate salts of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone. Each salt was scaled up and analyzed for crystallinity, thermal properties, water solubility, and hygroscopicity. All polymorphs or salts were contemplated for processability, therapeutic applications, and other factors. The scaled-up salt synthesis is described in this Example and in Table 1 (above) and characterized below.

[0085] Since HCl is a class I salt-forming acid, [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was synthesized to provide a class I salt with reduced safety risks compared to other salt forms. Class I salts form physiologically ubiquitous ions or occur as intermediate metabolites in biochemical pathways, allowing for unrestricted use. [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride formed in Example 2 was crystalline, polymorphic, and had good solubility in unbuffered water (less than 1 mg / mL). This unnamed polymorph of the hydrochloride salt also showed evidence of possible hydrate formation at about 30-40% RH, especially at about 50% RH.

[0086] The XRD pattern of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride salt formed in Examples 1 and 2 showed that the compound was crystalline, as shown in Figure 5. The crystalline polymorphism of the HCl salt formed in Examples 1 and 2 was classified into Forms A, B, C, and D. H , D, E, E1, F H , G HThe polymorphic form does not appear to correlate with any of the other polymorphic forms of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride characterized herein, including (see above and below), H, and I. This crystalline polymorph of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride formed in Examples 1 and 2 is characterized by an XRD pattern having peaks at about 10.8, 13.3, 21.5, 23.1, and 35.2 2θ±0.2 2θ. This crystalline polymorph of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride formed in Examples 1 and 2 is further characterized by an XRD pattern with peaks at 10.5, 14.1, 16.1, and 26.2 2θ±0.2 2θ. The DSC profile exhibited multiple thermal events before the final melting onset endotherm at about 235.7° C., as shown in FIG. 6. The TGA profile showed a continuous loss in weight with a weight loss of about 0.54% to 4.1% from 25° C. to 110° C., as shown in FIG. 7. Hygroscopicity was determined by dynamic vapor sorption (DVS). The DVS data exhibited non-stoichiometric uptake of water as hydrates that could be formed above 30-40% RH (relative humidity) in the composites, as shown in Figure 8, with a total adsorption of approximately 8.8 wt% to 14.9 wt% water at 90% RH.

[0087] [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone citrate had moderate crystallinity and good solubility (approximately 1 mg / mL) in unbuffered water. [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone citrate was polymorphic and showed evidence of possible dihydrate formation at approximately 30-40% RH, especially at 60% RH. The XRD pattern of a small scale citrate salt (synthesized according to Example 1) showed a poorly ordered crystalline solid, as shown in Figure 9. The crystalline polymorph of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone citrate is characterized by an XRD pattern with peaks at about 9.7, 10.7, 15.1, 15.6, and 22.1 2θ±0.2 2θ. The crystalline polymorph of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone citrate is further characterized by an XRD pattern with peaks at 18.6, 19.2, 26.4, and 27.1 2θ±0.2 2θ. The DSC profile showed a small exothermic transition at about 130° C., followed immediately by a broad melting onset endotherm at about 184.5° C., as shown in FIG. 10. The TGA profile showed a weight loss of about 0.38% to 1.13% from 25° C. to 125° C., followed by decomposition, which is shown graphically in FIG.

[0088] [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone phosphate (synthesized according to Example 1) exhibited good crystallinity and good solubility (less than 1 mg / mL) in unbuffered water. The XRD pattern of the crystalline polymorph of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone phosphate exhibited crystallinity with preferred grain orientation, as shown in FIG. 12. The crystalline polymorph of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone phosphate was characterized by an XRD pattern with peaks at about 5.7, 9.3, 12.4, 12.6, and 18.8 2θ±0.2 2θ. The crystalline polymorph of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone phosphate was further characterized by an XRD pattern with peaks at 9.7, 10.9, 11.6, and 20.7 2θ±0.2 2θ. The DSC profile exhibited a loss of volatiles from about 149° C. to 152° C., followed immediately by an exothermic recrystallization at 158.7° C., an onset of melting endotherm at about 216° C. to 219° C., followed by decomposition, as shown in FIG. 13. The TGA profile exhibited a loss of volatiles from 25° C. to 100° C., followed by a continuous loss in weight with a weight loss of about 2.6% to 2.88% due to further decomposition, as shown in FIG. 14.

[0089] [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone mesylate was highly crystalline and had good solubility (less than 1 mg / mL) in unbuffered water. The XRD pattern of the crystalline polymorph of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone mesylate (synthesized according to Example 1) showed a crystalline solid as shown in Figure 15. The crystalline polymorph of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone mesylate is characterized by an XRD pattern with peaks at about 8.3, 9.9, 10.9, 17.5, and 19.9 2θ±0.2 2θ. The crystalline polymorph of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone mesylate is further characterized by an XRD pattern with peaks at 12.1, 18.8, 21.9, 24.5, and 28.2 2θ±0.2 2θ. The DSC profile showed a fairly sharp melting onset endotherm with an extrapolated onset temperature at about 254° C.-265° C., a peak temperature at about 261° C.-268° C., and an enthalpy value of about 96.7 J / g-128.5 J / g, as shown in FIG. 16. The TGA profile showed a weight loss of 0.51% from about 25° C. to 120-150° C., followed by decomposition, as shown in FIG. 17.

[0090] A polymorphic screening of the hydrochloride (HCl) salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone was performed to determine the most thermodynamically stable polymorph of the HCl salt. New polymorphs of the HCl salt were created by recrystallization (Example 3), solvent slurry (Examples 4 and 5) experiments, or as described in Example 6 or elsewhere herein. The resulting samples were characterized using at least X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). Our studies revealed that [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone HCl salt is polymorphic and several solid forms have been created, identified as distinct, and characterized, as described in detail in Examples 3-6.

[0091] Example 3: Polymorphs produced by solvent recrystallization of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride

[0092] Polymorph Screening Overview: Polymorph screening results are provided below for each of polymorphs A-I of the hydrochloride salt of the compound [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone. The process of preparing these polymorphs is discussed below in the polymorph screening or characterization experiments. The objective of the polymorph screening was to make as many crystalline polymorphic forms of the hydrochloride salt as possible, examine their relative stability, and characterize the process by which they can be made. Screening was performed using solvent-based recrystallization followed by X-ray diffraction analysis of the solid state (Example 3). As also discussed herein, polymorph screening by suspension slurry experiments (Examples 4 and 5) was also employed to explore additional solid forms and investigate their relative stability. Detailed characterization of each of the polymorphs is provided in Example 6.

[0093] Solvent Recrystallization: Test materials were recrystallized using a variety of solvents with the scale of the recrystallization experiments being approximately 1-20 mL. Methods used a single and binary array of solvents, as well as saturation temperature, growth temperature, and evaporation rate (relative supersaturation) were criteria that were varied to determine optimal crystal growth conditions. Saturated solutions were prepared by contacting and stirring excess (as much as possible) test material with various solvent systems at saturation temperature. If solids remained in solution, the mother liquor was separated from the remaining solids by filtration. The mother liquor was then heated above the saturation temperature (superheated) to dissolve any remaining solids. The temperature of each solution was then adjusted to the growth temperature and a controlled nitrogen shear flow was introduced to initiate evaporation of the solvent.

[0094] The recrystallization conditions for the four solvent-based panels used during the study are summarized in Table 2. Each recrystallization panel contained between 8 and 18 wells. The wells within each panel contained different solvent compositions. Because each well had a different solvent composition, it served as a different crystal growth experiment.

[0095] [Table 2]

[0096] Table 3 outlines the recrystallization procedures employed (panel column), the solvents used (medium column), and the resulting polymorphic forms (XRD column) that were produced in the solvent-based portion of the polymorph screen. Based on XRD analysis performed on these polymorph screen samples, new polymorphs of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride were produced and characterized. The recrystallization processes in Table 3 produced polymorphs designated as Form A, Form B, Form E, and Form E1.

[0097] [Table 3]

[0098] Based on XRD analysis, new polymorphs of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride were obtained by performing recrystallization as described above. The polymorphs are designated as Form A, Form B, Form E, and Form E1, and are described in detail in Example 6. These polymorphs were prepared as follows.

[0099] The above recrystallization experiments demonstrated multiple processes by which polymorphic forms of the HCl salt can be made to include Form A, Form B, Form E, and Form E1. Form A was made by recrystallization from a 1-propanol / nitromethane binary solvent mixture via the procedure in Panel 4 (Tables 2 and 3). Briefly, [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was dissolved in 1-propanol / nitromethane at saturation concentration at 25° C., heated to 45-50° C., and spun in 1.5 psi N at 40° C. 2 The result provides a facile process for making Form A of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride.

[0100] Form B was also made by recrystallization from a methanol / acetonitrile binary solvent mixture via the procedure in Panel 4 (Tables 2 and 3). Briefly, [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was dissolved in methanol / acetonitrile at saturation concentration at 25° C., heated to 45-50° C., and recrystallized in 1.5 psi N at 40° C. 2 The solution was evaporated rapidly under reflux. The results provided a facile process for making Form B of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride.

[0101] Form E was made by recrystallization from 2-propanol via the procedure in Panel 1 (Tables 2 and 3). Briefly, [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was dissolved in 2-propanol at saturation concentration at 25° C., heated to 45-50° C., and resuspended in 1.5 psi N at ambient temperature. 2 Form E was also made by recrystallization from 1-propanol / dioxane binary solvent mixture via the procedure in Panel 3 (Tables 2 and 3). Briefly, [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was dissolved in 1-propanol / dioxane at saturation concentration at 25° C. and allowed to slowly evaporate at ambient temperature. Form E was also made by recrystallization from ethanol via the procedure in Panel 4 (Tables 2 and 3). Briefly, [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was dissolved in ethanol at saturation concentration at 25° C. and allowed to evaporate rapidly under a stream of water at 1.5 psi N at 40° C. 2 The above results provided three facile processes for making form E of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride. Form E1 differed only slightly from Form E in some peaks within the 10-12° 2θ region of their XRD patterns, suggesting very similar physical properties. Form E1 was prepared by recrystallization from a 2-propanol / dichloromethane binary solvent mixture via the procedure in Panel 4 (Tables 2 and 3). Briefly, [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was dissolved in 2-propanol / dichloromethane at saturation concentration at 25°C, heated to 45-50°C, and recrystallized in 1.5 psi N at 40°C. 2Form E1 was also made by recrystallization from a 2-propanol / trichloromethane binary solvent mixture via the procedure in Panel 4 (Tables 2 and 3). Briefly, [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was dissolved in 2-propanol / trichloromethane at saturation concentration at 25 °C, heated to 45-50 °C, and diluted with 1.5 psi N at 40 °C. 2 The above results provided three facile processes for making [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride form E1.

[0102] Example 4: Polymorphs generated via non-competitive slurry experiments of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride

[0103] In addition to the solvent recrystallization experiment (Example 3), non-competitive slurry (Example 4) and competitive slurry (Example 5) were carried out to create new solid forms. Non-competitive slurry experiments were carried out to search for new solid forms. These experiments relied on the difference in solubility of different polymorphic forms (if the compound is polymorphic). Therefore, only polymorphs with lower solubility (more stable) than the original crystalline form can result from non-competitive slurry experiments.

[0104] Essentially, when a solid is mixed with a solvent or solvents as a slurry (a solid suspended in a liquid), a saturated solution is obtained. The solution is saturated with respect to the dissolved polymorphic form. However, the solution is supersaturated with respect to any polymorphic form that is more stable (the more stable form has a lower solubility) than the initially dissolved polymorphic form. Thus, any of the more stable polymorphic forms may nucleate and precipitate from the solution. Furthermore, non-competitive slurry experiments are often useful to identify solvents that form solvates with a compound.

[0105] Slurry experiments were performed by exposing excess starting material (Form B in all cases in this experiment) to pure single and binary solvent systems and stirring the resulting suspensions at ambient temperature for several days. Solids were vacuum filtered and analyzed by XRD to determine the resulting form. Samples were not further dried prior to X-ray analysis to avoid possible desolvation or physical changes after isolation. A summary of the non-competitive slurry experiments in single and binary solvent systems is shown in Tables 4 and 5 (below).

[0106] [Table 4]

[0107] The XRD patterns of samples from the single solvent systems in methanol or ethanol slurries after 14 days were different from each other and from the starting material. Both of these were solvates that were not studied further (Table 4). The solid slurried in water produced a diffraction pattern indicative of very low order crystallinity. Samples from acetone and acetonitrile slurries after 14 days gave XRD patterns different from the starting material. This new form was designated Form D (Table 4). The remaining slurry experiments in tetrahydrofuran (THF), methylene chloride, ethyl acetate, toluene, and heptane did not result in significant changes to the starting polymorphic form (Form B) based on X-ray scattering behavior after 14 days of treatment.

[0108] As described in Table 4, a process to make form D was observed in these non-competitive slurry experiments where form B was slurried in the non-aqueous solvent acetone for 14 days. Briefly, excess form B was added to pure acetone until saturation. The resulting suspension was stirred at ambient temperature for 14 days. The solid was vacuum filtered and analyzed by XRD to determine that form D was made. To avoid possible desolvation or physical changes after isolation, the sample was not further dried before X-ray analysis. As described in Table 4, a process to make form D was observed in these non-competitive slurry experiments where form B was slurried in the non-aqueous solvent acetonitrile for 14 days. Briefly, excess form B was added to pure acetonitrile until saturation. The resulting suspension was stirred at ambient temperature for 14 days. The solid was vacuum filtered and analyzed by XRD to determine that form D was made. To avoid possible desolvation or physical changes after isolation, the sample was not further dried before X-ray analysis. These observations provide a process by which form D of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride may be made. The data suggests that form D is more stable than form B in some solvent systems.

[0109] [Table 5]

[0110] XRD patterns of samples from binary solvent systems methanol / water, methanol (MeOH) / acetone, and trifluoroethanol (TFE) / ethyl acetate (EtOAc) slurry after 11 days gave patterns with low crystallinity (Table 5). Sample from methanol / dichloromethane (DCM) produced a different XRD pattern than the starting material and was grouped as a solvate. Slurry samples from ethanol / toluene, acetonitrile (ACN) / acetone, ethanol / acetonitrile, 1-propanol / ethyl acetate (EtOAc), and 2-propanol / tetrahydrofuran (THF) had different XRD patterns than the starting material and were ultimately designated as Form E1 (Table 5). Combination of trifluoroethanol (TFE) / dichloride methane (DCM) slurry experiments did not result in significant changes to the starting polymorphic form (Form B) based on X-ray scattering behavior after 11 days of treatment.

[0111] Form E1 was generated from non-competitive slurry experiments starting from Form B incubated in five different binary solvent systems (see rows 3, 5, and 7-9 of Table 5 in Example 4). As described in Table 5, a process to make Form E1 was observed in these non-competitive slurry experiments where Form B was slurried in a non-aqueous binary solvent system of ethanol / toluene for 11 days. Briefly, excess Form B was added to an ethanol / toluene mixture until saturation. The resulting suspension was stirred at ambient temperature for 11 days. The solid was vacuum filtered and analyzed by XRD to determine that Form E1 was made. To avoid possible desolvation or physical changes after isolation, the samples were not further dried prior to X-ray analysis. As described in Table 5, a different process to make Form E1 was observed in these non-competitive slurry experiments where Form B was slurried in a non-aqueous binary solvent system of acetonitrile (ACN) / acetone for 11 days. Briefly, excess form B was added to an acetonitrile (ACN) / acetone mixture until saturation. The resulting suspension was stirred at ambient temperature for 11 days. The solid was vacuum filtered and analyzed by XRD to determine that form E1 was produced. To avoid possible desolvation or physical changes after isolation, the sample was not further dried before X-ray analysis. As described in Table 5, a different process for producing form E1 was observed in these non-competitive slurry experiments where form B was slurried in a non-aqueous binary solvent system of ethanol / acetonitrile for 11 days. Briefly, excess form B was added to an ethanol / acetonitrile mixture until saturation. The resulting suspension was stirred at ambient temperature for 11 days. The solid was vacuum filtered and analyzed by XRD to determine that form E1 was produced. To avoid possible desolvation or physical changes after isolation, the sample was not further dried before X-ray analysis. An alternative process for making Form E1 was observed in these non-competitive slurry experiments in which Form B was slurried in a non-aqueous binary solvent system of 1-propanol / ethyl acetate (EtOAc) for 11 days, as described in Table 5. Briefly, excess Form B was added to a 1-propanol / ethyl acetate (EtOAc) mixture until saturation. The resulting suspension was stirred at ambient temperature for 11 days.The solid was vacuum filtered and analyzed by XRD to determine that Form E1 was produced. To avoid possible desolvation or physical changes after isolation, the sample was not further dried before X-ray analysis. As described in Table 5, a different process for producing Form E1 was observed in these non-competitive slurry experiments in which Form B was slurried in a non-aqueous binary solvent system of 2-propanol / tetrahydrofuran (THF) for 11 days. Briefly, excess Form B was added to a 2-propanol / tetrahydrofuran (THF) mixture until saturation. The resulting suspension was stirred at ambient temperature for 11 days. The solid was vacuum filtered and analyzed by XRD to determine that Form E1 was produced. To avoid possible desolvation or physical changes after isolation, the sample was not further dried before X-ray analysis. These data demonstrated that form E1 was more stable than form B in many solvent systems and supported form E1 (forms E and E1) as the relatively stable polymorph of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride compared to form B.

[0112] Example 5: Polymorphs generated via competitive slurry experiments of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride

[0113] In addition to the solvent recrystallization and non-competitive slurry experiments, competitive slurry experiments were performed to generate new polymorphs and to determine the most stable polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride. The experiments relied on the difference in solubility of the different polymorphic forms. Therefore, only polymorphic forms (and solvates) that have a lower solubility (more stable) than the initially dissolved form can result from the competitive slurry experiments. In essence, dissolving a solid in a (slurry) solvent eventually produces a saturated solution. The solution is saturated with respect to the dissolved polymorphic form. However, the solution is supersaturated with respect to any polymorphic form that is more stable (the more stable form has a lower solubility) than the initially dissolved polymorphic form. Thus, any of the more stable polymorphic forms can nucleate and precipitate from the solution. Additionally, competitive slurry experiments are often useful to identify solvents that form solvates with an active pharmaceutical ingredient (API).

[0114] Slurry experiments were performed by exposing excess material of the two (polymorphic) forms to a small amount of pure solvent and stirring the resulting suspension at ambient temperature for several days. The solids were filtered and analyzed by XRD to determine the resulting form. Samples were not dried prior to X-ray analysis to avoid possible desolvation or physical changes after isolation. Table 6 contains the results of these competitive slurry experiments.

[0115] [Table 6]

[0116] Form E was produced when Form B and Form D were co-incubated in 1-propanol for about 2 weeks, indicating the relative stability of Form E compared to Form B or Form D (Table 6, row 5). Briefly, excess Form B and Form D were added to pure 1-propanol until saturation. The resulting suspension was stirred at ambient temperature for about 2 weeks. The solid was vacuum filtered and analyzed by XRD to determine that Form E was produced. To avoid possible desolvation or physical changes after isolation, the sample was not further dried prior to X-ray analysis. Form E was also produced when Form A and Form B were co-incubated in 1-propanol for about 2 weeks (Table 6, row 9). Briefly, excess Form A and Form B were added to pure 1-propanol until saturation. The resulting suspension was stirred at ambient temperature for about 2 weeks. The solid was vacuum filtered and analyzed by XRD to determine that Form E was produced. The samples were not further dried prior to X-ray analysis to avoid possible desolvation or physical changes after isolation. The data suggested that Form E is relatively stable compared to Forms A, B, and D. This is consistent with data from recrystallization experiments in which Form E (and Form E1) were generated from multiple solvent systems, and noncompetitive slurry experiments in which Form E1 was generated from Form B in multiple binary solvent systems.

[0117] Form E1 differs only slightly from Form E in some peaks within the 10-12° 2θ region of their XRD patterns, suggesting very similar physical properties. The data in this example suggested that Form E1 is more stable than Form E, but their physical properties are expected to be similar. Form E1 is a soluble form of Form A, Form B, and Form C. H Forms E1 were generated from competitive slurry experiments (Example 5) described in rows 7 and 10-12 of Table 6, which included binary combinations of Forms C, D, and E, suggesting that Form E1 is relatively stable compared to these other forms. H and form B were produced when co-incubated in 1-propanol for approximately 2 weeks (Table 6, row 7). Hand Form B were added to pure 1-propanol until saturated. The resulting suspension was stirred at ambient temperature for about 2 weeks. The solid was vacuum filtered and analyzed by XRD to determine that Form E1 was produced. To avoid possible post-isolation desolvation or physical changes, the sample was not further dried before X-ray analysis. Form E1 was also produced when Form A and Form D were co-incubated in 1-propanol for about 2 weeks (Table 6, row 10). Briefly, excess Form A and Form D were added to pure 1-propanol until saturated. The resulting suspension was stirred at ambient temperature for about 2 weeks. The solid was vacuum filtered and analyzed by XRD to determine that Form E1 was produced. To avoid possible post-isolation desolvation or physical changes, the sample was not further dried before X-ray analysis. Form E1 was also produced when Form B and Form E were co-incubated in 1-propanol for about 2 weeks (Table 6, row 11). Briefly, excess forms B and E were added to pure 1-propanol until saturation. The resulting suspension was stirred at ambient temperature for approximately 2 weeks. The solid was vacuum filtered and analyzed by XRD to determine that form E1 was produced. To avoid possible desolvation or physical changes after isolation, the sample was not further dried before X-ray analysis. Form E1 was also produced when forms D and E were co-incubated in 1-propanol for approximately 2 weeks (Table 6, row 12). Briefly, excess forms D and E were added to pure 1-propanol until saturation. The resulting suspension was stirred at ambient temperature for approximately 2 weeks. The solid was vacuum filtered and analyzed by XRD to determine that form E1 was produced. To avoid possible desolvation or physical changes after isolation, the sample was not further dried before X-ray analysis.

[0118] Recrystallization (Example 3) and non-competitive slurry (Example 4) polymorph screening experiments suggested that Forms E and E1 were the most stable forms produced in those experiments. However, samples of Forms E or E1 kept at ambient conditions converted to Form H, suggesting that Form H was more stable than either Forms E or E1. To test this hypothesis, a competitive slurry experiment (Example 5) was performed to demonstrate that Form H was rapidly and completely converted from Form E to Form H.

[0119] Form H was synthesized by competitively slurrying Form E and Form H in 2-butanol or 2-propanol for 1 day (Table 6, rows 13 and 14). In one embodiment, Form H was generated when Form E and Form H were co-incubated in 2-propanol for 1 day (Table 6, row 13). Briefly, excess Form E and Form H were added to pure 2-propanol until saturation. The resulting suspension was stirred at ambient temperature for 1 day. The solid was vacuum filtered and analyzed by XRD to determine that Form H was produced. To avoid possible desolvation or physical changes after isolation, the sample was not further dried prior to X-ray analysis. In another experiment, Form H was generated when Form E and Form H were co-incubated in 2-butanol for 1 day (Table 6, row 14). Briefly, excess Form E and Form H were added to pure 2-butanol until saturation. The resulting suspension was stirred at ambient temperature for 1 day. The solids were vacuum filtered and analyzed by XRD to determine that form H had been produced. Samples were not further dried prior to X-ray analysis to avoid possible desolvation or physical changes after isolation. These rapid 1 day conversions to produce form H in Table 6, compared to 11 days or about 14 days for other slurry conversions, suggested that form H is relatively stable compared to form E. Initial slurry experiments (all samples except the last two in Table 6) showed that form E or E1 were the most stable forms observed during the study, with their physical properties being similar. However, competitive slurries of forms E and H in two different solvents showed that form H is more stable than form E (and possibly form E1 as well). Further evidence supporting that Form H was more stable than Form E or Form E1 is provided in Example 6, where differential scanning calorimetry (DSC) thermograms showed a higher melting point for Form H (a sharp, high enthalpy endotherm with an onset of 247.4° C., a peak maximum of 250.1° C., and an enthalpy of melting of 158.0 J / g (FIG. 45)) compared to Forms E and E1 (broad melting onset endotherms at approximately 239.5° C. and 243.2° C., respectively, and a relatively low enthalpy of melting followed immediately by decomposition (FIGS. 32 and 34, respectively)).Additionally, large scale Form H is produced by seeding a small amount of Form H into the process of producing Form E. Based on competitive slurry and DSC experiments, Form H is predicted to be the thermodynamically stable form.

[0120] Example 6: Characterization of polymorphs of the HCl salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone by XRD, DSC, TGA, DVS etc. This part of the report summarizes the polymorphs produced in a polymorph screening study conducted on [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride. Polymorphism is the ability of a chemical substance to exist in different three-dimensional arrangements in the solid state. Different polymorphic forms of a compound can have different physical properties. The overall objective of this effort was to screen [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride for polymorphic behavior. The screen was designed to prepare as many novel crystalline forms as possible and characterize these polymorphs for use in pharmaceutical products. The screen was performed using solvent recrystallization under a variety of conditions as well as competitive and noncompetitive slurry experiments to manipulate the solid form of the test substance.

[0121] Samples generated during the study were characterized using differential scanning calorimetry (DSC), polarized light microscopy, thermogravimetric analysis (TGA), X-ray powder diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), and dynamic vapor sorption (DVS). Polymorph screening revealed that [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride is polymorphic, and several solid forms were prepared and characterized. Of these, the first stable form prepared was Form E1, which was very similar to Form E. These were essentially the same, except for minor changes in the diffraction pattern and DSC thermogram. Form H was prepared from samples of Form E or Form E1 stored at ambient conditions. Form H was characterized as a stable crystalline polymorph and was more stable than Form E in competitive slurry experiments. When Form E and / or Form E1 were subsequently prepared on a kilogram scale, the conversion of Form E or Form E1 to Form H was observed to be rapid and complete due to the presence of seed crystals of Form H (Example 7), confirming that Form H is a thermodynamically stable polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride.

[0122] From the scale-up of the salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone (Example 2), the hydrochloride salt was selected for further study. The HCl salt was characterized as being polymorphic as multiple polymorphic forms were produced and characterized as described below. Form A, Form B, Form C of the HCl salt. H , Form D, Form E, Form E1, Form F H , form G H Form H, and Form I were prepared and characterized as follows and are summarized in Table 7. Each polymorphic form was studied to determine differentiation based on diffraction behavior. Characterization of each hydrochloride salt polymorphic form began with X-ray powder diffraction (XRD) data comparison of each form to the others. This was typically followed by DSC and TGA analysis. Table 7 below summarizes the various forms prepared during the study.

[0123] [Table 7]

[0124] Forms A and B were made from recrystallization as described in Example 3. Forms D, E, E1, and H were made by recrystallization (Example 3), non-competitive slurry (Example 4), and / or competitive slurry (Example 5) experiments. Form F H , form G H Form H, and Form I were produced in samples held at room temperature. The process for producing Form H involves competitive slurry of Form E in 2-butanol or 2-propanol as described in Example 5, or seeding of Form H crystals into the synthesis of other polymorphic forms of the HCl salt, including Form E and Form E1 (Example 7).

[0125] [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride Form A (Form A) was prepared by recrystallization from a 1-propanol / nitromethane binary solvent mixture via the procedure of Panel 4 of Example 3 (Tables 2 and 3). Briefly, [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was dissolved in 1-propanol / nitromethane at saturation concentration at 25° C., heated to 45-50° C. to dissolve the solid, and recrystallized at 1.5 psi N at 40° C. 2The solid form A was formed by rapid evaporation under a stream of water to produce a solid form A. Form A had a reproducible powder pattern and an XRD pattern indicating it was crystalline, as shown in FIG. 35. Form A was characterized by an XRD pattern with peaks at about 9.6, 12.0, 19.2, 23.6, and 24.4 2θ±0.2 2θ. Form A was further characterized by an XRD pattern with peaks at 16.3, 18.1, and 28.9 2θ±0.2 2θ. TGA demonstrated that form A was free of volatiles with a weight loss of about 0.04% from 25° C. to 150° C., as shown in FIG. 36. The DSC thermogram of form A exhibited a melting onset endotherm with a mean onset of about 250.3° C., as shown in FIG. 37. These thermal events were attributed to the melting and decomposition behavior of the form. A dynamic vapor sorption (DVS) plot of Form A indicates that the material is very hydrophobic and appears to be prone to hydrate formation. A total weight gain of about 0.4% at 90% RH was observed (not shown).

[0126] [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride Form B (Form B) was prepared by recrystallization from a methanol / acetonitrile binary solvent mixture via the procedure of Panel 4 of Example 3 (Tables 2 and 3). Briefly, [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was dissolved in methanol / acetonitrile at saturation concentration at 25° C., heated to 45-50° C. to dissolve any solids, and recrystallized at 1.5 psi N at 40° C. 2Rapid evaporation under a stream of water produced Form B. Form B was stable (i.e., unchanged) in non-competitive slurry experiments (Example 4, Tables 4 and 5), suggesting that it is stable in many single solvents, including tetrahydrofuran (THF), ethyl acetate, methylene chloride, toluene, and heptane, as well as in the trifluoroethanol (TFE) / dichloromethane (DCM) binary solvent mixture. In non-competitive slurry experiments, Form B was converted to Form D only in acetone or acetonitrile (Table 4). Additionally, as noted in Table 6 (row 4) of Example 5, Form B was converted to Form C in ethyl acetate. H and Form B by competitive slurrying, which shows the relative strength of Form C compared to Form B. H In brief, the relative stability of the excess of form C H and Form B were added to pure ethyl acetate until saturated. The resulting suspension was stirred at ambient temperature for approximately 2 weeks. The solid was vacuum filtered and analyzed by XRD to determine that Form B had been produced. The sample was not further dried prior to X-ray analysis to avoid possible desolvation or physical changes after isolation. Form B had diffraction properties distinct from other polymorphic forms. The XRD pattern of Form B, as shown in FIG. 18, had a reproducible powder pattern and was shown to be crystalline. Form B was characterized by an XRD pattern with peaks at approximately 9.5, 12.1, 18.0, 18.9, and 23.0 2θ±0.2 2θ. Form B was further characterized by an XRD pattern with peaks at 19.2, 28.5, 29.5, and 31.8 2θ±0.2 2θ. The TGA thermogram demonstrated that Form B exhibited an average weight loss of less than 0.05% at 150° C., as shown in FIG. 19. The DSC thermogram of Form B exhibited a sharp melting onset endotherm with an average onset of about 247.4° C., as shown in FIG. 20. These thermal events were attributed to the melting and decomposition behavior of the form. The solid-state FT-IR spectrum of Form B is shown in FIG. 21. This form appeared to be a metastable form of the HCl salt.

[0127] [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride Form C H is the hydrate (form C) formed in the sample kept at room temperature. H ) Form C H The XRD pattern of Form C was crystalline, as shown in FIG. H was characterized by an XRD pattern having peaks at about 5.1, 13.1, 16.6, 22.5, and 25.7 2θ±0.2 2θ. Form C H was further characterized by an XRD pattern with peaks at 10.3, 18.0, 23.7, 28.7, and 29.7 2θ±0.2 2θ. TGA confirmed Form C, as shown in FIG. H demonstrated a weight loss of about 5.3% at 150° C., which corresponds approximately to the loss of one mole of water from the crystal lattice. H The DSC thermogram of Form C exhibited a large, broad endotherm with an onset of about 152.7° C., which may be due to loss of residual water. This was followed by a broad exotherm at about 200° C. and a broad endothermic melt with an extrapolated onset of 233.8° C., followed by decomposition, as shown in FIG. 24. H DVS scan of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride form C showed moisture adsorption-desorption isotherm and kinetic plot. H revealed very low uptake of water adsorption, likely due to the dry portion of the DVS scan being insufficient to remove the original moles of water found in the crystal structure (not shown). The monohydrate sample uptakes up to 0.95 wt % at high humidity and then returns to its starting mass upon completion of the scan (not shown).

[0128] [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride form D (form D) was first prepared in non-competitive slurry experiments where form B was slurried in either the non-aqueous solvent acetone or acetonitrile for 14 days, as described in Table 4 of Example 4. In these non-competitive slurry experiments where form B was slurried in the non-aqueous solvent acetone for 14 days, as described in Table 4 of Example 4, the process of preparing form D was observed. Briefly, excess form B was added to pure acetone until saturation. The resulting suspension was stirred at ambient temperature for 14 days. The solid was vacuum filtered and analyzed by XRD to determine that form D was prepared. To avoid possible desolvation or physical changes after isolation, the sample was not further dried prior to X-ray analysis. As described in Table 4 of Example 4, in these non-competitive slurry experiments, where form B was slurried in the non-aqueous solvent acetonitrile for 14 days, another process for making form D was observed. Briefly, excess form B was added to pure acetonitrile until saturation. The resulting suspension was stirred at ambient temperature for 14 days. The solid was vacuum filtered and analyzed by XRD to determine that form D was made. To avoid possible desolvation or physical changes after isolation, the sample was not further dried prior to X-ray analysis. These observations provide a process by which form D of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride may be made. The data suggests that form D was more stable than form B in some solvent systems. The XRD pattern of form D showed a clear crystalline powder pattern, as shown in FIG. 25. Form D was characterized by an XRD pattern with peaks at about 9.4, 15.1, 17.3, 22.1, and 23.2 2θ±0.2 2θ. Form D was further characterized by an XRD pattern with peaks at 10.5, 18.1, 22.8, 24.8, and 30.3 2θ±0.2 2θ. The TGA thermogram showed a weight loss of about 0.13% at 150° C. and a continued weight loss at higher temperatures, as shown in FIG.The DSC thermogram of Form D exhibited a small, broad solid-solid phase transition endotherm with an onset of about 144.2° C., a peak temperature of about 156° C. and an enthalpy of about 8.1 J / g, followed by a melting endotherm with an extrapolated onset of 244.6° C. and a peak temperature of 250.7° C., followed by decomposition, as shown in Figure 27. The solid-state FT-IR spectrum of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride Form D is shown in Figure 28.

[0129] [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride form E (form E) and E1 (form E1) were relatively stable forms as noted by their synthesis in competitive slurry experiments starting from form B (Table 6, Example 5). In one embodiment, form E was produced when form B and form D were co-incubated in 1-propanol for about 2 weeks, indicating the relative stability of form E compared to forms B and D (Table 6, row 5). Briefly, excess forms B and D were added to pure 1-propanol until saturation. The resulting suspension was stirred at ambient temperature for about 2 weeks. The solid was vacuum filtered and analyzed by XRD to determine that form E was produced. To avoid possible desolvation or physical changes after isolation, the sample was not further dried prior to X-ray analysis. In another embodiment, form E was produced when form A and form B were co-incubated in 1-propanol for about 2 weeks (Table 6, row 9). Briefly, excess form A and form B were added to pure 1-propanol until saturation. The resulting suspension was stirred at ambient temperature for about 2 weeks. The solid was vacuum filtered and analyzed by XRD to determine that form E was produced. To avoid possible desolvation or physical changes after isolation, the sample was not further dried prior to X-ray analysis. Overall, the data suggested that form E is relatively stable compared to forms A, B, and D. This is consistent with data from recrystallization experiments where form E (and form E1) were produced from multiple solvent systems.

[0130] Form E was also made by three different recrystallization processes including 2-propanol, 1-propanol / 1-dioxane mixture, or ethanol. In one embodiment, Form E was made by recrystallization from 2-propanol via the procedure in Example 3, Panel 1 (Tables 2 and 3). Briefly, [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was dissolved in 2-propanol at saturation concentration at 25° C., heated to 45-50° C. to dissolve the solid, and recrystallized in 1.5 psi N at ambient temperature. 2 Form E was produced by rapid evaporation under a stream of water. In another embodiment, Form E was produced by recrystallization from a 1-propanol / dioxane binary solvent mixture via the procedure in Panel 3 of Example 3 (Tables 2 and 3). Briefly, [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was dissolved in 1-propanol / dioxane at saturation concentration at 25° C. and the solvent was allowed to slowly evaporate at ambient temperature to produce Form E. In another embodiment, Form E was produced by recrystallization from ethanol via the procedure in Panel 4 of Example 3 (Tables 2 and 3). Briefly, [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was dissolved in ethanol at saturation at 25 °C, heated to 45-50 °C to dissolve any solids, and the solvent was diluted with N at 1.5 psi at 40 °C. 2 Rapid evaporation under stream produced Form E.

[0131] Form E1 differs only slightly from Form E in some peaks within the 10-12° 2θ region of their XRD patterns, suggesting very similar physical properties. Overall, Form E1 exhibits excellent solubility compared to Forms A, B, and C, as evidenced by the results of noncompetitive (only Form B) and competitive (all forms) slurry experiments. H , Form D, and Form E.

[0132] Form E1 was made by two different recrystallization processes from 2-propanol / dichloromethane and 2-propanol / trichloromethane. In one embodiment, Form E1 was made by recrystallization from a 2-propanol / dichloromethane binary solvent mixture via the procedure in Panel 4 of Example 3 (Tables 2 and 3). Briefly, [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was dissolved in 2-propanol / dichloromethane at saturation concentration at 25° C., heated to 45-50° C. to dissolve the solid, and recrystallized in 1.5 psi N at 40° C. 2 Form E1 was prepared by rapid evaporation under a stream of water. In another embodiment, Form E1 was prepared by recrystallization from a 2-propanol / trichloromethane binary solvent mixture via the procedure of Example 3, Panel 4 (Tables 2 and 3). Briefly, [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was dissolved in 2-propanol / trichloromethane at saturation concentration at 25° C., heated to 45-50° C. to dissolve the solid, and then recrystallized under 1.5 psi N at 40° C. 2 Rapid evaporation under flow produced Form E1.

[0133] Form E1 was made from a non-competitive slurry experiment starting from Form B incubated in five different binary solvent systems (see rows 3, 5, and 7-9 of Table 5 in Example 4). In one embodiment, Form E1 was made by a non-competitive slurry experiment in which Form B was slurried in a non-aqueous binary solvent system of ethanol / toluene for 11 days. Briefly, an excess of Form B was added to the ethanol / toluene mixture until saturation. The resulting suspension was stirred at ambient temperature for 11 days. The solid was vacuum filtered and analyzed by XRD to determine that Form E1 was made. To avoid possible desolvation or physical changes after isolation, the sample was not further dried prior to X-ray analysis. In another embodiment, Form E1 was made by a non-competitive slurry experiment in which Form B was slurried in a non-aqueous binary solvent system of acetonitrile (ACN) / acetone for 11 days. Briefly, an excess of Form B was added to the acetonitrile (ACN) / acetone mixture until saturation. The resulting suspension was stirred at ambient temperature for 11 days. The solid was vacuum filtered and analyzed by XRD to determine that Form E1 was produced. The sample was not further dried prior to X-ray analysis to avoid possible post-isolation desolvation or physical changes. In another embodiment, Form E1 was produced by a non-competitive slurry experiment in which Form B was slurried in a non-aqueous binary solvent system of ethanol / acetonitrile for 11 days. Briefly, excess Form B was added to an ethanol / acetonitrile mixture until saturation. The resulting suspension was stirred at ambient temperature for 11 days. The solid was vacuum filtered and analyzed by XRD to determine that Form E1 was produced. The sample was not further dried prior to X-ray analysis to avoid possible post-isolation desolvation or physical changes. In another embodiment, Form E1 was produced by a non-competitive slurry experiment in which Form B was slurried in a non-aqueous binary solvent system of 1-propanol / ethyl acetate (EtOAc) for 11 days. Briefly, excess Form B was added to a 1-propanol / ethyl acetate (EtOAc) mixture until saturation. The resulting suspension was stirred at ambient temperature for 11 days. The solid was vacuum filtered and analyzed by XRD to determine that Form E1 was produced.To avoid possible desolvation or physical changes after isolation, the sample was not further dried before X-ray analysis. In another embodiment, Form E1 was made by a non-competitive slurry experiment in which Form B was slurried in a non-aqueous binary solvent system of 2-propanol / tetrahydrofuran (THF) for 11 days. Briefly, excess Form B was added to a 2-propanol / tetrahydrofuran (THF) mixture until saturation. The resulting suspension was stirred at ambient temperature for 11 days. The solid was vacuum filtered and analyzed by XRD to determine that Form E1 was made. To avoid possible desolvation or physical changes after isolation, the sample was not further dried before X-ray analysis. These data in Example 4 demonstrated that form E1 was more stable than form B in many binary solvent systems and supported form E1 as the relatively stable polymorph of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride compared to form B.

[0134] Form E1 also contains Forms A, B, and C co-incubated in 1-propanol for approximately two weeks, as described in rows 7 and 10-12 of Table 6 in Example 5. H The data was generated from four different competitive slurry experiments involving binary combinations of Form E1, Form D, and Form E. The data demonstrated increased stability of Form E1 compared to these other forms. In one embodiment, Form E1 is Form C. H and Form B were produced when co-incubated in 1-propanol for approximately 2 weeks (Table 6, row 7). Hand Form B were added to pure 1-propanol until saturated. The resulting suspension was stirred at ambient temperature for about 2 weeks. The solid was vacuum filtered and analyzed by XRD to determine that Form E1 was produced. To avoid possible desolvation or physical changes after isolation, the sample was not further dried before X-ray analysis. In another embodiment, Form E1 was produced when Form A and Form D were co-incubated in 1-propanol for about 2 weeks (Table 6, row 10). Briefly, excess Form A and Form D were added to pure 1-propanol until saturated. The resulting suspension was stirred at ambient temperature for about 2 weeks. The solid was vacuum filtered and analyzed by XRD to determine that Form E1 was produced. To avoid possible desolvation or physical changes after isolation, the sample was not further dried before X-ray analysis. In another embodiment, Form E1 was produced when Form B and Form E were co-incubated in 1-propanol for about 2 weeks (Table 6, row 11). Briefly, excess forms B and E were added to pure 1-propanol until saturation. The resulting suspension was stirred at ambient temperature for about 2 weeks. The solid was vacuum filtered and analyzed by XRD to determine that form E1 was produced. To avoid possible desolvation or physical changes after isolation, the sample was not further dried before X-ray analysis. In another embodiment, form E1 was produced when form D and form E were co-incubated in 1-propanol for about 2 weeks (Table 6, row 12). Briefly, excess forms D and E were added to pure 1-propanol until saturation. The resulting suspension was stirred at ambient temperature for about 2 weeks. The solid was vacuum filtered and analyzed by XRD to determine that form E1 was produced. To avoid possible desolvation or physical changes after isolation, the sample was not further dried before X-ray analysis. In some embodiments, form E and form E1 are discussed together as apparently stable polymorphs. The data in this example may be interpreted as indicating that form E1 is more stable than form E, although their physical properties are expected to be roughly similar. There is no data to support that form E or form E1 are more stable than form H, which is believed to be the most stable polymorph.

[0135] The XRD patterns of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride forms E and E1, which show crystalline nature, are shown in Figures 29 and 30, respectively. The two diffraction patterns appear very similar except for slight differences between the two patterns in the 10-12° 2θ region. Form E was characterized by an XRD pattern with peaks at approximately 9.4, 17.3, 22.1, 23.4, and 24.8 2θ ± 0.2 2θ. Form E was further characterized by an XRD pattern with peaks at 12.9, 15.0, 18.1, 21.0, and 30.3 2θ ± 0.2 2θ. Form E1 was characterized by an XRD pattern with peaks at about 9.4, 10.9, 17.3, 22.1, and 23.2 2θ±0.2 2θ. Form E1 was further characterized by an XRD pattern with peaks at 13.0, 15.1, 18.1, 20.9, and 24.8 2θ±0.2 2θ. The TGA thermogram of Form E exhibited a weight loss of about 0.66% at 150° C., as shown in FIG. 31. The DSC thermogram of Form E exhibited an onset melting endotherm at about 239.6° C., followed immediately by a large broad decomposition with an unstable baseline, as shown in FIG. 32. The solid-state FT-IR spectrum of Form E is shown in FIG. 33. The DSC thermogram of Form E exhibited an onset melting endotherm at about 243.2° C., followed immediately by a large broad decomposition with an unstable baseline, as shown in FIG. 34. The slightly higher temperature endotherm of Form E1 compared to Form E also suggests a slightly greater stability of Form E1, which is consistent with the slurry experiments described above.

[0136] [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride Form F H (Form F H ) has diffraction properties different from the other polymorphic forms and was produced in samples kept at room temperature. H was not observed in polymorph screening attempts. Form F HForm F had a reproducible powder pattern and an XRD pattern indicative of being crystalline and a hydrate, as shown in Figure 38. H Form F was characterized by an XRD pattern having peaks at about 9.06, 10.4, 18.85, 25.48, and 27.97 2θ±0.2 2θ. H Form F was further characterized by an XRD pattern with peaks at 12.9, 20.9, and 26.14 2θ±0.2 2θ. H The DSC thermogram of Form F showed a larger split endotherm with an onset of about 90.8° C. and a peak maximum of 99.7° C. H The KF moisture content of Form F was 14% by weight (not shown). H The solution NMR spectrum of was consistent with the expected structure of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride (not shown).

[0137] [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride form G H (Form G polymorphism H ) has diffraction properties different from the other forms, was prepared in samples kept at room temperature, and was assigned as a hydrate. H The XRD pattern of Form G was shown to be moderately crystalline with a reproducible powder pattern, as shown in FIG. H was characterized by an XRD pattern having peaks at about 11.8, 14.5, 16.8, 23.1, and 28.5 2θ±0.2 2θ. Form G H was further characterized by an XRD pattern with peaks at 10.4, 22.3, 24.7, and 25.3 2θ±0.2 2θ. The TGA thermogram indicated Form G H Form G demonstrated an average weight loss of 4.8% at 150° C., as shown in FIG. HThe DSC thermogram of Form G exhibited two endotherms with extrapolated onsets at 140.5° C. and 246.5° C., as shown in FIG. H The KF moisture content was 4.4% by weight (not shown).

[0138] [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride form H (form H) was produced in samples of form E and form E1 kept at ambient conditions and was designated as the dry polymorphic form. Form H was also produced by competitively slurrying form E and form H in 2-butanol or 2-propanol for 1 day (Table 6, rows 13 and 14 in Example 5), which suggested that form H was relatively stable compared to form E. In one embodiment, form H was produced when form E and form H were co-incubated in 2-propanol for 1 day (Table 6, row 13). Briefly, excess forms E and H were added to pure 2-propanol until saturation. The resulting suspension was stirred at ambient temperature for 1 day. The solid was vacuum filtered and analyzed by XRD to determine that form H was produced. To avoid possible desolvation or physical changes after isolation, the samples were not further dried before X-ray analysis. In another embodiment, Form H was produced when Form E and Form H were co-incubated in 2-butanol for 1 day (Table 6, row 14). Briefly, excess Form E and Form H were added to pure 2-butanol until saturation. The resulting suspension was stirred at ambient temperature for 1 day. The solid was vacuum filtered and analyzed by XRD to determine that Form H was produced. To avoid possible desolvation or physical changes after isolation, the samples were not further dried before X-ray analysis. From the initial competitive slurry experiments (all samples except the last two in Table 6), Form E or Form E1 was found to be the most stable form observed during the study. However, competitive slurries of Forms E and H in two different solvents showed that Form H was more stable than Form E. Based on these slurry experiments, extensive crystal seeding (Example 7), and DSC thermograms, Form H is expected to be the thermodynamically stable form. The XRD pattern of Form H, as shown in Figure 43, exhibited a crystalline powder pattern. The XRD pattern of Form H indicates that it was highly crystalline. Form H was characterized by an XRD pattern with peaks at about 11.8, 20.1, 23.6, 25.0, and 26.5 2θ±0.2 2θ.Form H was further characterized by an XRD pattern with peaks at 8.6, 12.5, 18.6, 21.2, and 28.1 2θ±0.2 2θ. The TGA thermogram showed a loss of about 0.03 wt % at 150° C., as shown in FIG. 44. The DSC thermogram of Form H showed a melting onset endotherm with an onset of 247.5° C., a peak maximum at 250.1° C., and an enthalpy of melting of 158.0 J / g, as shown in FIG. 45. The KF water content of Form H was 0.21 wt % (not shown). The solution NMR spectrum of Form H is consistent with the expected structure of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride (not shown).

[0139] [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride Form I (Form I) was produced after slurrying in 1:1 ethanol / ethyl acetate (EtOH / EtOAc). Form I was converted to Form C after storage at ambient conditions for one month. H and Form H, suggesting that it is a relatively unstable polymorph. The XRD diffraction pattern of Form I is shown in Figure 46. Form I of the HCl salt was characterized by an XRD pattern with peaks at about 10.0, 10.6, 16.6, 23.7, and 25.7 2θ ± 0.2 2θ. Form I was further characterized by an XRD pattern with peaks at 11.8, 15.9, 26.7, and 27.6 2θ ± 0.2 2θ, as shown in Figure 46.

[0140] Overall, Form E / E1 was first observed in many recrystallization and slurry experiments, indicating that it was the most stable form observed in these early studies. However, further studies have shown that Form H is more stable than Form E as well as Form E1, which likely shares many physical properties with Form E. Based on the above data, Form H was considered to be the thermodynamically stable form of the compound. Forms A, B, D, and I are considered to be metastable polymorphic forms, while Form C H, F H , and G H As described in detail above, forms A, B and C of the HCl salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone are H , D, E, F H , G H A comparison of the XRD patterns of H and I is provided in FIG.

[0141] Example 7: Large scale synthesis of the HCl salt form H of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone (API HCl) from intermediate C-5.

[0142] In the following process for making [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride (API HCl) on a kilogram scale, API HCl form E or form E1 was initially produced. Forms E and E1 preparations converted to form H at ambient conditions, indicating the relative stability of form H. Furthermore, characterization such as in Examples 5 and 6 confirmed that form H was the most stable of the polymorphic forms of API HCl. Importantly, form H was not observed to convert to any other polymorphic form. Thus, in the following kilogram scale synthesis process, seed crystals of form H were used in steps 2 and 17 to rapidly and completely convert the crude API HCl product to pure API HCl, obtaining only form H. This product is suitable for use in pharmaceutical products.

[0143] Step 1 - Preparing for Pre-Processing

[0144] Prior to the addition of any reagents, the reaction vessel was verified to be within tolerance, clean, dry, and in proper operating configuration. Prior to the first batch, critical process equipment used in the reactor was verified with calibration and functioning properly. The reaction system was pressurized with nitrogen to a pressure of at least 25 psig. Each part of the system and interconnected piping were pressure checked with nitrogen. The pressure check included all lines up to the last valve. The system was held for at least 30 minutes such that the pressure drop did not exceed 1 psig. Leaks were repaired and retested as necessary. Upon completion, the pressure was released and spot venting was performed. The reactor was repressurized with nitrogen to a pressure of at least 25 psig. Each part of the system and interconnected piping were pressure checked with nitrogen. The pressure check included all lines up to the last valve. The vessel was held for at least 30 minutes such that the pressure drop did not exceed 1 psig. Leaks were repaired and retested as necessary. Upon completion, the pressure was released to check venting. The filter dryer was vacuum checked to 27" Hg or less. Once at 27" Hg or less vacuum, it was isolated and held for at least 30 minutes. The filter dryer passed if it did not lose more than 2" Hg for at least 30 minutes. Leaks were repaired as necessary and retested.

[0145] Step 2 - [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride (API HCl) reaction step: [ka]

[0146] The reactor data acquisition system was turned on and the date and time were confirmed to be correct. The cooling water supply to the reactor overhead condenser was started. The reactor was inerted with nitrogen and brought to atmospheric pressure at the end of the inerting process. The reactor was isolated from the condenser, the cooling medium supply to the reactor jacket was started and the jacket set temperature was adjusted to 22 °C. 1 kg of intermediate C5 (see above) was charged to the reactor, taking care not to fill the agitator. The reactor was slowly inerted with nitrogen and left under vacuum at the end of the inerting process. 9.152 kg of ethanol was charged to the reactor, the reactor agitator speed was set to the lowest setting, the agitator was started, the agitation was adjusted to 100 RPM and the mixture was stirred for at least 10 minutes. The temperature was then held at 20-25 °C. The reactor was configured for the reaction by charging the reactor with 1.600 kg of concentrated HCl, verifying the flow of cooling water through the reactor condenser, venting the reactor through the condenser, and initiating a nitrogen sweep of the reactor vent. The reactor batch temperature was adjusted to 74°C-78°C. The reaction was held at 74°C-78°C for 1 hour and then began cooling the batch to 20°C-25°C over 1-2 hours. During this cool down, once the batch was at 65°C-70°C, a 1 ounce sample of the reactor contents was collected for analysis by HPLC. Approximately 0.010 kg (10 grams) of API HCl Form H seed crystals were charged to the reactor, taking care not to fill the agitator, and the batch was cooled to 20°C-25°C and held at 20°C-25°C for at least 12 hours. The batch was then further cooled to 0°C-5°C and the batch was held at 0°C-5°C for at least 2 hours.

[0147] Step 3 - Filtration of API HCl

[0148] The filter dryer was prepared for filtration by inerting it with nitrogen, making sure the pressure relief drum was attached, making sure the filter dryer was grounded, and making sure the filter dryer agitator was off and raised to its highest position. The slurry in the reactor was filtered through the filter dryer and the filtrate was collected in a new drum. The slurry was slowly charged in small increments at first to allow the filter cake to settle. Near the start of the filtration, a sample of the filtrate was collected to ensure there were no solids. The reactor was inspected for residual solids and, if any, was rinsed with ethanol through the filter dryer. 1.263 kg of ethyl acetate was charged to the reactor to rinse the reactor and the rinse was cooled to 0-5°C. The wet cake was deliquored and smooth, after which the solvent in the reactor was drained into the filter dryer and from the filter dryer into a new drum. The wet cake was deliquored.

[0149] Step 4 – Crude API HCl Drying

[0150] Prepared the APOVAC vacuum system, started flow to the condenser, verified that the ring liquid was filled to the overflow line, and verified that the distillate receiver was empty. Operating parameters were: (1) Cooling medium: chilled water or glycol at 2-8°C; (2) Pre-condenser cooling medium: chilled water or glycol at 2-8°C, ring liquid cooler: 5 gpm (minimum), exhaust condenser: 2 gpm (minimum); Fill ring liquid (if new or additional required): potable water. The vacuum block valve was slowly opened and full vacuum was pulled on the filter dryer (vacuum less than 27" Hg), then a regulated water flow at 52-58°C was started through the filter dryer jacket and the filter dryer was checked every 4 hours (+ / - 30 minutes). The product was continued to be dried (jacket inlet temperature 52-58°C, vacuum, nitrogen sweep) and after at least 12 hours of drying, the filter dryer contents were tested for volatiles by loss on drying method using a TGA unit (105°C). The dryer contents continued to be sampled approximately every 8 hours until the residual volatile content was 1 wt% or less. Once the wet cake was partially dry, agitation was started in the filter dryer to aid in the drying process, the filter dryer was cooled completely and the dryer was brought to atmospheric pressure using nitrogen. The dryer was held at 25-30°C for at least 30 minutes before sampling for HPLC analysis. The crude API HCl was removed from the filter dryer using 15 L of Curtec Drained into a Keg. A one ounce sample was submitted for HPLC to detect any chemical impurities and XRPD analysis was performed to confirm the appropriate polymorphic form (preferably Form H). Residual solvent was also measured.

[0151] If impurities were found, additional processing steps were performed to bring the batch material to the target specifications. For example, acetone trituration (up to two times; steps 5-10), ethanol:ethyl acetate trituration (steps 11-13), or water trituration (steps 14-16) were performed for impurities, and a crystal form correction was performed for any polymorphic crystal form other than API HCl form H (steps 17-19). If no impurities were found and pure API HCl polymorph form H was obtained (by XRPD), no additional processing was required; i.e., optional steps 5-19 may be omitted.

[0152] Desired goals: Any unknown impurity: ≦0.10% Total impurities:≦1.50% ROI:≦0.1% Ethanol <5000PPM Ethyl acetate <5000PPM

[0153] Step 5 – Optional acetone trituration of crude API HCl (if impurities present)

[0154] If impurities remain, steps 5-7 were carried out to completion. Started the cooling water feed to the reactor overhead condenser and inerted the reactor with nitrogen to atmospheric pressure at the end of the inerting process. The reactor was then isolated from the condenser and started the cooling media feed to the reactor jacket and adjusted the jacket set temperature to 22 °C. Taking care not to fill the agitator, all of the crude API HCl from step 4 was charged to the reactor and the reactor was slowly inerted with nitrogen to avoid splashing of solids. Charged 11.887 kg of acetone per kg of crude API HCl added to the reactor. Set the reactor agitator speed to the lowest, started the agitator, adjusted the agitation to 100 RPM, and stirred the mixture for at least 10 minutes. Adjusted the reactor batch temperature to 54 °C-58 °C and held the batch temperature at 54 °C-58 °C for at least 12 hours. Cooled the batch to 20-24 °C and allowed the batch to mix for 15 minutes at 20-24 °C.

[0155] Step 6 – Filtration of the milled API

[0156] The filter dryer was prepared for filtration by inerting the dryer with nitrogen, making sure the pressure relief drum was attached, making sure the filter dryer was grounded, and making sure the dryer agitator was off and raised to its highest position. The slurry in the reactor was then filtered through the dryer and the filtrate was collected in a drum. The slurry was slowly charged in small increments at first to allow the filter cake to settle. Near the start of the filtration, a sample of the filtrate was collected and confirmed to be free of solids. The reactor was inspected for solids and, if present, rinsed into the dryer. The wet cake was deliquified and smoothed through the dryer, then the solvent in the reactor was drained into the dryer and from the dryer into a new drum (labeled Crude API HCI Acetone Rinse). The wet cake was deliquified.

[0157] Step 7 - Drying the Milled API

[0158] Prepared the APOVAC vacuum system, started flow to the condenser, verified that the ring liquid was filled to the overflow line, and verified that the distillate receiver was empty. Operating parameters were: (1) Cooling media: chilled water or glycol at 2-8°C; Pre-condenser cooling media: chilled water or glycol at 2-8°C; Ring liquid cooler: 5 gpm (minimum), exhaust condenser: 2 gpm (minimum); Ring liquid (if new or additional required): potable water. The vacuum block valve was slowly opened, full vacuum was pulled on the dryer (vacuum less than 27" Hg) and conditioned water at 47-53°C was started to flow through the dryer jacket. The progress of the dryer was checked at 4 hour (+ / - 30 minute) intervals. The product was continued to be dried (jacket inlet temperature 47-53°C, vacuum, nitrogen sweep) and after at least 12 hours of drying, the contents of the filter dryer were sampled and the samples were tested for volatiles by loss on drying method using a TGA unit (105°C). The contents of the dryer were continued to be sampled every ≥ 8 hours until the residual volatile content was 1 wt% or less. Once the wet cake was partially dry, agitation was started in the dryer to aid in the drying process. Once the in-process drying controls met the required requirements, the dryer was cooled completely and the dryer was brought to atmospheric pressure using nitrogen and the dryer was held at 25-30°C for at least 30 minutes before sampling. One ounce samples of API HCl were collected from the dryer for purity testing, appropriate polymorphic form testing via XRPD, and HPLC analysis for residual solvents. Crude API The HCl was drained from the dryer into a 15 L Curtec Keg. Considering the results against the target ranges specified at the end of step 4, additional processing within this batch record may have been required. If all results were within the purity specifications and only polymorphic Form H of API HCl was obtained (by XRPD), then no additional processing was required. Otherwise, impurities can be removed by an optional second acetone trituration (steps 8-10), an optional ethanol / ethyl acetate trituration (steps 11-13), or an optional deionized water trituration (steps 14-16) to remove impurities, or Form H can be obtained by an optional API HCl form correction (steps 17-19).

[0159] Step 8 - Optional second acetone grind (if impurities are present)

[0160] If impurities remain, steps 8-10 were performed and completed. The reactor and filter dryer were washed as described above, the cooling water supply to the reactor overhead condenser was started, the reactor was inerted with nitrogen, and the reactor was brought to atmospheric pressure at the end of the inerting process. The reactor was isolated from the condenser, the cooling medium supply to the reactor jacket was started, and the jacket set temperature was adjusted to 22°C. All of the crude API HCl from step 7 or any other drying step was charged to the reactor, taking care not to fill the agitator. The reactor was inerted slowly with nitrogen to avoid splashing of solids. 11.887 kg per kg of crude API HCl was charged to the reactor, the reactor agitator speed was turned to the lowest setting, the agitator was started, the agitation was adjusted to 100 RPM, and the mixture was stirred for at least 10 minutes. The reactor batch temperature was then adjusted to 54°C-58°C and this temperature was held for at least 12 hours. The batch was cooled to 20-24°C and the batch was allowed to mix at 20-24°C for 15 minutes.

[0161] Step 9 – Filtration of the milled API

[0162] The filter dryer was prepared for filtration by inerting the dryer with nitrogen, making sure the pressure relief drum was attached, making sure the filter dryer was grounded, and making sure the dryer agitator was off and raised to its highest position. The reactor slurry was filtered through the dryer and the filtrate was collected in a new drum. The slurry was slowly charged in small increments at first to allow the filter cake to settle. Near the beginning of the filtration, a sample of the filtrate was collected and confirmed to be free of solids. If solids remained in the filtrate, it was filtered again. The reactor was inspected for solids and if significant solids remained, the filtrate was recycled and an additional acetone rinse was added to remove them. The wet cake was deliquified and smoothed through the filter dryer. The solvent in the reactor was drained into the dryer and then from the dryer into a new drum. The wet cake was deliquified.

[0163] Step 10 - Drying the Milled API

[0164] The APOVAC vacuum system was primed and flow to the condenser was started, ring liquid was ensured to be filled to the overflow line, and distillate receiver was ensured to be empty. Operating parameters were as follows: Cooling Media: Chilled water or glycol at 2-8°C; Pre-condenser Cooling Media: Chilled water or glycol at 2-8°C; Ring Liquid Cooler: 5 gpm (minimum), Exhaust Condenser: 2 gpm (minimum), and Ring Liquid (if new or additional required): Potable water. The vacuum block valve was slowly opened, full vacuum was pulled on the dryer (vacuum less than 27" Hg), a regulated water flow at 47-53°C was initiated through the dryer jacket, and monitoring of the dryer was initiated every 4 hours (+ / - 30 minutes). The product continued to be dried (jacket inlet temperature 47-53°C, vacuum, nitrogen sweep) and after at least 12 hours of drying, the filter dryer contents were sampled and tested for volatiles by loss on drying method using a TGA unit (105°C). Sampling of the dryer contents continued every ≥ 8 hours until the residual volatile content was 1 wt% or less. Once the wet cake was partially dry, agitation was initiated in the dryer to aid in the drying process. Once the in-process drying controls met the required requirements, the dryer was cooled completely, the dryer was brought to atmospheric pressure using nitrogen, and the dryer was held at 25-30°C for at least 30 minutes before sampling. One ounce samples were collected from the dryer for API HCl for HPLC analysis. API HCl was removed from the dryer using a 15L Curtec Drained into a Keg. A one ounce sample was submitted for HPLC purity testing, XRPD testing for the desired polymorphic form H, and residual solvent. If all results were within specifications and polymorphic form H of API HCl was obtained (by XRPD), no further processing was required. Otherwise, impurities can be removed by optional ethanol / ethyl acetate trituration (steps 11-13) and / or optional deionized water trituration (steps 14-16) to remove impurities, or form H can be made by optional API HCl form correction (steps 17-19) to make form H.

[0165] Step 11 - Optional Ethanol / Ethyl Acetate Trituration (if impurities present)

[0166] If impurities remain, steps 11-13 were performed to completion. The reactor and filter dryer were washed as described above, the cooling water feed to the reactor overhead condenser was started, the reactor was inerted with nitrogen, and the reactor was brought to atmospheric pressure at the end of the inerting process. The reactor was isolated from the condenser, the cooling medium feed to the reactor jacket was started, and the jacket set temperature was adjusted to 22°C. All of the crude API HCl from step 10 or any other drying step was charged to the reactor, taking care not to fill the agitator. The reactor was inerted slowly with nitrogen to avoid splashing solids. 4.500 kg of ethyl acetate per kg of crude API HCl was charged to the reactor, the reactor agitator speed was set to the lowest setting, the agitator was started, the agitation was adjusted to 100 RPM, and the mixture was stirred for at least 10 minutes. The reactor batch temperature was adjusted to 58°C-62°C, and the batch temperature was held at 58°C-62°C for at least 24 hours. The batch was cooled to 20-25°C and mixed at 20-24°C for 15 minutes.

[0167] Step 12 – Filtration of the milled API

[0168] The filter dryer was prepared for filtration by inerting the dryer with nitrogen, ensuring that the pressure relief drum was attached, ensuring that the filter dryer was grounded, and ensuring that the dryer agitator was off and raised to its highest position. The slurry in the reactor was filtered through the dryer and the filtrate was collected in a new drum. The slurry was charged slowly in small increments at first to allow the filter cake to settle. Near the beginning of the filtration, a sample of the filtrate was taken to ensure that there were no solids. If any solids remained in the filtrate, it was filtered again. The reactor was inspected for solids and if any significant solids remained, the filtrate was recycled. 0.900 kg of ethyl acetate per kg of crude API HCl and 0.790 kg of ethanol per kg of crude API HCl were then added to the reactor to rinse. The reactor agitator speed was then set to the lowest setting, the agitator started, and the agitation adjusted to 100 RPM. The reactor contents were adjusted to 2°C-8°C. The wet cake was deliquified and smoothed in a dryer, and the solvent in the reactor was drained into the dryer, which in turn drained into a new drum. The wet cake was deliquified again.

[0169] Step 13 - Drying the Milled API

[0170] Prepare the APOVAC vacuum system, start flow to the condenser, ensure the ring liquid is filled to the overflow line, and ensure the distillate receiver is empty. Operating parameters are as follows: Cooling Media: Chilled water or glycol at 2-8°C; Pre-condenser Cooling Media: Chilled water or glycol at 2-8°C; Ring Liquid Cooler: 5 gpm (minimum), Exhaust Condenser: 2 gpm (minimum), and Ring Liquid (if new or additional required): Potable water. The vacuum block valve was slowly opened, full vacuum was pulled on the dryer (less than 27" Hg vacuum), a regulated water flow at 52-58°C was started through the dryer jacket, and monitoring of drying was started every 4 hours (+ / - 30 minutes). The product continued to be dried (jacket inlet temperature 52-58°C, vacuum, nitrogen sweep) and after at least 12 hours of drying, the filter dryer contents were sampled and tested for volatiles by loss on drying method using a TGA unit (105°C). Sampling of the dryer contents continued every ≥ 8 hours until the residual volatile content was 1 wt% or less. Once the wet cake was partially dry, agitation was started in the dryer to aid in the drying process. Once the in-process drying controls met the required requirements, the dryer was cooled completely, the dryer was brought to atmospheric pressure using nitrogen, and the dryer was held at 25-30°C for at least 30 minutes before sampling. One ounce samples were collected from the dryer for API HCl for HPLC, XRPD, and residual solvent testing. API HCl was removed from the dryer using a 15L Curtec Discharge into Kegs. If all results were within specifications and only polymorphic Form H of API HCl was obtained (by XRPD), no further processing was required. Otherwise, impurities can be removed by optional deionized water trituration (Steps 14-16) or Form H can be produced by optional API HCl form correction (Steps 17-19).

[0171] Step 14 - Optional DI Water Grinding (if impurities are present)

[0172] If impurities remain, steps 14-16 were performed to completion. The reactor and filter dryer were washed as described above, the cooling water feed to the reactor overhead condenser was started, the reactor was inerted with nitrogen, and the reactor was brought to atmospheric pressure at the end of the inerting process. The reactor was isolated from the condenser, the cooling media feed to the reactor jacket was started, and the jacket set temperature was adjusted to 22°C. All of the crude API HCl from step 13 or any other drying step was charged to the reactor, taking care not to fill the agitator. The reactor was inerted slowly with nitrogen to avoid splashing of solids. 10 kg of WFI (water for injection) quality water was charged per kg of crude API HCl charged to the reactor, the reactor agitator speed was set to the lowest setting, the agitator was started, the agitation was adjusted to 100 RPM, and the mixture was stirred for at least 10 minutes. The reactor batch temperature was adjusted to 58°C-62°C, and the batch temperature was held at 58°C-62°C for at least 4 hours. The batch was cooled to 20-24°C over at least 1 hour.

[0173] Step 15 – Filtration of the milled API

[0174] The filter dryer was prepared for filtration by inerting the dryer with nitrogen, making sure the pressure relief drum was attached, making sure the filter dryer was grounded, and making sure the dryer agitator was off and raised to its highest position. The slurry in the reactor was filtered through the dryer and the filtrate was collected in a new drum. The slurry was charged slowly in small increments at first to allow the filter cake to settle. Near the beginning of the filtration, a sample of the filtrate was taken to ensure there were no solids. If any solids remained in the filtrate, it was filtered again. The reactor was inspected for solids and if any significant solids remained, the filtrate was recycled. It was then rinsed by adding 10 kg of WFI quality water per kg of crude API HCl to the reactor. The solvent in the reactor was drained into the dryer and then from the dryer into a new drum. The wet cake was deliquified.

[0175] Step 16 - Drying the Milled API

[0176] The APOVAC vacuum system was primed and flow to the condenser was started, ring liquid was ensured to be filled to the overflow line, and distillate receiver was ensured to be empty. Operating parameters were as follows: Cooling Media: Chilled water or glycol at 2-8°C; Pre-condenser Cooling Media: Chilled water or glycol at 2-8°C; Ring Liquid Cooler: 5 gpm (minimum), Exhaust Condenser: 2 gpm (minimum), and Ring Liquid (if new or additional required): Potable water. The vacuum block valve was slowly opened, full vacuum was pulled on the dryer (less than 27" Hg vacuum), a regulated water flow at 50-60°C was started through the dryer jacket, and monitoring of drying was started every 4 hours (+ / - 30 minutes). The product continued to be dried (jacket inlet temperature 50-60°C, vacuum, nitrogen sweep) and after at least 12 hours of drying, the filter dryer contents were sampled and tested for volatiles by loss on drying method using a TGA unit (105°C). Sampling of the dryer contents continued every ≥ 8 hours until the residual volatile content was 1 wt% or less. Once the wet cake was partially dry, agitation was started in the dryer to aid in the drying process. Once the in-process drying controls met the required requirements, the dryer was cooled completely, the dryer was brought to atmospheric pressure using nitrogen, and the dryer was held at 25-30°C for at least 30 minutes before sampling. One ounce samples were collected from the dryer for API HCl for HPLC, XRPD, and residual solvent testing. API HCl was removed from the dryer using a 15L Curtec Discharge into Kegs. If all results were within specifications and only polymorphic Form H of API HCl was obtained (by XRPD), no further processing was required. If Form H was not obtained, the optional API HCl Form Correction (Steps 17-19) was performed.

[0177] Step 17 – Correction for API HCl Form

[0178] If Form H was not observed in step 16 or any of the dryer steps above, steps 17-19 were performed. The reactor was inerted with nitrogen and brought to atmospheric pressure at the end of the inerting process. The reactor was isolated from the condenser, cooling media to the reactor jacket was started, and the jacket set temperature was adjusted to 22°C. All of the crude API HCl from step 16 or the previously performed grinding was charged to the reactor, taking care not to fill the agitator. The reactor was inerted slowly with nitrogen to avoid splashing of solids. 3.945 kg of ethanol per kg of crude API HCl and 4.510 kg of ethyl acetate per kg of crude API HCl were charged to the reactor, the reactor agitator speed was set to the lowest, the agitator was started, the agitation was adjusted to 100 RPM, and the mixture was stirred for at least 10 minutes at 20-25°C. 0.010 kg of API HCl form H seed crystals were charged to the reactor, taking care not to fill the agitator. Upon completion of dosing, the reactor was configured by closing the reactor dosing valve, checking the flow of cooling water through the reactor condenser, venting the reactor through the condenser, and initiating a nitrogen sweep of the reactor vent. The reactor batch temperature was adjusted to 58°C-62°C and monitoring was initiated approximately every 2 hours (+ / - 30 minutes) until form conversion was complete. The reaction was held between 58°C-62°C for at least 24 hours. A one ounce sample of the reactor contents was collected by: (1) applying 5 psig nitrogen pressure to the reactor, (2) collecting a one ounce sample to flush the sample line, (3) collecting a one ounce sample of the reactor contents, and (4) venting the reactor to a spot exhaust with a slow nitrogen purge at the vent. The reactor contents sample (second sample) was analyzed by XRPD to confirm that the appropriate polymorph, Form H, was obtained. If form H does not form within the first 24 hours, the reaction can be held between 58 °C - 62 °C and sampled for up to two additional 24 hour replicates until form H forms. Once form H has formed, cool the batch to 20 - 25 °C and hold for at least 20 minutes.

[0179] Step 18 – Filtration of API HCl Form H

[0180] The reactor was prepared for filtration in the filter dryer by inerting the dryer with nitrogen, making sure the pressure relief drum was attached, making sure the filter was grounded, and making sure the dryer agitator was off and raised to its highest position. The slurry in the reactor was filtered in the dryer and the filtrate was collected in a new drum. The slurry was slowly charged in small increments at first to allow the filter cake to settle. Near the beginning of the filtration, a sample of the filtrate was taken to ensure there were no solids. If any solids remained in the filtrate, it was filtered again. The reactor was inspected for solids and if any significant solids remained, the filtrate was recycled. The reactor was then rinsed by adding 0.789 kg of ethanol per kg of crude API HCl added to the reactor and 0.902 kg of ethyl acetate per kg of crude API HCl added to the reactor. The rinse was cooled to 2-8°C. The wet cake was deliquified and smoothed. The solvent in the reactor was drained into the dryer and from the dryer into a new drum. The wet cake was deliquored again.

[0181] Step 19 – Drying API HCl Form H

[0182] The APOVAC vacuum system was primed and flow to the condenser was started, ring liquid was ensured to be filled to the overflow line, and distillate receiver was ensured to be empty. Operating parameters were as follows: Cooling Media: Chilled water or glycol at 2-8°C; Pre-condenser Cooling Media: Chilled water or glycol at 2-8°C; Ring Liquid Cooler: 5 gpm (minimum), Exhaust Condenser: 2 gpm (minimum), and Ring Liquid (if new or additional required): Potable water. The vacuum block valve was slowly opened, full vacuum was pulled on the dryer (less than 27" Hg vacuum), a regulated water flow at 52-58°C was started through the dryer jacket, and monitoring of drying was started every 4 hours (+ / - 30 minutes). The product continued to be dried (jacket inlet temperature 52-58°C, vacuum, nitrogen sweep) and after at least 12 hours of drying, the filter dryer contents were sampled and tested for volatiles by loss on drying method using a TGA unit (105°C). Sampling of the dryer contents continued every ≥ 8 hours until the residual volatile content was 1 wt% or less. Once the wet cake was partially dry, agitation was started in the dryer to aid in the drying process. Once the in-process drying controls met the required requirements, the dryer was cooled completely and the dryer was brought to atmospheric pressure using nitrogen. Two ounce samples were collected from the dryer for API HCl for analysis by HPLC, Karl Fischer, Appearance, XRPD and Residual Solvent Testing. If the GC results for residual solvents were higher than target, the material was dried for an additional hour and retested. API The HCl was discharged from the dryer into 15 L Curtec Kegs. All results were within specification and only polymorphic form H of API HCl was obtained (by XRPD) so no further processing was required.

[0183] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes and equivalents will immediately occur to those skilled in the art, and it is therefore to be understood that the appended claims are intended to cover all such modifications and changes that fall within the true spirit of the invention.

Claims

1. A crystalline polymorphic Form A of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized by an X-ray powder diffraction (XRD) pattern with peaks at 9.6, 12.0, 19.2, 23.6, and 24.4 2θ±0.2 2θ.

2. The crystalline polymorphic Form A of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 1, further characterized by an XRD pattern substantially as shown in FIG.

3. The crystalline polymorphic Form A of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 1, further characterized by XRD peaks at 16.3, 18.1, and 28.9 2θ±0.2 2θ.

4. A crystalline polymorphic Form B of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized by an X-ray powder diffraction (XRD) pattern with peaks at 9.5, 12.1, 18.0, 18.9, and 23.0 2θ±0.2 2θ.

5. The crystalline polymorphic form B of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 4, further characterized by an XRD pattern substantially as shown in FIG.

6. The crystalline polymorphic form B of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 4, further characterized by XRD peaks at 19.2, 28.5, 29.5, and 31.8 2θ±0.2 2θ.

7. A crystalline polymorphic form C of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized by an X-ray powder diffraction (XRD) pattern with peaks at 5.1, 13.1, 16.6, 22.5, and 25.7 2θ±0.2 2θ. Ｈ .

8. The crystalline polymorphic form C of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 7, further characterized by an XRD pattern substantially as shown in FIG. Ｈ .

9. The crystalline polymorphic form C of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 7, further characterized by XRD peaks at 10.3, 18.0, 23.7, 28.7, and 29.7 2θ±0.2 2θ. Ｈ .

10. A crystalline polymorphic form D of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized by an X-ray powder diffraction (XRD) pattern with peaks at 9.4, 15.1, 17.3, 22.1, and 23.2 2θ±0.2 2θ.

11. The crystalline polymorphic form D of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 10, further characterized by an XRD pattern substantially as shown in FIG.

12. The crystalline polymorphic form D of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 10, further characterized by XRD peaks at 10.5, 18.1, 22.8, 24.8, and 30.3 2θ±0.2 2θ.

13. A crystalline polymorphic Form E of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized by an X-ray powder diffraction (XRD) pattern with peaks at 9.4, 17.3, 22.1, 23.4, and 24.8 2θ±0.2 2θ.

14. The crystalline polymorphic Form E of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 13, further characterized by an XRD pattern substantially as shown in FIG.

15. The crystalline polymorphic Form E of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 13, further characterized by XRD peaks at 12.9, 15.0, 18.1, 21.0, and 30.3 2θ±0.2 2θ.

16. A crystalline polymorphic form E1 of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized by an X-ray powder diffraction (XRD) pattern with peaks at 9.4, 10.9, 17.3, 22.1, 23.4, and 24.8 2θ±0.2 2θ.

17. The crystalline polymorphic form E1 of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 16, further characterized by an XRD pattern substantially as shown in FIG.

18. 17. The crystalline polymorphic form E1 of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 16, further characterized by XRD peaks at 13.0, 15.1, 18.1, 20.9, and 24.8 2θ±0.2 2θ.

19. A crystalline polymorphic Form F of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized by an X-ray powder diffraction (XRD) pattern with peaks at 9.06, 10.4, 18.85, 25.48, and 27.97 2θ±0.2 2θ. Ｈ .

20. The crystalline polymorphic form F of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 19, further characterized by XRD peaks at 12.9, 20.9, and 26.14 2θ±0.2 2θ. Ｈ .

21. The crystalline polymorphic form F of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 19, further characterized by an XRD pattern substantially as shown in FIG. Ｈ .

22. 20. The crystalline polymorphic form F of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 19, having a differential scanning calorimetry (DSC) thermogram showing a more resolved endotherm with an onset of about 90.8° C. and a peak maximum of 99.7° C. Ｈ .

23. A crystalline polymorphic form G of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized by an X-ray powder diffraction (XRD) pattern with peaks at 11.8, 14.5, 16.8, 23.1, and 28.5 2θ±0.2 2θ. Ｈ .

24. The crystalline polymorphic form G of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 23, further characterized by XRD peaks at 10.4, 22.3, 24.7, and 25.3 2θ±0.2 2θ. Ｈ .

25. The crystalline polymorphic form G of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 23, further characterized by an XRD pattern substantially as shown in FIG. Ｈ .

26. A crystalline polymorphic Form H of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized by an X-ray powder diffraction (XRD) pattern with peaks at 11.8, 20.1, 23.6, 25.0, and 26.5 2θ±0.2 2θ.

27. 27. The crystalline polymorphic form H of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 26, further characterized by XRD peaks at 8.6, 12.5, 18.6, 21.2, and 28.1 2θ±0.2 2θ.

28. 27. The crystalline polymorphic form H of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 26, further characterized by an XRD pattern substantially as shown in FIG.

29. 27. The crystalline polymorphic form H of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 26, having a thermogravimetric analysis (TGA) thermogram with an average weight loss of 0.03% at 150°C.

30. 27. The crystalline polymorphic Form H of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 26, having a differential scanning calorimetry (DSC) thermogram with a melting endotherm with an onset of 247.5°C and a peak maximum of 250.1°C.

31. A crystalline polymorphic Form I of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized by an X-ray powder diffraction (XRD) pattern with peaks at 10.0, 10.6, 16.6, 23.7, and 25.7 2θ±0.2 2θ.

32. 32. The crystalline polymorphic Form I of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 31, further characterized by XRD peaks at 11.8, 15.9, 26.7, and 27.6 2θ±0.2 2θ.

33. The crystalline polymorphic Form I of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 31, further characterized by an XRD pattern substantially as shown in FIG.

34. Forms A, B and C, characterized by XRD patterns substantially as shown in FIG. Ｈ , form D, form E, form F Ｈ , form G Ｈ 30. The hydrochloride salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone, characterized by at least a polymorph of Form E1, characterized by an XRD pattern substantially as shown in FIG.

35. A crystalline polymorphic Form II of the free base of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone, characterized by an X-ray powder diffraction pattern (XRD) with peaks at 10.8, 15.3, 15.9, 18.6, and 25.9 2θ±0.2 2θ.

36. 36. The crystalline polymorphic Form II of the free base of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone according to claim 35, further characterized by an XRD pattern substantially as shown in FIG.

37. 37. The crystalline polymorphic Form II of the free base of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone of claim 36, further characterized by XRD peaks at 14.4, 17.8, 20.0, 24.7, and 26.8 2θ±0.2 2θ.

38. A crystalline polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized by an X-ray powder diffraction (XRD) pattern with peaks at 10.8, 13.3, 21.5, 23.1, and 35.2 2θ±0.2 2θ.

39. 39. The crystalline polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 38, further characterized by an XRD pattern substantially as shown in FIG.

40. 39. The crystalline polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride of claim 38, further characterized by XRD peaks at 10.5, 14.1, 16.1, and 26.2 2θ±0.2 2θ.

41. A crystalline polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone mesylate, characterized by an X-ray powder diffraction (XRD) pattern with peaks at 8.3, 9.9, 10.9, 17.5, and 19.9 2θ±0.2 2θ.

42. 42. The crystalline polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone mesylate according to claim 41, further characterized by an XRD pattern substantially as shown in FIG.

43. 42. The crystalline polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone mesylate of claim 41, further characterized by XRD peaks at 12.1, 18.8, 21.9, 24.5, and 28.2 2θ±0.2 2θ.

44. 27. A process for making form E of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride by recrystallization of any form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride from 2-propanol, 1-propanol / 1-dioxane mixture, or ethanol, wherein form E is characterized by an X-ray powder diffraction (XRD) pattern having peaks at 9.4, 17.3, 22.1, 23.4, and 24.8 2θ±0.2 2θ, or is further characterized by an XRD pattern substantially as shown in FIG.

45. Form E can be prepared by adding the salt at saturation concentration in 2-propanol at 25° C., heating to 45-50° C. to dissolve the solids, and subjecting the salt to 1.5 psi N ２ 45. The process of claim 44, wherein the solid form is prepared by rapid evaporation under a stream of water to produce solid form E.

46. 45. The process of claim 44, wherein said Form E is made by adding said salt at saturation concentration to a 1-propanol / 1-dioxane mixture at 25° C. and slowly evaporating the solvent at ambient temperature to produce solid Form E.

47. Form E may be prepared by adding the salt to ethanol at saturation concentration at 25° C., heating to 45-50° C. to dissolve any solids, and then evaporating under 1.5 psi N at 40° C. ２ 45. The process of claim 44, wherein said process is made by rapid evaporation of the solvent under flow to produce form E.

48. 30. A process for making form E1 of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride by recrystallization of any form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride from 2-propanol / dichloromethane or 2-propanol / trichloromethane, wherein form E1 is characterized by an X-ray powder diffraction (XRD) pattern having peaks at 9.4, 10.9, 17.3, 22.1, and 23.2 2θ±0.2 2θ, or is further characterized by an XRD pattern substantially as shown in FIG.

49. Form E1 can be prepared by adding the salt at saturation concentration to a 2-propanol / dichloromethane binary solvent mixture at 25° C., heating to 45-50° C. to dissolve the solids, and subjecting the mixture to 1.5 psi N ２ 49. The process of claim 48, wherein the solid form is made by rapid evaporation of the solvent under flow to produce solid form E1.

50. Form E1 can be prepared by adding the salt at saturation concentration to a 2-propanol / trichloromethane binary solvent mixture at 25° C., heating to 45-50° C. to dissolve the solids, and subjecting the mixture to 1.5 psi N ２ 49. The process of claim 48, wherein the solid form is made by rapid evaporation of the solvent under flow to produce solid form E1.

51. A process for making form H of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride by incubating form E or form E1 at ambient temperature.

52. A process for making form H of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride by competitively slurrying forms E and H in 2-butanol or 2-propanol for 1 day, wherein the sample is not further dried prior to X-ray analysis of the resulting form H to avoid possible desolvation or physical changes after isolation; Form E is characterized by an X-ray powder diffraction (XRD) pattern having peaks at 9.4, 17.3, 22.1, 23.4, and 24.8 2θ±0.2 2θ, or further characterized by an XRD pattern substantially as shown in FIG. 29 ; Form H is characterized by an X-ray powder diffraction (XRD) pattern having peaks at 11.8, 20.1, 23.6, 25.0, and 26.5 2θ±0.2 2θ, or further characterized by an XRD pattern substantially as shown in FIG. 43 .

53. 53. The process of claim 52, wherein said form H is synthesized by co-incubation of form E and form H in 2-butanol for 1 day, said co-incubation comprising adding said form E and said form H to pure 2-butanol until saturation, stirring the resulting suspension at ambient temperature for 1 day, and vacuum filtering the solid to produce form H.

54. 53. The process of claim 52, wherein said form H is synthesized by co-incubation of form E and form H in 2-propanol for 1 day, said co-incubation comprising adding said form E and said form H to pure 2-propanol until saturation, stirring the resulting suspension at ambient temperature for 1 day, and vacuum filtering the solid to produce form H.

55. 1. A process for making form H of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride by seeding form H crystals of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride to synthesize other polymorphic forms of said salt, comprising: Form H is characterized by an X-ray powder diffraction (XRD) pattern having peaks at 11.8, 20.1, 23.6, 25.0, and 26.5 2θ±0.2 2θ, or further characterized by an XRD pattern substantially as shown in FIG. 43 .

56. 56. The process of claim 55, wherein the other polymorphic form is form E, wherein form E is characterized by an XRD pattern having peaks at 9.4, 17.3, 22.1, 23.4, and 24.8 2θ±0.2 2θ, or further characterized by an XRD pattern substantially as shown in FIG.

29.

57. 56. The process of claim 55, wherein the other polymorphic form is form E1, wherein form E1 is characterized by an XRD pattern having peaks at 9.4, 10.9, 17.3, 22.1, and 23.2 2θ±0.2 2θ, or further characterized by an XRD pattern substantially as shown in Figure 30.

58. The use of particular polymorphs of the present invention in pharmaceutical agents used to treat disease.

59. 59. The method of claim 58, wherein the disease is cancer.

60. 60. The method of claim 59, wherein the cancer is prostate cancer, breast cancer, or skin cancer such as melanoma.

61. 59. The method of claim 58, wherein the disease is a viral infection.

63. 62. The method of claim 61, wherein the viral infection is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or influenza.

64. 59. The method of claim 58, wherein the disease is an inflammatory disease.

65. 65. The method of claim 64, wherein the inflammatory disease affects the lungs.

66. 66. The method of claim 65, wherein the inflammatory disease is an infectious disease.

67. 65. The method of claim 64, wherein the inflammatory disease caused acute respiratory distress syndrome (ARDS).

68. 68. The use of any one of claims 59 to 67, wherein the polymorph is any one of form E, form E1, or form H of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride.

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