Polymorphs of [2-(1h-indol-3-yl)-1h-imidazol-4-yl] (3, 4, 5-trimethoxy) methanone and salts thereof

Abstract

The present invention encompasses polymorphic forms of [2-(1H-indol-3-yl)-1H-imidazol-4-yl] (3, 4, 5-trimethoxyphenyl) methanone, and salts thereof. These polymorphs are characterized by their x-ray diffraction patterns and DSC thermograms, as well as other methods. The polymorphic substances are used for preparing pharmaceutical compositions and products.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 336,193, filed on April 28, 2022, and U.S. Provisional Application No. 63 / 336,198, filed on April 28, 2022, which are hereby incorporated by reference. Background Art

[0003] The discovery of novel polymorphs helps to reduce the limitations in preclinical or clinical studies and drug manufacturing processes caused by poor or limited drug solubility, which is usually a challenge in drug development. Polymorphs can provide stable, easy-to-handle drug forms that can simplify processing and administration. However, when considering the various novel polymorphic forms that a compound or its pharmaceutically acceptable salt or solvate may exhibit, finding suitable polymorphs may be a time-consuming and difficult task. There are a variety of polymorphs to choose from, so that the physicochemical properties of the compound can be adjusted by selecting polymorphs, which promotes the manufacture of commercial drug products by the compound. The improvement of physicochemical properties can be achieved by changing 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 stacking array) polymorphs. Without losing drug activity, polymorphs or solvates, salts, hydrates, etc. of unmodified compounds can be screened. The latter three physical forms are different in chemical composition, and therefore technically, they are pseudopolymorphs. Once polymorphism or pseudopolymorphism is established, alternative forms can also be characterized to reveal those with favorable properties. Properties that vary between different polymorphic forms include thermodynamic properties, such as melting and sublimation temperatures and vapor pressures, enthalpy, entropy, heat capacity, free energy, chemical potential, and solubility; kinetic properties, such as dissolution rates, solid-state reaction rates, physical / chemical stability, nucleation / crystal growth rates; 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.

[0004] The most important characteristics during drug discovery and development include solubility, dissolution rate, bioavailability and physical / chemical stability. Other favorable differences in physicochemical properties can include higher melting points, more favorable powder properties, etc., due to the use of optimal polymorphs with higher storage stability in formulations, such as at higher temperatures and / or higher relative humidity, or easier or cheaper manufacturing and / or distribution procedures. In many known cases, there are several polymorphs, and crystallization can be performed simultaneously. However, the system tends to move to thermodynamic equilibrium. In other words, the metastable form in any system will eventually be transformed into the most stable form. Therefore, solid dosage forms should adopt the most stable form to avoid changes in their physicochemical properties. However, the approach to reaching the final state depends on kinetics and other factors, which require that all metastable forms found and the specific conditions that cause mutual conversion to other thermodynamically more stable forms be extensively tested.

[0005] In some cases, certain stable crystalline polymorphs are initially discovered because the energy barrier to nucleation of these less stable polymorphs is relatively low compared to the most stable form. However, much later, these polymorphs may be found to convert to the most thermodynamically stable polymorph. Although the conversion of the less stable form to the most stable form under ambient conditions may be too slow for commercial applications, the process of obtaining a 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 to nucleation of the most stable polymorph, resulting in a method for directly and rapidly preparing pure preparations of the most thermodynamically stable polymorph.

[0006] Polymorphs are found by recrystallization from a single solvent or solvent mixture, heating to induce transformation (e.g., a monotropic polymorph will not change to another form over the entire temperature range), slurry experiments, and other methods known to those skilled in the art. Formulations of active pharmaceutical ingredients (APIs) require the most thermodynamically stable polymorphic form because less stable forms can easily transform into thermodynamically stable forms, such as during compression or storage, resulting in intolerable changes in the properties of the drug product over time, which may lead to FDA withdrawal of the drug product.

[0007] Tubulin inhibitors show 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 show great potential as therapeutic agents. However, none of these colchicine binding site inhibitors have been approved for oncology or virology indications, while colchicine has been approved for anti-inflammatory uses such as gout and familial Mediterranean fever (FMF). [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone is such a tubulin inhibitor compound that is used to treat 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 (WO2022 / 216308) such as acute respiratory distress syndrome (ARDS). The compounds and their activities are disclosed in PCT publications WO2010 / 74776; WO2011 / 109059; WO2012 / 027481; WO2021 / 203100 and WO2022 / 216308, which are hereby incorporated by reference.

[0008] The production of stable polymorphic forms of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone or a pharmaceutically acceptable salt or solvate thereof is advantageous at least for the synthesis, processing and preparation of formulations of the compound. Summary of the invention

[0009] One embodiment of the present invention encompasses a crystalline polymorph Form A of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride characterized by being substantially as Fig.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.

[0010] One 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 (referred to as Form B) characterized (in Example 3) by an XRD pattern having peaks at 9.5, 12.1, 18.0, 18.9 and 23.0 2θ±0.2 2θ. Crystalline polymorph Form B of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride may be further characterized by being substantially as Fig.18 Alternatively, the crystalline polymorph Form B of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride may be further characterized by XRD peaks at 19.2, 28.5, 29.5 and 31.8 2θ±0.2 2θ. The crystalline polymorph Form B of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride may be prepared as in Example 3.

[0011] Another embodiment of the present invention is directed to a crystalline polymorph Form C of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride H , which is characterized by being substantially as Fig. 22 In one aspect of this embodiment, Form C H 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. In another aspect of this embodiment, Form C H The XRD pattern is characterized by having peaks at about 10.3, 18.0, 23.7, 28.7, and 29.7 2θ ± 0.2 2θ.

[0012] Another embodiment of the present invention is directed to a crystalline polymorph Form D of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride characterized by being substantially as follows Fig.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.

[0013] 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 (referred to as Form E) 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. Crystalline polymorph Form E of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride can be further characterized by being substantially as Fig.29 Alternatively, the crystalline polymorph Form E of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride can be further characterized by XRD peaks at 12.9, 15.0, 18.1, 21.0 and 30.3 2θ±0.2 2θ. The crystalline polymorph Form E of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride is formed by the method as described in Examples 4 and 5. One embodiment relates to a method of preparing Form E. In one aspect of this embodiment, Form E is prepared by recrystallization from 2-propanol, 1-propanol / 1-dioxane mixture or ethanol. In one aspect of this embodiment, Form E is prepared by recrystallizing [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, which is added to 2-propanol at saturated concentration at 25° C., heated to 45-50° C. to dissolve the solid, and rapidly evaporated at ambient temperature under a flow of 1.5 psi of N2 to produce solid Form E. In another aspect of this embodiment, Form E is prepared by recrystallizing [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, which is added to 1-propanol / 1-dioxane mixture at saturated concentration at 25° C., and slowly evaporating the solvent at ambient temperature to produce solid Form E. In another embodiment of this embodiment, Form E is prepared by recrystallizing [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, which is added to ethanol at a saturated concentration at 25°C, heated to 45-50°C to dissolve any solids, and rapidly evaporating the solvent at 40°C under a flow of 1.5 psi of N2 to produce Form E.

[0014] 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 (referred to as Form E1) 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. Crystalline polymorph Form E1 of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride may be further characterized by being substantially as Fig.30 Alternatively, the crystalline polymorph Form E1 of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride can be further characterized by XRD peaks at 13.0, 15.1, 18.1, 20.9 and 24.8 2θ±0.2 2θ. The crystalline polymorph Form E1 of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride is formed by the method described in Examples 4 and 5. One embodiment relates to a method for preparing Form E1. In one aspect of this embodiment, Form E1 is prepared by recrystallization from 2-propanol / dichloromethane or 2-propanol / trichloromethane. In one aspect of this embodiment, Form E1 is prepared by recrystallizing [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, which is added to a 2-propanol / dichloromethane binary solvent mixture at a saturated concentration at 25°C, heated to 45-50°C to dissolve the solid, and rapidly evaporated at 40°C under a N2 flow of 1.5 psi to produce solid Form E1. In another aspect of this embodiment, Form E1 is prepared by recrystallizing [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, which is added to a 2-propanol / trichloromethane binary solvent mixture at a saturated concentration at 25°C, heated to 45-50°C to dissolve the solid, and rapidly evaporated at 40°C under a N2 flow of 1.5 psi to produce solid Form E1.

[0015] 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 (referred to as Form F H), characterized by an X-ray powder diffraction (XRD) pattern having peaks at 9.06, 10.4, 18.85, 25.48 and 27.97 2θ ± 0.2 2θ. Crystalline polymorphic form F of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride H The characteristic may be further characterized by XRD peaks at 12.9, 20.9 and 26.14 2θ ± 0.2 2θ. Alternatively, the crystalline polymorph Form F of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride H can be further characterized by being substantially as Fig.38 XRD pattern depicted in. Crystalline polymorphic form F of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride H having a differential scanning calorimetry (DSC) thermogram exhibiting a large split endotherm with an onset at about 90.8°C and a peak maximum at 99.7°C, substantially as Fig.39 Described in.

[0016] In 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 (referred to as Form G H ), characterized by an X-ray powder diffraction (XRD) pattern having peaks at 11.8, 14.5, 16.8, 23.1 and 28.5 2θ ± 0.2 2θ. Crystalline polymorphic form G of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride H The characteristic may be further characterized by XRD peaks at 10.4, 22.3, 24.7 and 25.3 2θ ± 0.2 2θ. Alternatively, the crystalline polymorph Form G of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride H can be further characterized by being substantially as Fig.40 XRD pattern depicted in. 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 having an average value of 4.8% weight loss at 150°C ( Fig.41). Crystalline polymorphic form G of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride H The DSC thermogram has two endotherms with extrapolated onsets at 140.5°C and 246.5°C. Fig.42 ).

[0017] 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 (referred to as Form H), 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. 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 polymorph Form H of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride may be further characterized by being substantially as Fig.43 The XRD pattern depicted in. The crystalline polymorph Form H of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride has a thermogravimetric analysis (TGA) thermogram having an average value of 0.03% weight loss at 150°C, as shown in Fig.44 The crystalline polymorph 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 having a melting onset endotherm starting at 247.5°C and a peak maximum at 250.1°C, as shown in Fig.45Depicted in. In one embodiment, Form H is prepared under ambient conditions. In some embodiments, Form H is prepared from Form E under ambient conditions. In some embodiments, Form H is prepared from Form E1 under ambient conditions. In a certain embodiment, Form H is prepared from other polymorphic forms under ambient conditions. In one embodiment, Form H is prepared by one of two competitive slurry experiments, in which Form E and Form H are slurried in 2-butanol or 2-propanol for 1 day. In these embodiments, in order to avoid possible desolvation or physical changes after separation, the sample is not further dried before X-ray analysis. In one embodiment, the method for preparing Form H involves co-incubating Form E and Form H in 2-butanol for 1 day. In this embodiment, Form E and Form H are added to pure 2-butanol until saturated, the resulting suspension is stirred at ambient temperature for 1 day, and the solid is vacuum filtered and analyzed by XRD to determine that the resulting form is Form H. In another embodiment, the method for preparing Form H involves co-incubating Form E and Form H in 2-propanol for 1 day. In this embodiment, Form E and Form H are added to neat 2-propanol until saturated, the resulting suspension is stirred at ambient temperature for 1 day, and the solid is vacuum filtered and analyzed by XRD to confirm that the resulting form is Form H.

[0018] 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, referred to as Form I, characterized by an X-ray powder diffraction (XRD) pattern having peaks at 10.0, 10.6, 16.6, 23.7, and 25.7 2θ±0.2 2θ. 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 polymorph Form I of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride may be further characterized by being substantially as Fig.46 XRD pattern depicted in .

[0019] In another embodiment, the present invention encompasses the hydrochloride salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone characterized by at least the following polymorphic forms: characterized by as described herein and Fig.47 The X-ray powder diffraction (XRD) patterns shown in Form A, Form B, Form C H , Form D, Form E, Form E1, Form FH , Form G H , Form H and Form I.

[0020] 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, referred to as Form II, characterized by an X-ray powder diffraction (XRD) pattern having peaks at 10.8, 15.3, 15.9, 18.6, and 25.9 2θ±0.2 2θ. The crystalline polymorph 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 being substantially as Figure 1 Alternatively, the crystalline polymorph 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.

[0021] 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 can be further characterized by being substantially as Figure 5 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±0.22θ. 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.

[0022] 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 being substantially as Fig.15 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.

[0023] In another embodiment of the present invention, the polymorphs of the present invention are used to treat a disease. Some of these embodiments encompass the use of the polymorphs of the present invention for treating cancer. In some of these embodiments, as known to the skilled person, the cancer is prostate cancer, breast cancer, skin cancer or cancer of other organs. Some of these embodiments encompass the use of the polymorphs of the present invention for treating 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 the polymorphs of the present invention for treating inflammatory diseases. In some of these embodiments, the inflammatory disease affects the lungs. In other embodiments of these embodiments, the inflammatory disease is an infection. In some embodiments, the inflammatory disease has caused acute respiratory distress syndrome (ARDS). In some of these embodiments, the use of the polymorphs of the present invention for diseases comprises 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

[0024] Figure 1 Shown is an X-ray powder diffraction (XRD) pattern of polymorphic Form II of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone free base (Form II).

[0025] Figure 2 A differential scanning calorimetry (DSC) thermogram of Form II is shown.

[0026] Figure 3 A thermogravimetric analysis (TGA) thermogram of Form II is illustrated.

[0027] Figure 4 Shown are samples of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone free base slurried in acetone (top spectrum), THF (second spectrum down), and toluene (third spectrum down), which produced Figure 1 The XRD pattern of Form II is similar to that of Form II, 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.

[0028] Figure 5 An XRD pattern of a polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride is shown, indicating that the salt form is crystalline. This unnamed crystalline polymorphic form of the hydrochloride salt was prepared by the method of Example 1 or 2 (small-scale synthesis and scale-up of the hydrochloride salt).

[0029] Figure 6 The DSC curve of an unnamed crystalline form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride prepared by the method of Example 1 or 2 is shown, which shows multiple thermal events before the final melting onset endotherm at approximately 211.9°C.

[0030] Figure 7 The TGA curve of an unnamed crystalline form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride prepared by the method of Example 1 or 2 is shown, which shows a continuous weight loss of about 0.54% to 4.1% from 25°C to 110°C.

[0031] Fig. 8A 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 prepared by the method of Example 1 or 2 are presented, which show non-stoichiometric uptake of water in the form of a hydrate in a complex that can be formed at relative humidity (RH) above 30-40%. Figure 8B A DVS with a top line for adsorption and a bottom line for desorption is shown.

[0032] Fig. 9 The XRD pattern of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone citrate prepared by the method of Example 1 or 2 is shown, indicating a low-order crystalline solid.

[0033] Fig.10 The DSC curve of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone citrate of Example 1 or 2 is shown, which exhibits a small exothermic transition at approximately 130°C, followed by a broad melting onset endotherm at approximately 184.5°C.

[0034] Fig.11 The TGA curve of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone citrate of Example 1 or 2 is shown, which shows a weight loss of about 0.38% to 1.13% from 25° C. to 125° C., followed by decomposition.

[0035] Fig.12 The XRD pattern of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone phosphate prepared by the method of Example 1 or 2 is shown, wherein the crystallinity indicates a preferred crystallite orientation.

[0036] Fig.13 The DSC curve of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone phosphate of Example 1 or 2 is shown, which shows a volatilization loss at about 149°C to 152°C, followed by exothermic recrystallization at 158.7°C, and a melting onset endotherm at about 216°C to 219°C, followed by decomposition.

[0037] Fig.14 The TGA curve of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone phosphate of Example 1 or 2 is shown, which shows a continuous weight loss, wherein the weight loss is about 2.6% to 2.88%, which may be due to volatilization loss from 25°C to 100°C, followed by further decomposition.

[0038] Fig.15 The XRD pattern of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone methanesulfonate prepared by the method of Example 1 or 2 is shown, which shows a crystalline solid.

[0039] Fig.16The DSC curve of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone methanesulfonate of Example 1 or 2 is shown, which exhibits a fairly obvious 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.

[0040] Fig.17 The TGA curve of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone methanesulfonate of Example 1 or 2 is shown, which shows a weight loss of 0.51% from about 25°C to 120-150°C, followed by decomposition.

[0041] Fig.18 Shown is the XRD pattern of polymorph Form B of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, prepared by recrystallization from a binary solvent mixture of methanol / acetonitrile as described in Example 3 (Form B).

[0042] Fig.19 A TGA thermogram of Form B is presented, showing an average value of less than 0.05% weight loss at 150°C.

[0043] Fig. 20 A DSC thermogram of Form B is presented which exhibits a distinct melting onset endotherm with an average onset of approximately 247.4 °C.

[0044] Fig.21 A solid-state Fourier transform infrared (FT-IR) spectrum of Form B is shown.

[0045] Fig. 22 The polymorphic form C of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride prepared as described in Example 6 is shown. H (Form C H )'s XRD pattern; the form is a hydrate.

[0046] Fig.23 Shows form C H TGA thermogram of .

[0047] Fig.24 Shows form C H DSC thermogram of .

[0048] Fig.25Shown is an XRD pattern of polymorphic Form D (Form D) of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride prepared by the noncompetitive slurry method described in Example 4.

[0049] Fig.26 The TGA thermogram of Form D is shown.

[0050] Fig. 27 The DSC thermogram of Form D is shown.

[0051] Fig.28 The solid state FTIR spectrum of Form D is shown.

[0052] Fig.29 Shown is the XRD pattern of polymorph Form E of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, which was prepared as a result of the various methods described in Examples 3 and 5 (Form E).

[0053] Fig.30 Shown is an XRD pattern of polymorphic Form E1 of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, which was prepared as a result of the various methods described in Examples 3-5 (Form E1).

[0054] Fig.31 A TGA thermogram of Form E is presented, which exhibits a weight loss of approximately 0.66% at 150 °C.

[0055] Fig.32 A DSC thermogram of Form E is presented which exhibits a melting onset endotherm at approximately 239.6°C followed by extensive decomposition.

[0056] Fig.33 The solid state FTIR spectrum of Form E is shown.

[0057] Fig.34 A DSC thermogram of Form El is presented which exhibits a melting onset endotherm at approximately 243.2 °C followed by extensive decomposition.

[0058] Fig.35 Shown is an XRD pattern of polymorph Form A of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride prepared in Example 3 by recrystallization from 1-propanol / nitromethane as described herein (Form A).

[0059] Fig.36 A TGA thermogram of Form A free of volatiles is shown, with a weight loss of about 0.04% from 25°C to 150°C.

[0060] Fig.37 A DSC thermogram of Form A is presented which exhibits a melting onset endotherm with an average onset of approximately 250.3 °C.

[0061] Fig.38 The polymorphic form F of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride prepared according to Example 6 is shown. H (Form F H )’s XRD pattern.

[0062] Fig.39 Shows form F H The DSC thermogram of the present invention exhibits a large split endotherm starting at about 90.8° C. with peak maxima at 99.7° C. and 119.6° C. The Karl Fischer (KF) moisture content is 14 wt %.

[0063] Fig.40 The polymorphic form G of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride prepared according to Example 6 is shown. H (Form G H )’s XRD pattern.

[0064] Fig.41 Showing form G H TGA thermogram of .

[0065] Fig.42 Showing form G H DSC thermogram of .

[0066] Fig.43 The XRD pattern of polymorphic Form H (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 is shown.

[0067] Fig.44 Shown is a TGA thermogram of Form H [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride.

[0068] Fig.45 The DSC thermogram of Form H is shown.

[0069] Fig.46The 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 is shown.

[0070] Fig.47 Shown in forms A, B, C H , D, E, F H , G H Overlay of XRD diffraction patterns of I. DETAILED DESCRIPTION

[0071] Polymorphism is the ability of a chemical entity to exist in different three-dimensional arrangements in the solid state. Different polymorphic forms of a compound can have different physicochemical properties. [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone is a tubulin inhibitor compound that is used to treat 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 relates to the synthesis (preparation method or process) and compositions of stable polymorphic forms of the compound [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone and pharmaceutically acceptable salts and solvates thereof, and methods of using them. Particular emphasis is placed on the characterization of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride and its hydrates. Without being limited by theory, it is believed that stable polymorphic forms will be useful during transportation and formulation of the compound and obtaining generally pure compounds. The most desirable form is the most thermodynamically stable polymorphic form. In order to determine the most thermodynamically stable compound and its polymorphs, samples of the free base and its pharmaceutically acceptable salts, solvates and hydrates of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone 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 as described herein. Further, those skilled in the art will appreciate that these compounds and their novel polymorphs may have advantages in the treatment of cancer, viral infections and inflammatory diseases, such as increasing the solubility or bioavailability of the API, or increasing the stability of the drug product containing the API.

[0072] Characterization of the free base of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone (Example 1): The method for preparing the crystalline polymorph Form II (Form II) of the free base of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone was by recrystallizing the amorphous form of the free base (Form I) ( Figure 1 ). Other methods for preparing Form II of the free base include non-competitive single solvent slurry experiments using the amorphous form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone free base (Form I) by the method described in Example 4. An excess of the free base (Form I) is slurried in methanol, ethanol, acetone, acetonitrile, ethyl acetate, THF, or toluene. The suspension is slurried at ambient temperature for several days. The solids are collected by filtration and analyzed by XRD. Samples slurried in acetone, THF, and toluene produce Form II of the free base, as shown by the superposition of the XRD spectra from these experiments ( Figure 4 ). Figure 1 An X-ray powder diffraction (XRD) pattern of Form II of the free base is presented. Form II of the free base is characterized by an XRD pattern having peaks at approximately 10.8, 15.3, 15.9, 18.6 and 25.9 2θ ± 0.2.

[0073] Form II of the free base is further characterized by an XRD pattern having peaks at 14.4, 17.8, 20.0, 24.7, and 26.8 2Θ ± 0.2 2Θ.

[0074] like Figure 2 As shown, the DSC thermogram of Form II of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone free base shows a distinct melting endotherm with an extrapolated onset temperature of 205.2°C and a peak temperature of 208.7°C. The enthalpy indicated by DSC is 103.9 J / g. A small endothermic drop observed at 190°C may indicate a phase transition. The TGA thermogram shows that [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone free base Form II loses about 0.2 wt% at 150°C, and as Figure 3 As shown above, a sample 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 a reaction similar to Figure 1 The XRD pattern of Form II indicates that the free base is in a stable form ( Figure 4). This also indicates that the slurry process for preparing Form II of the free base from the amorphous Form I of the free base can alternatively be achieved using acetone, THF or toluene.

[0075] Salt Screening of Free Base [2-(1H-Indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone (Example 1): Salt screening studies were performed to identify suitable polymorphic salts formed by reaction of a hydrochloric acid library with [2-(1H-Indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone free base. Initially, salt characterization was performed with four salts at a small scale (40 mg) and was believed to produce the desired polymorph. Small scale synthesis and characterization were performed as described in Example 1. Preferred salts were the hydrochloride, citrate, phosphate, and methanesulfonate 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 considered for processability, therapeutic use and other factors. Scaled-up salt synthesis is described in Example 2 and Table 1 (in Example 2).

[0076] Scale-up of hydrochloride, citrate, phosphate and mesylate salts (Example 2): Monohydrochloride (HCl), citrate, monophosphate (phosphate) and mesylate polymorphs were selected for scale-up. Salts were prepared on a 200-500 mg scale to facilitate additional testing and to determine reproducibility. A typical procedure is shown in Table 1 of Example 2. Solids were collected by evaporation under ambient conditions with a nitrogen purge of approximately 2 psi. All solids produced the same XRD pattern as seen in earlier small-scale experiments and were reproducible.

[0077] As described in Examples 1 and 2, salt screening studies were performed to identify suitable polymorphic salts formed by reaction of a hydrochloric acid library with [2-(1H-indol-3-yl)-1H-imidazole-4-yl](3,4,5-trimethoxyphenyl)methanone free base. Initially, salt characterization was performed with four salts on a small scale (40 mg) and was considered to produce the desired polymorphs. Small-scale synthesis and characterization were performed as described in Example 1. The preferred salts of Example 1 are the hydrochloride, citrate, phosphate, and methanesulfonate salts of [2-(1H-indol-3-yl)-1H-imidazole-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 considered for processability, therapeutic use, and other factors. The scaled-up salt synthesis is described in this Example and Table 1.

[0078] One embodiment of the present invention relates 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 relates to any polymorph 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 are distinguished by X-ray powder diffraction (XRD) spectroscopy and further characterized by DSC, TGA, DVS and other methods as described herein. Some embodiments of the present invention encompass methods by which specific polymorphs can be synthesized. In some embodiments, the polymorphs of interest can be synthesized by one or more of the following: a recrystallization method, or a non-competitive or competitive slurry method as described herein for each polymorph. In another embodiment of the present invention, a specific polymorph is used in a drug product for treating a disease. In some embodiments, a specific polymorph is used in a drug product for treating cancer. In some embodiments, as known to the skilled person, the cancer is prostate cancer, breast cancer, skin cancer such as melanoma or cancer of other organs. In some embodiments, a specific polymorph is used in a drug product for treating a viral infection. In some embodiments, the viral infection is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or influenza. In some embodiments, a specific polymorph is used in a drug product for treating an inflammatory disease. In some embodiments, the inflammatory disease affects the lungs. In some embodiments, the inflammatory disease is an infection. In some embodiments, the inflammatory disease has caused acute respiratory distress syndrome (ARDS).

[0079] As used herein, "drug product" means a therapeutically effective amount of a specific polymorph of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride and various excipients, such as suitable diluents, preservatives, solubilizers, emulsifiers, adjuvants and / or carriers.

[0080] One embodiment of the present invention relates to a polymorph of the hydrochloride salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone characterized in that it is substantially as follows Figure 5In another embodiment, this crystalline polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride 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. In another embodiment, this crystalline polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride is further characterized by an XRD pattern having peaks at about 10.5, 14.1, 16.1, and 26.2 2θ±0.2 2θ.

[0081] Another embodiment of the present invention is directed to a crystalline polymorph Form A of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride characterized by being substantially as follows Fig.35In 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. One embodiment relates to a method of preparing Form A. In one aspect of this embodiment, Form A is prepared by recrystallization from a 1-propanol / nitromethane binary solvent mixture. In another aspect of this embodiment, Form A is prepared from [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, which is added to 1-propanol / nitromethane at saturated concentration at 25°C, heated to 45-50°C to dissolve the solid, and rapidly evaporated at 40°C under a flow of 1.5 psi of N2 to produce solid Form A. In another embodiment of the invention, Form A is used in a pharmaceutical product for treating a disease. Some of these embodiments encompass the use of Form A in a pharmaceutical product for treating cancer. In some of these embodiments, the cancer is prostate cancer, breast cancer, skin cancer, or cancer of other organs, as known to a skilled artisan. Some of these embodiments encompass the use of Form A in a pharmaceutical product for treating 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 encompass the use of Form A in a pharmaceutical product for treating an inflammatory disease. In some of these embodiments, the inflammatory disease affects the lungs. In others of these embodiments, the inflammatory disease is an infection. In some embodiments, the inflammatory disease has caused acute respiratory distress syndrome (ARDS).

[0082] Another embodiment of the present invention is directed to a crystalline polymorph Form B of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride characterized by being substantially as follows Fig.18In one aspect of this embodiment, Form B is 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 is 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 is prepared by recrystallization from a methanol / acetonitrile binary solvent mixture. In another aspect of this embodiment, Form E is prepared from [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, which is added to methanol / acetonitrile at saturation concentration at 25°C, heated to 45-50°C to dissolve the solid, and flash evaporated at 40°C under a 1.5 psi N2 flow to produce solid Form B. In another aspect of this embodiment, Form B is prepared from Form C H Form B is prepared by competitive slurrying of Form C and Form B in ethyl acetate. In this embodiment, Form B is prepared by adding excess Form C to pure ethyl acetate. H and Form B until saturated, the resulting suspension is stirred at ambient temperature for about two weeks, and the solid is vacuum filtered and analyzed by XRD to determine that the resulting form is Form B. In another embodiment of the present invention, Form B is used in a pharmaceutical product for treating a disease. Some of these embodiments encompass the use of Form B in a pharmaceutical product for treating cancer. In some of these embodiments, as known to the skilled person, the cancer is prostate cancer, breast cancer, skin cancer, or cancer of other organs. Some of these embodiments encompass the use of Form B in a pharmaceutical product for treating 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 encompass the use of Form B in a pharmaceutical product for treating an inflammatory disease. In some of these embodiments, the inflammatory disease affects the lungs. In other embodiments of these embodiments, the inflammatory disease is an infection. In some embodiments, the inflammatory disease has caused acute respiratory distress syndrome (ARDS).

[0083] Another embodiment of the present invention is directed to a crystalline polymorph Form C of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride H , which is characterized by being substantially as Fig. 22 In one aspect of this embodiment, Form C His characterized by an XRD pattern having peaks at about 5.1, 13.1, 16.6, 22.5, and 25.7 2θ ± 0.2 2θ. In another aspect of this embodiment, Form C 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. In another embodiment of the invention, Form C H Use in a pharmaceutical product for treating a disease. Some of these embodiments encompass the use of Form C in a pharmaceutical product for treating cancer. H In some of these embodiments, the cancer is prostate cancer, breast cancer, skin cancer, or cancer of other organs, as known to the skilled artisan. Some of these embodiments encompass the use of Form C in a pharmaceutical product for treating a viral infection. H In some of these embodiments, the viral infection is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or influenza. In some of these embodiments, the use of Form C in a pharmaceutical product for treating 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 has caused acute respiratory distress syndrome (ARDS).

[0084] Another embodiment of the present invention is directed to a crystalline polymorph Form D of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride characterized by being substantially as follows Fig.25In 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. One embodiment relates to the preparation of Form D. In one aspect of this embodiment, Form D is prepared by a non-competitive slurry experiment, wherein Form B is slurried in a non-aqueous solvent, acetone or acetonitrile, for 14 days. In one embodiment, the method for preparing Form D involves non-competitive slurrying of Form B in acetone for 14 days. In this embodiment, an excess of Form B is added to pure acetone until saturated, the resulting suspension is stirred at ambient temperature for fourteen days, and the solid is vacuum filtered and analyzed by XRD to determine that the resulting form is Form D. In another embodiment, the method for preparing Form D involves non-competitive slurrying of Form B in acetonitrile for 14 days. In this embodiment, an excess of Form B is added to pure acetonitrile until saturated, the resulting suspension is stirred at ambient temperature for fourteen days, and the solid is vacuum filtered and analyzed by XRD to determine that the resulting form is Form D. In another embodiment of the invention, Form D is used in a pharmaceutical product for treating a disease. Some of these embodiments encompass the use of Form D in a pharmaceutical product for treating cancer. In some of these embodiments, as known to the skilled person, the cancer is prostate cancer, breast cancer, skin cancer, or cancer of other organs. Some of these embodiments encompass the use of Form D in a pharmaceutical product for treating 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 encompass the use of Form D in a pharmaceutical product for treating an inflammatory disease. In some of these embodiments, the inflammatory disease affects the lungs. In other embodiments of these embodiments, the inflammatory disease is an infection. In some embodiments, the inflammatory disease has caused acute respiratory distress syndrome (ARDS).

[0085] Another embodiment of the present invention is directed to a crystalline polymorph Form E of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride characterized by being substantially as Fig.29In one aspect of this embodiment, Form E is 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 is characterized by an XRD pattern having peaks at about 12.9, 15.0, 18.1, 21.0, and 30.3 2θ ± 0.2 2θ. Except for a minor difference between the two diffraction patterns in the 10-12 ° 2θ region, the two patterns of Form E and Form E1 appear very similar.

[0086] One embodiment relates to the preparation of Form E. In one aspect of this embodiment, Form E is prepared by recrystallization from 2-propanol, 1-propanol / 1-dioxane mixtures, or ethanol. In one aspect of this embodiment, Form E is prepared by recrystallization of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, which is added to 2-propanol at saturation concentration at 25°C, heated to 45-50°C to dissolve the solid, and rapidly evaporated at ambient temperature under a flow of 1.5 psi of N2 to produce solid Form E. In another aspect of this embodiment, Form E is prepared by recrystallization of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, which is added to 1-propanol / 1-dioxane mixtures at saturation concentration at 25°C, and slowly evaporating the solvent at ambient temperature to produce solid Form E. In another embodiment of this embodiment, Form E is prepared by recrystallizing [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, which is added to ethanol at saturation concentration at 25°C, heated to 45-50°C to dissolve any solids, and the solvent is rapidly evaporated at 40°C under a flow of 1.5 psi of N2 to produce Form E. In one embodiment, Form E is prepared by a competitive slurry experiment in which a binary combination of Form A, Form B, and Form D is slurried in 1-propanol for about two weeks. In one aspect of this embodiment, the method for preparing Form E involves 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 are added to neat 1-propanol until saturated, the resulting suspension is stirred at ambient temperature for about two weeks, and the solids are vacuum filtered and analyzed by XRD to determine that the resulting form is Form E. In another embodiment, the method for preparing Form E involves 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 are added to pure 1-propanol until saturated, the resulting suspension is stirred at ambient temperature for about two weeks, and the solid is vacuum filtered and analyzed by XRD to determine that the resulting form is Form E. In another embodiment of the present invention, Form E is used in a pharmaceutical product for treating a disease. Some of these embodiments encompass the use of Form E in a pharmaceutical product for treating cancer. In some of these embodiments, as known to the skilled person, the cancer is prostate cancer, breast cancer, skin cancer, or cancer of other organs. Some of these embodiments encompass the use of Form E in a pharmaceutical product for treating 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 encompass the use of Form E in a pharmaceutical product 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 has caused acute respiratory distress syndrome (ARDS).

[0087] Another embodiment of the present invention is directed to a crystalline polymorph Form E1 of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride characterized in that it is substantially as follows Fig.30 In one aspect of this embodiment, Form E1 is 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 is characterized by an XRD pattern having peaks at about 13.0, 15.1, 18.1, 20.9, and 24.8 2θ ± 0.2 2θ. Except for a slight difference between the two diffraction patterns in the 10-12 ° 2θ region, the two patterns of Form E and Form E1 appear very similar.

[0088] One embodiment relates to the preparation of Form E1. In one aspect of this embodiment, Form E1 is prepared by recrystallization from 2-propanol / dichloromethane or 2-propanol / trichloromethane. In one aspect of this embodiment, Form E1 is prepared by recrystallization of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, which is added to a 2-propanol / dichloromethane binary solvent mixture at saturated concentration at 25°C, heated to 45-50°C to dissolve the solid, and rapidly evaporated at 40°C under a N2 flow of 1.5 psi to produce solid Form E1. In another aspect of this embodiment, Form E1 is prepared by recrystallizing [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, which is added to a saturated concentration in a 2-propanol / chloroform binary solvent mixture at 25°C, heated to 45-50°C to dissolve the solid, and rapidly evaporated at 40°C under a N2 flow of 1.5 psi to produce solid Form E1.

[0089] One embodiment relates to the preparation of Form E1. In one aspect of this embodiment, the method for preparing Form E1 involves non-competitive slurrying of Form B in any one of five binary solvent mixtures for 11 days, and the binary solvent mixture comprises ethanol / toluene, acetonitrile (ACN) / acetone, ethanol / acetonitrile, 1-propanol / ethyl acetate (EtOAc) or 2-propanol / tetrahydrofuran (THF). In these embodiments, in order to avoid possible desolvation or physical changes after separation, the sample is not further dried before X-ray analysis. In this embodiment, the method for preparing Form E1 involves non-competitive slurrying of Form B in a non-aqueous binary solvent system of ethanol / toluene for 11 days. In this embodiment, an excess of Form B is added to the ethanol / toluene mixture until saturated, the resulting suspension is stirred at ambient temperature for eleven days, and the solid is vacuum filtered and analyzed by XRD to determine that the resulting form is Form E1. In another embodiment, the method for preparing Form E1 involves non-competitive slurrying of Form B in a non-aqueous binary solvent system of acetonitrile (ACN) / acetone for 11 days. In this embodiment, an excess of Form B is added to an acetonitrile (ACN) / acetone mixture until saturated, the resulting suspension is stirred at ambient temperature for eleven days, and the solid is vacuum filtered and analyzed by XRD to determine that the resulting form is Form E1. In another embodiment, the method for preparing Form E1 involves non-competitive slurrying of Form B in a non-aqueous binary solvent system of ethanol / acetonitrile for 11 days. In this embodiment, an excess of Form B is added to an ethanol / acetonitrile mixture until saturated, the resulting suspension is stirred at ambient temperature for eleven days, and the solid is vacuum filtered and analyzed by XRD to determine that the resulting form is Form E1. In another embodiment, the method for preparing Form E1 involves 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, an excess of Form B is added to a 1-propanol / ethyl acetate (EtOAc) mixture until saturated, the resulting suspension is stirred at ambient temperature for eleven days, and the solid is vacuum filtered and analyzed by XRD to determine that the resulting form is Form E1. In another embodiment, the method for preparing Form E1 involves non-competitive slurrying of Form B in a non-aqueous binary solvent system of 2-propanol / tetrahydrofuran (THF) for 11 days. In this embodiment, an excess of Form B is added to the 2-propanol / tetrahydrofuran (THF) mixture until saturated, the resulting suspension is stirred at ambient temperature for eleven days, and the solid is vacuum filtered and analyzed by XRD to confirm that the resulting form is Form E1.

[0090] In one embodiment, Form E1 is prepared by any of four competitive slurry experiments, wherein Form A, Form B, Form CH A binary combination of Form E1, Form D, and Form E is slurried in 1-propanol for about two weeks. In these embodiments, to avoid possible desolvation or physical changes after separation, the sample is not further dried before X-ray analysis. In one embodiment, the method for preparing Form E1 involves slurrying Form C H and Form B in 1-propanol for about 2 weeks. In this embodiment, Form C H and Form B are added to pure 1-propanol until saturated, the resulting suspension is stirred at ambient temperature for about two weeks, and the solid is vacuum filtered and analyzed by XRD to determine that the resulting form is Form E1. In another embodiment, the method for preparing Form E1 involves co-incubating Form A and Form D in 1-propanol for about 2 weeks. In this embodiment, Form A and Form D are added to pure 1-propanol until saturated, the resulting suspension is stirred at ambient temperature for about two weeks, and the solid is vacuum filtered and analyzed by XRD to determine that the resulting form is Form E1. In another embodiment, the method for preparing Form E1 involves co-incubating Form B and Form E in 1-propanol for about 2 weeks. In this embodiment, Form B and Form E are added to pure 1-propanol until saturated, the resulting suspension is stirred at ambient temperature for about two weeks, and the solid is vacuum filtered and analyzed by XRD to determine that the resulting form is Form E1. In another embodiment, the method for preparing Form E1 involves co-incubating Form D and Form E in 1-propanol for about 2 weeks. In this embodiment, Form D and Form E are added to pure 1-propanol until saturated, the resulting suspension is stirred at ambient temperature for about two weeks, and the solid is vacuum filtered and analyzed by XRD to determine that the resulting form is Form E1. In another embodiment of the present invention, Form E1 is used in a pharmaceutical product for treating a disease. Some of these embodiments encompass the use of Form E1 in a pharmaceutical product for treating cancer. In some of these embodiments, as known to the skilled person, the cancer is prostate cancer, breast cancer, skin cancer, or cancer of other organs. Some of these embodiments encompass the use of Form E1 in a pharmaceutical product for treating 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 encompass the use of Form E1 in a pharmaceutical product for treating an inflammatory disease. In some of these embodiments, the inflammatory disease affects the lungs. In other embodiments of these embodiments, the inflammatory disease is an infection. In some embodiments, the inflammatory disease has caused acute respiratory distress syndrome (ARDS).

[0091] Another embodiment of the present invention is directed to a crystalline polymorph Form F of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride H , which is characterized by being substantially as Fig.38 In one aspect of this embodiment, Form F H 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. In another aspect of this embodiment, Form F H An XRD pattern characterized by peaks at about 12.9, 20.9, and 26.14 2θ ± 0.2 2θ. One embodiment involves the preparation of Form F from Form E or Form E1 under ambient conditions. H In another embodiment of the invention, Form F H Use in a pharmaceutical product for treating a disease. Some of these embodiments encompass the use of Form F in a pharmaceutical product for treating cancer. H In some of these embodiments, the cancer is prostate cancer, breast cancer, skin cancer, or cancer of other organs, as known to the skilled artisan. Some of these embodiments encompass the use of Form F in a pharmaceutical product for treating a viral infection. H In some of these embodiments, the viral infection is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or influenza. In some of these embodiments, the use of Form F in a pharmaceutical product for treating 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 has caused acute respiratory distress syndrome (ARDS).

[0092] Another embodiment of the present invention is directed to a crystalline polymorph Form G of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride H , which is characterized by being substantially as Fig.40 In one aspect of this embodiment, Form G H 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. In another aspect of this embodiment, Form G HAn XRD pattern characterized by peaks at about 10.4, 22.3, 24.7, and 25.3 2θ ± 0.2 2θ. One embodiment involves the preparation of Form G from Form E or Form E1 under ambient conditions. H In another embodiment of the invention, Form G H Use in a pharmaceutical product for treating a disease. Some of these embodiments encompass the use of Form G in a pharmaceutical product for treating cancer. H In some of these embodiments, the cancer is prostate cancer, breast cancer, skin cancer, or cancer of other organs, as known to the skilled artisan. Some of these embodiments encompass the use of Form G in a pharmaceutical product for treating a viral infection. H In some of these embodiments, the viral infection is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or influenza. In some of these embodiments, the use of Form G in a pharmaceutical product for treating 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 has caused acute respiratory distress syndrome (ARDS).

[0093] Another embodiment of the present invention is directed to a crystalline polymorph Form H of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride characterized by being substantially as follows Fig.43 In one aspect of this embodiment, Form H is 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 is characterized by an XRD pattern having peaks at about 8.6, 12.5, 18.6, 21.2, and 28.1 2θ ± 0.2 2θ. One embodiment relates to preparing Form H from Form E under ambient conditions. Another embodiment relates to preparing Form H from Form E1 under ambient conditions. Another embodiment relates to preparing Form H from any polymorphic form of [2-(1H-indol-3-yl)-1H-imidazole-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride stored under ambient conditions. In one embodiment, the conversion to Form E, Form El or any other polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride occurs under ambient conditions in the absence of any Form H seed crystals.

[0094] In one embodiment, Form H is prepared by one of two competitive slurry experiments, in which Form E and Form H are slurried in 2-butanol or 2-propanol for 1 day. In these embodiments, in order to avoid possible desolvation or physical changes after separation, the sample is not further dried before X-ray analysis. In one embodiment, the method for preparing Form H involves co-incubating Form E and Form H in 2-butanol for 1 day. In this embodiment, Form E and Form H are added to pure 2-butanol until saturated, the resulting suspension is stirred at ambient temperature for 1 day, and the solid is vacuum filtered and analyzed by XRD to determine that the resulting form is Form H. In another embodiment, the method for preparing Form H involves co-incubating Form E and Form H in 2-propanol for 1 day. In this embodiment, Form E and Form H are added to pure 2-propanol until saturated, the resulting suspension is stirred at ambient temperature for 1 day, and the solid is vacuum filtered and analyzed by XRD to determine that the resulting form is Form H. In one embodiment, a method for preparing substantially pure Form H involves synthesizing [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 method for preparing substantially pure Form H involves converting Form E to Form H in the presence of trace amounts of Form H seed crystals. In some embodiments, kilogram quantities of Form H can be prepared from crude [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride of any polymorphic form in the presence of gram quantities 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.

[0095] In another embodiment of the invention, Form H is used in a pharmaceutical product for treating a disease. Some of these embodiments encompass the use of Form H in a pharmaceutical product for treating cancer. In some of these embodiments, as known to the skilled person, the cancer is prostate cancer, breast cancer, skin cancer, or cancer of other organs. Some of these embodiments encompass the use of Form H in a pharmaceutical product for treating 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 encompass the use of Form H in a pharmaceutical product for treating an inflammatory disease. In some of these embodiments, the inflammatory disease affects the lungs. In other embodiments of these embodiments, the inflammatory disease is an infection. In some embodiments, the inflammatory disease has caused acute respiratory distress syndrome (ARDS).

[0096] Another embodiment of the present invention is directed to a crystalline polymorph Form I of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride characterized by being substantially as follows Fig.46 In one aspect of this embodiment, Form I of the HCl salt is 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 is 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 pharmaceutical product for treating a disease. Some of these embodiments encompass the use of Form I of the HCl salt in a pharmaceutical product for treating cancer. In some of these embodiments, as known to the skilled person, the cancer is prostate cancer, breast cancer, skin cancer, or cancer of other organs. Some of these embodiments encompass the use of Form I of the HCl salt in a pharmaceutical product for treating 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 encompass the use of Form I of the HCl salt in a pharmaceutical product for treating 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 has caused acute respiratory distress syndrome (ARDS).

[0097] One embodiment of the present invention relates to a methanesulfonate salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone. Another embodiment of the present invention relates to a polymorph of a methanesulfonate salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone as characterized herein. In one embodiment, a crystalline polymorph of a methanesulfonate salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone is characterized as being substantially as Fig.15 In one aspect of this embodiment, the crystalline polymorph of the mesylate salt is characterized by an XRD pattern having peaks at about 8.3, 9.9, 10.9, 17.5, and 19.9 2θ0.2 2θ. In another aspect of this embodiment, the crystalline polymorph of the mesylate salt is characterized by an XRD pattern having peaks at about 12.1, 18.8, 21.9, 24.5, and 28.2 2θ0.2 2θ.

[0098] One embodiment of the present invention relates 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 relates to a polymorph of a phosphate salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone as characterized herein. In one embodiment, a crystalline polymorph of a phosphate salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone is characterized as being substantially as Fig.12 In one aspect of this embodiment, the crystalline polymorph of the phosphate salt is characterized by an XRD pattern having peaks at about 5.7, 9.3, 12.4, 12.6, and 18.8 2θ0.2 2θ. In another aspect of this embodiment, the crystalline polymorph of the phosphate salt is characterized by an XRD pattern having peaks at about 9.7, 10.9, 11.6, and 20.7 2θ0.2 2θ.

[0099] One embodiment of the present invention relates 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 relates to a polymorph of a citrate salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone as characterized herein. In one embodiment, a crystalline polymorph of a citrate salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone is characterized as being substantially as Fig. 9In one aspect of this embodiment, the crystalline polymorph of the citrate salt is characterized by an XRD pattern having peaks at about 9.7, 10.7, 15.1, 15.6, and 22.1 2θ0.2 2θ. In another aspect of this embodiment, the crystalline polymorph of the citrate salt is characterized by an XRD pattern having peaks at about 18.6, 19.2, 26.4, and 27.1 2θ0.2 2θ.

[0100] 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 a lower safety risk relative to other salt forms. The use of Class I salts is not limited because they form physiologically ubiquitous ions or occur as intermediate metabolites in biochemical pathways. The [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride formed in Example 2 is crystalline polymorphic and has good solubility in unbuffered water (less than 1 mg / mL). This unnamed polymorph of the hydrochloride also shows evidence of the potential formation of hydrates at about 30-40% RH (relative humidity), specifically at about 50% RH.

[0101] The XRD pattern of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride formed in Example 2 shows that the compound is crystalline, as shown in FIG. Figure 5 This unnamed crystalline polymorph does not appear to be related to any other polymorphic forms of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride characterized herein, including Forms A, B, C, 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 is characterized by an XRD pattern having peaks at approximately 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 is further characterized by an XRD pattern having peaks at 10.5, 14.1, 16.1 and 26.2 2θ±0.2 2θ. Figure 6As shown, the DSC curve shows multiple thermal events before the final melting onset endotherm at about 235.7°C. Figure 7 As shown, the TGA curve shows a continuous weight loss from 25°C to 110°C, with a weight loss of about 0.54% to 4.1%. The hygroscopicity was determined using dynamic vapor sorption (DVS). As shown in Figure 8, the DVS data showed non-stoichiometric water uptake, as hydrates may form in the composite above 30-40% RH, and at 90% RH, the total adsorption of water was about 8.8 wt% to 14.9 wt%.

[0102] [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone citrate has moderate crystallinity and good solubility in unbuffered water (approximately 1 mg / mL). [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone citrate is polymorphic and shows evidence of possible dihydrate formation at approximately 30-40% RH, specifically 60% RH (data not shown). Fig. 9 As shown, the XRD pattern of the small scale citrate salt (synthesized according to Example 1) indicates a low-order crystalline solid. The crystalline polymorph of crystalline [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone citrate is characterized by an XRD pattern having peaks at approximately 9.7, 10.7, 15.1, 15.6 and 22.1 2θ±0.2 2θ. The crystalline polymorph of crystalline [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone citrate is further characterized by an XRD pattern having peaks at approximately 18.6, 19.2, 26.4 and 27.1 2θ±0.2 2θ. As Fig.10 As shown, the DSC curve exhibits a small exothermic transition at about 130° C., followed by a broad melting onset endotherm at about 184.5° C. The TGA curve shows a weight loss of about 0.38% to 1.13% from 25° C. to 125° C., followed by decomposition, as Fig.11 Displayed graphically.

[0103] [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone phosphate synthesized according to Example 1 showed good crystallinity and good solubility in unbuffered water (less than 1 mg / mL). The XRD pattern of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone phosphate showed that the crystallinity showed a preferred crystallite orientation, such as Fig.12As shown. 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 having 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 is further characterized by an XRD pattern having peaks at 9.7, 10.9, 11.6 and 20.7 2θ±0.2 2θ. As shown Fig.13 As shown, the DSC curve exhibits a volatile loss at about 149°C to 153°C, followed by an exothermic recrystallization at 158.7°C, and a melting onset endotherm at about 216°C to 219°C, followed by decomposition. Fig.14 As shown, the TGA curve shows a continuous weight loss, wherein the weight loss is about 2.6% to 2.88%, which may be due to the volatilization loss from 25°C to 100°C, followed by further decomposition.

[0104] [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone mesylate is highly crystalline with good solubility in unbuffered water (less than 1 mg / mL). The XRD pattern of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone mesylate synthesized according to Example 1 shows the following: Fig.15 The crystalline solid is shown. 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 having peaks at approximately 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 having peaks at 12.1, 18.8, 21.9, 24.5, and 28.2 2θ±0.2 2θ. Fig.16 As shown, the DSC curve exhibits a fairly clear melting onset endotherm with an extrapolated onset temperature of about 254°C to 265°C, a peak temperature of about 261°C to 268°C, and an enthalpy of about 96.7 J / g to 128.5 J / g. The TGA curve shows a weight loss of 0.51% from about 25°C to 120-150°C, followed by decomposition, as shown in FIG. Fig.17 The following examples are presented in order to more fully demonstrate the preferred embodiments of the present invention. However, the examples should in no way be construed as limiting the broad scope of the present invention.

[0105] Example

[0106] Differential Scanning Calorimetry (DSC)

[0107] DSC data were 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 degrees Celsius / minute from 25°C to about 250°C or 300°C using a 50 ml / minute nitrogen purge.

[0108] Proton NMR spectroscopy ( 1 H-NMR)

[0109] Samples were prepared by dissolving 1 to 10 mg of active pharmaceutical ingredient (API) in deuterated chloroform containing 0.05% (v / v) tetramethylsilane (TMS). Spectra were collected on a Bruker 400 MHz NMR spectrometer at ambient temperature.

[0110] X-ray powder diffraction (XRD)

[0111] Solids produced by recrystallization plates, slurry experiments and other means were analyzed by powder XRD. In order to mitigate the preferred grain effect, a two-dimensional detection system was used to collect all XRD screening data. The two-dimensional detector is integrated along concentric Debye cones, which helps to reduce the variation of the graph. If bright spots appear in conical rings, it indicates a strong preferred grain effect, which may lead to considerable variability in the observed diffraction patterns. Although some samples of [2-(1H-indol-3-yl)-1H-imidazole-4-yl](3,4,5-trimethoxyphenyl)methanone HCl salt tend to exhibit a mild preferred grain effect, [2-(1H-indol-3-yl)-1H-imidazole-4-yl](3,4,5-trimethoxyphenyl)methanone HCl salt does not seem to suffer from a severe preferred grain effect in general. This results in low variability in the XRD data of 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 typically 120 seconds. A 1.5406 angstrom CuKα radiation source operating at 40 kV and 40 mA was used to irradiate the sample. The X-ray optical system consisted of a Gobel reflector and a 0.5 mm pinhole collimator. θ-θ continuous scanning was used, with a sample-detector distance of 30 cm and an effective 2θ range of 4 to 400 2θ. The sample was mounted on a low background quartz plate.

[0112] Hygroscopicity - Dynamic Vapor Sorption (DVS)

[0113] DVS is a gravimetric technique that measures how quickly and how much solvent (water) is absorbed by a sample. The relative humidity or vapor concentration surrounding the sample is varied while measuring the change in sample mass. A vapor sorption isotherm shows the equilibrium amount of vapor absorbed as a function of relative humidity. The mass value for each relative humidity step is used to generate the isotherm. The isotherm is divided into two parts: adsorption for increasing humidity steps and desorption for decreasing humidity steps. Kinetic data plots are also used to show the change in mass and humidity over time.

[0114] The samples were analyzed using a TA Q5000 automatic dynamic vapor sorption analyzer. The samples were dried at a temperature above ambient temperature for a certain period of time and then cooled to 25°C, where they were purged with dry nitrogen until they no longer lost weight at 0% RH (relative humidity). The samples were then subjected to 0 to 90% RH, returning to 10% RH at 25°C in steps of 10% RH.

[0115] Thermogravimetric analysis (TGA)

[0116] Solids produced from recrystallization plates, slurry experiments, and other means were analyzed by TGA. TGA is an analytical test that determines the mass loss of volatile materials as the sample temperature is increased. The conditions for TGA are as specified by the TGA values ​​reported herein. If not specified, the default conditions are: sample size 5-20 mg (or appropriate); temperature range: 25°C to 150°C; heating rate: 10°C / min; purge gas: nitrogen; and replicates: single analysis.

[0117] Solid-state Fourier transform infrared spectroscopy (FT-IR)

[0118] Solids generated from recrystallization plates, slurry experiments, and other means are 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 compared to a reference sample. Based on the submitted materials, this test method is used to identify or characterize polymorphic materials by infrared spectroscopy. Samples submitted for identity confirmation are analyzed by comparing the sample spectrum to the reference spectrum. When the FT-IR spectrum of a substance matches the spectrum of the reference, the substance is positively identified. Spectra are considered to match when the number, relative intensity, and wavenumber (cm-1) of observed vibrational bands are consistent between the spectra. If differences appear in the IR spectra of the analyte and the standard, possibly due to hydration, dissolve the sample in equal parts of the test substance and the standard, dissolved in equal volumes of a suitable solvent, evaporate the solution to dryness in a similar container under the same conditions, and repeat the test on the residue. The instrument used in this method is a Thermo Scientific Nicolet iS20 FTIR spectrometer equipped with the Thermo Scientific OMNIC TM Software and spectrometer-compatible FTIR accessories (as needed), including the following: (1) Attenuated Total Reflectance (ATR) accessories (e.g., Harrick SplitPea TM Internal Reflectance Nanosampler, Thermo Scientific Smart TM iTX); (2) transmission sample holder accessories (e.g., for KBr plates, removable KBr liquid cells, KBr pellets, disposable PTFE cards); (3) pellet molds and presses (as needed); (4) vacuum oven or desiccator (as needed); or (5) forced air drying oven (as needed). The following reagents, consumables, culture media, and solutions are used as needed: (1) KBr plates (as needed); (2) removable KBr liquid cells (as needed); (3) spectral / IR grade KBr powder (as needed); (4) disposable PTFE cards (as needed); (5) appropriate solvents for dissolving samples (as needed); and (6) general laboratory equipment (spatula, mortar and pestle, vials, flasks, etc.). In general, the physical properties of the sample and the purpose of the test dictate the specific method and instrument accessories used to collect the FTIR spectrum. Liquid samples are applied directly to the 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 of about 1:100), compressed into pellets, and then analyzed. Alternatively, the sample could be dissolved in a suitable solvent and the spectrum collected using a removable liquid cell.

[0119] Karl Fischer titration (KF)

[0120] Solids generated from recrystallization plates, slurry experiments, and other means are analyzed by this procedure to determine the water content. After being weighed on an analytical balance capable of weighing accurately to 0.1 mg, the samples are tested in a Karl Fischer apparatus suitable for coulometric and volumetric titrations. Prior to analyzing the test samples, the Karl Fischer apparatus is calibrated using deionized (DI) water or a certified water standard. Likewise, the calibration of the analytical balance is verified prior to weighing the samples. Add the sample directly to the container solution. If this is not possible, dissolve the sample in an appropriate solvent, then inject it, and analyze a solvent blank.

[0121] Hot stage microscopy

[0122] The Linkam hot stage accessory is used with a microscope. The sample is mounted on a microscope slide with a cover glass. The sample is heated from room temperature to melting using a Linkam TMS 94 temperature controller and Linksys 32 data capture software system. Possible observations such as phase changes, melting, recrystallization, decomposition, etc. are recorded.

[0123] Visual solubility

[0124] A milligram amount of each sample was placed in a vial. A certain amount of solvent was added, and the vial was stirred for a few minutes, followed by a visual inspection of the remaining solid. Solvent was added stepwise until the solid dissolved, or the maximum volume of solvent was added and the experiment was terminated.

[0125] Example 1: Free base polymorph characterization; and small scale salt synthesis

[0126] The amorphous form of the free base, referred to as Form I of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone, was used as the source material for polymorph screening of the free base. The polymorphs of the free base were screened by the recrystallization and solvent slurry methods described in Examples 3 and 4. The method for preparing the crystalline polymorph Form II (Form II) of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone free base was by recrystallizing the amorphous form of the free base (Form I) ( Figure 1). Other methods for producing Form II of the free base include non-competitive single solvent slurry experiments using the amorphous form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone free base (Form I) by the method described in Example 4. An excess of the free base (Form I) is slurried in methanol, ethanol, acetone, acetonitrile, ethyl acetate, tetrahydrofuran (THF), or toluene. The suspension is slurried at ambient temperature for several days. The solids are collected by filtration and analyzed by X-ray powder diffraction (XRD). Samples slurried in acetone, THF, and toluene produce Form II of the free base, as shown by the superposition of the XRD spectra from these experiments, as shown in FIG. Figure 4 shown. Figure 1 The XRD pattern of Form II of the free base from recrystallization is shown. Form II of the free base is 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 is further characterized by an XRD pattern with peaks at 14.4, 17.8, 20.0, 24.7 and 26.8 2θ ± 0.2 2θ.

[0127] like Figure 2 As shown, the DSC of Form II of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone free base shows a distinct melting endotherm with an extrapolated onset temperature of 205.2°C and a peak temperature of 208.7°C. The enthalpy indicated by DSC is 103.9 J / g. A small endothermic drop observed at 190°C may indicate a phase transition. Thermogravimetric analysis (TGA) thermograms indicate that Form II of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone free base loses about 0.2 wt% at 150°C, and as Figure 3 As shown, the weight continues to decrease. As described above, a sample 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 (according to the method of Example 4) produced a similar Figure 1 This indicates that the XRD pattern of Form II represents the stable form of the free base ( Figure 4 ). This also indicates that the solvent slurry process for preparing Form II of the free base from the amorphous Form I of the free base can alternatively be achieved using acetone, THF or toluene.

[0128] Small-scale polymorphic salt synthesis: A typical experiment for the synthesis of polymorphic salts was performed as follows. The free base of [2-(1H-indol-3-yl)-1H-imidazole-4-yl](3,4,5-trimethoxyphenyl)methanone was dissolved in methanol (about 5 mL), a hydrochloric acid solution (0.1 mmol / mL in methanol) was added, and the solution was mixed. The ratio of free base to acid was about 1:1.1 molar ratio. The sample was crystallized at ambient temperature under a nitrogen purge (about 1 psi). The separated samples were examined by XRD. At least hydrochloric acid, citric acid, phosphoric acid and methanesulfonic acid were used to produce (mono) hydrochloride, citrate, (mono) phosphate and methanesulfonate. These same salts were scaled up to confirm that the XRD patterns and DSC, TGA and DVS outputs were reproducible and used for any required additional characterization.

[0129] Example 2: Scale-up of polymorphic salt synthesis and characterization of scaled-up salts

[0130] Select monohydrochloride (referred to as HCl or hydrochloride elsewhere in this article), citrate, monophosphate (referred to as phosphate elsewhere in this article) and mesylate (mesylate) polymorphic salt for scale-up. Salt is prepared with the scale of 200-500mg, in order to facilitate other testing and determine reproducibility. Typical program is shown in Table 1. Under ambient conditions, with nitrogen purge of about 2psi, solids are collected by evaporation. All solids produce the same XRD pattern as seen in early small-scale experiments, and are reproducible.

[0131]

[0132] As described in Examples 1 and 2, salt screening studies were performed to identify suitable polymorphic salts formed by reaction of a hydrochloric acid library with [2-(1H-indol-3-yl)-1H-imidazole-4-yl](3,4,5-trimethoxyphenyl)methanone free base. Initially, salt characterization was performed with four salts on a small scale (40 mg) and was considered to produce the desired polymorph. Small-scale synthesis and characterization were performed as described in Example 1. The preferred salts of Example 1 are the hydrochloride, citrate, phosphate, and methanesulfonate salts of [2-(1H-indol-3-yl)-1H-imidazole-4-yl](3,4,5-trimethoxyphenyl)methanone. Each salt was amplified and analyzed for crystallinity, thermal properties, water solubility, and hygroscopicity. All polymorphs or salts were considered for processability, therapeutic use, and other factors. The amplified salt synthesis is described in this Example and Table 1 (above) and characterized below.

[0133] 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 a lower safety risk relative to other salt forms. The use of Class I salts is not limited because they form physiologically ubiquitous ions or occur as intermediate metabolites in biochemical pathways. The [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride formed in Example 2 is crystalline polymorphic and has good solubility in unbuffered water (less than 1 mg / mL). This unnamed polymorph of the hydrochloride also shows evidence of the potential formation of hydrates at about 30-40% RH, specifically at about 50% RH.

[0134] The XRD pattern of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride formed in Examples 1 and 2 shows that the compound is crystalline, as shown in FIG. Figure 5 The crystalline polymorphs of the HCl salt formed in Examples 1 and 2 do not appear to be related to any other polymorphic forms of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride characterized herein, including Forms A, B, C, and D. H ,D,E,E1,F H , G H , H and I (see above and below). 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 approximately 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 having peaks at 10.5, 14.1, 16.1 and 26.2 2θ±0.2 2θ. Figure 6 As shown, the DSC curve shows multiple thermal events before the final melting onset endotherm at about 235.7°C. Figure 7As shown, the TGA curve shows a continuous weight loss from 25°C to 110°C, with a weight loss of about 0.54% to 4.1%. The hygroscopicity was determined using dynamic vapor sorption (DVS). As shown in Figure 8, the DVS data showed non-stoichiometric water uptake, as hydrates may form in the composite above 30-40% RH (relative humidity), and at 90% RH, the total uptake of water was about 8.8 wt% to 14.9 wt%.

[0135] [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone citrate has moderate crystallinity and good solubility in unbuffered water (approximately 1 mg / mL). [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone citrate is polymorphic and shows evidence of possible dihydrate formation at approximately 30-40% RH, specifically 60% RH. Fig. 9 As shown, the XRD pattern of the small scale citrate salt (synthesized according to Example 1) indicates a low-order crystalline solid. 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 having peaks at approximately 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 having peaks at 18.6, 19.2, 26.4 and 27.1 2θ±0.2 2θ. As Fig.10 As shown, the DSC curve exhibits a small exothermic transition at about 130° C., followed by a broad melting onset endotherm at about 184.5° C. The TGA curve shows a weight loss of about 0.38% to 1.13% from 25° C. to 125° C., followed by decomposition, as Fig.11 Displayed graphically.

[0136] [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone phosphate synthesized according to Example 1 showed good crystallinity and good solubility in unbuffered water (less than 1 mg / mL). The XRD pattern of the crystalline polymorph of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone phosphate showed that the crystallinity showed a preferred grain orientation, such as Fig.12As shown. 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 having peaks at approximately 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 is further characterized by an XRD pattern having peaks at 9.7, 10.9, 11.6 and 20.7 2θ±0.22θ. As shown Fig.13 As shown, the DSC curve exhibits a volatile loss at about 149°C to 152°C, followed by an exothermic recrystallization at 158.7°C, and a melting onset endotherm at about 216°C to 219°C, followed by decomposition. Fig.14 As shown, the TGA curve shows a continuous weight loss, wherein the weight loss is about 2.6% to 2.88%, which may be due to the volatilization loss from 25°C to 100°C, followed by further decomposition.

[0137] [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone mesylate is highly crystalline with good solubility in unbuffered water (less than 1 mg / mL). 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 shows the following: Fig.15 The crystalline solid is shown. 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 having peaks at approximately 8.3, 9.9, 10.9, 17.5, and 19.9 2θ±0.22θ. 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 having peaks at 12.1, 18.8, 21.9, 24.5, and 28.2 2θ±0.2 2θ. Fig.16 As shown, the DSC curve exhibits a fairly clear melting onset endotherm with an extrapolated onset temperature of about 254°C to 265°C, a peak temperature of about 261°C to 268°C, and an enthalpy of about 96.7 J / g to 128.5 J / g. The TGA curve shows a weight loss of 0.51% from about 25°C to 120-150°C, followed by decomposition, as shown in FIG. Fig.17 What is shown.

[0138] The hydrochloride (HCl) salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone was subjected to a polymorph screening to determine the most thermodynamically stable polymorph of the HCl salt. New polymorphs of the HCl salt were prepared 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). The studies revealed that the HCl salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone was polymorphic, and as described in detail in Examples 3-6, several solid state forms were prepared, identified as distinct, and characterized.

[0139] Example 3: [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone salt Polymorphs prepared by solvent recrystallization of acid salts

[0140] Overview of polymorph screening: The following provides the results of polymorph screening for each of the polymorphs A to I of the hydrochloride salt of the compound [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone. The methods for preparing these polymorphs are discussed in the polymorph screening or characterization experiments below. The purpose of polymorph screening is to prepare as many hydrochloride crystalline polymorph forms as possible, study their relative stabilities, and characterize their preparation methods. Screening was performed using solvent-based recrystallization, followed by X-ray diffraction analysis of the solids (Example 3). Polymorph screening performed by suspension slurry experiments (Examples 4 and 5) was also used to find additional solid-state forms and explore their relative stabilities, which are also discussed herein. Example 6 gives detailed characteristics of each polymorph.

[0141] Solvent Recrystallization: The test material is recrystallized using various solvents, with the scale of the recrystallization experiment being approximately 1 to 20 mL. The method uses single and binary solvent arrays and saturation temperature, growth temperature, and evaporation rate (relative supersaturation) are different criteria for determining optimal crystal growth conditions. Saturated solutions are prepared by stirring an excess (as much as possible) of the test material in contact with various solvent systems at saturation temperature. If solids remain in the solution, the mother liquor is separated from the residual solids by filtration. The mother liquor is then heated to above the saturation temperature (superheated) to dissolve any residual solids. The temperature of each solution is then adjusted to the growth temperature, and a controlled nitrogen shear flow is introduced to start solvent evaporation.

[0142] Table 2 summarizes the recrystallization conditions for the four solvent-based panels used during the study. Each recrystallization plate contained between 8 and 18 wells. The wells in each panel contained a different solvent composition. Since the solvent composition in each well was different, it served as a different crystal growth experiment.

[0143]

[0144] Table 3 summarizes the recrystallization procedure used (Panel column), the solvent used (Vehicle column), and the resulting polymorphic forms prepared in the solvent-based portion of the polymorph screen (XRD column). Based on the XRD analysis performed on these polymorph screen samples, new polymorphs of [2-(1H-indol-3-yl)-1H-imidazole-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride were prepared and characterized. The recrystallization method in Table 3 produced polymorphs designated Form A, Form B, Form E, and Form El.

[0145]

[0146] 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 recrystallization as described above. The polymorphs were named Form A, Form B, Form E and Form E1 and are described in detail in Example 6. These polymorphs were prepared as follows:

[0147] The above recrystallization experiments demonstrate that a variety of methods can be used to prepare polymorphic forms of the HCl salt, including Form A, Form B, Form E, and Form E1. Form A (Tables 2 and 3) was prepared by recrystallization from a 1-propanol / nitromethane binary solvent mixture by the procedure of Panel 4. Briefly, [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was dissolved in 1-propanol / nitromethane at saturated concentration at 25°C, heated to 45-50°C, and rapidly evaporated at 40°C under a N2 flow of 1.5psi. The results provide a convenient method for preparing Form A of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride.

[0148] Form B (Tables 2 and 3) was also prepared by recrystallization from a methanol / acetonitrile binary solvent mixture by the procedure of Panel 4. Briefly, [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was dissolved in methanol / acetonitrile at saturated concentration at 25°C, heated to 45-50°C, and rapidly evaporated at 40°C under a N2 flow of 1.5 psi. The results provide a convenient method for preparing Form B of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride.

[0149] Form E (Tables 2 and 3) was prepared by recrystallization from 2-propanol by the procedure of panel 1. Briefly, [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was dissolved in 2-propanol at saturated concentration at 25°C, heated to 45-50°C, and rapidly evaporated under a flow of 1.5 psi of N2 at ambient temperature. Form E (Tables 2 and 3) was also prepared by recrystallization from a 1-propanol / dioxane binary solvent mixture by the procedure of panel 3. Briefly, [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was dissolved in 1-propanol / dioxane at saturated concentration at 25°C, and slowly evaporated at ambient temperature. Form E (Tables 2 and 3) was also prepared by recrystallization from ethanol by the procedure of panel 4. Briefly, [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was dissolved in ethanol at saturated concentration at 25° C., heated to 45-50° C., and rapidly evaporated under a 1.5 psi N2 flow at 40° C. The above results provide three convenient methods for preparing Form E of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride.

[0150] Form E1 differs slightly from Form E only in some peaks in the 10-12° 2θ region of their XRD patterns, indicating that they have very similar physical properties. Form E1 (Tables 2 and 3) was prepared by recrystallization from a 2-propanol / dichloromethane binary solvent mixture by the procedure of Panel 4. Briefly, [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was dissolved in 2-propanol / dichloromethane at a saturated concentration at 25°C, heated to 45-50°C, and rapidly evaporated at 40°C under a N2 flow of 1.5 psi. Form E1 (Tables 2 and 3) was also prepared by recrystallization from a 2-propanol / trichloromethane binary solvent mixture by the procedure of Panel 4. Briefly, [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride was dissolved in 2-propanol / chloroform at saturated concentration at 25° C., heated to 45-50° C., and rapidly evaporated under a 1.5 psi N2 flow at 40° C. The above results provide three convenient methods for preparing Form E1 of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride.

[0151] Example 4: [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone salt Polymorphs prepared by non-competitive slurry experiment of acid salts

[0152] In addition to the solvent recrystallization experiments (Example 3), non-competitive slurry (Example 4) and competitive slurry (Example 5) experiments were performed to prepare new solid forms. Non-competitive slurry experiments were performed to find new solid forms. These experiments rely on the solubility differences of different polymorphic forms (if the compound is polymorphic). Therefore, only polymorphs with lower solubility (more stable) than the original crystalline form can be produced from non-competitive slurry experiments.

[0153] In essence, when a solid is mixed with one or more solvents as a slurry (solid suspended in a liquid), this produces a saturated solution. The solution is saturated with respect to the dissolved polymorphic form. However, for any polymorphic form that is more stable (the more stable form has a lower solubility) than the initially dissolved polymorphic form, the solution is supersaturated. Therefore, any more stable polymorphic form can nucleate and precipitate out of solution. In addition, non-competitive slurry experiments are often helpful in identifying solvents that form solvates with compounds.

[0154] Slurry experiments were performed by exposing excess starting material (Form B in all cases) to pure single and binary solvent systems and stirring the resulting suspensions at ambient temperature for several days. The solids were vacuum filtered and analyzed by XRD to determine the resulting form. To avoid possible desolvation or physical changes after separation, the samples were not further dried before X-ray analysis. A summary of non-competitive slurry experiments in single and binary solvent systems is shown in Tables 4 and 5 (below).

[0155]

[0156] After 14 days, the XRD patterns of the samples from the single solvent system in methanol or ethanol slurry are different from each other and different from the starting material. Both of these are solvates that are not further studied (Table 4). The diffraction pattern produced from the solid slurried in water shows a very low degree of crystallinity. After 14 days, the samples from acetone and acetonitrile slurries produced an XRD pattern different from the starting material. This new form is named as Form D (Table 4). Based on the X-ray scattering behavior after processing 14 days, the remaining slurry experiments in tetrahydrofuran (THF), dichloromethane, ethyl acetate, toluene and heptane did not cause significant changes in the starting polymorphic form (Form B).

[0157] A method for preparing Form D was observed in these non-competitive slurry experiments, wherein Form B was slurried in a non-aqueous solvent, acetone, for 14 days, as described in Table 4. Briefly, an excess of Form B was added to pure acetone until saturated. The resulting suspension was stirred at ambient temperature for fourteen days. The solid was vacuum filtered and analyzed by XRD to determine that Form D was prepared. In order to avoid possible desolvation or physical changes after separation, the sample was not further dried before X-ray analysis. Another method for preparing Form D was observed in these non-competitive slurry experiments, wherein Form B was slurried in a non-aqueous solvent, acetonitrile, for 14 days, as described in Table 4. Briefly, an excess of Form B was added to pure acetonitrile until saturated. The resulting suspension was stirred at ambient temperature for fourteen days. The solid was vacuum filtered and analyzed by XRD to determine that Form D was prepared. In order to avoid possible desolvation or physical changes after separation, the sample was not further dried before X-ray analysis. These observations provide a method by which Form D of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride can be prepared. The data indicate that Form D is more stable than Form B in some solvent systems.

[0158]

[0159] The XRD pattern of the sample from binary solvent system methanol / water, methanol (MeOH) / acetone and trifluoroethanol (TFE) / ethyl acetate (EtOAc) slurry after 11 days gives the figure with low crystallinity (Table 5). The sample from methanol / dichloromethane (DCM) produces the XRD pattern different from the starting material and is classified as solvate. The slurry samples from ethanol / toluene, acetonitrile (ACN) / acetone, ethanol / acetonitrile, 1-propanol / ethyl acetate (EtOAc) and 2-propanol / tetrahydrofuran (THF) have the XRD pattern different from the starting material and are finally designated as form E1 (Table 5). Based on the X-ray scattering behavior after processing 11 days, the combination of trifluoroethanol (TFE) / dichloromethane (DCM) slurry experiment does not cause the significant change of the starting polymorphic form (Form B).

[0160] Form E1 was obtained from non-competitive slurry experiments starting from Form B incubated in five different binary solvent systems (see Table 5, rows 3, 5, and 7-9 of Example 4). A method for preparing Form E1 was observed in these non-competitive slurry experiments, wherein Form B was slurried in a non-aqueous binary solvent system of ethanol / toluene for 11 days, as described in Table 5. In brief, an excess of Form B was added to the ethanol / toluene mixture until saturated. The resulting suspension was stirred at ambient temperature for eleven days. The solid was vacuum filtered and analyzed by XRD to determine that Form E1 was prepared. In order to avoid possible desolvation or physical changes after separation, the sample was not further dried before X-ray analysis. Another method for preparing Form E1 was observed in these non-competitive slurry experiments, wherein Form B was slurried in a non-aqueous binary solvent system of acetonitrile (ACN) / acetone for 11 days, as described in Table 5. In brief, an excess of Form B was added to an acetonitrile (ACN) / acetone mixture until saturated. The resulting suspension was stirred at ambient temperature for eleven days. Solid vacuum filtered and analyzed by XRD to determine that form E1 has been prepared. In order to avoid possible desolvation or physical changes after separation, the sample was not further dried before X-ray analysis. Another method for preparing form E1 was observed in these non-competitive slurry experiments, wherein form B was slurried in the non-aqueous binary solvent system of ethanol / acetonitrile for 11 days, as described in Table 5. In brief, excessive form B was added to the ethanol / acetonitrile mixture until saturated. The resulting suspension was stirred at ambient temperature for eleven days. Solid vacuum filtered and analyzed by XRD to determine that form E1 has been prepared. In order to avoid possible desolvation or physical changes after separation, the sample was not further dried before X-ray analysis. Another method for preparing form E1 was observed in these non-competitive slurry experiments, wherein form B was slurried in the non-aqueous binary solvent system of 1-propanol / ethyl acetate (EtOAc) for 11 days, as described in Table 5. In brief, excessive form B was added to 1-propanol / ethyl acetate (EtOAc) mixture until saturated. The obtained suspension was stirred at ambient temperature for eleven days. The solid was vacuum filtered and analyzed by XRD to determine that form E1 was prepared. In order to avoid possible desolvation or physical changes after separation, the sample was not further dried before X-ray analysis. Another method for preparing form E1 was observed in these non-competitive slurry experiments, in which form B was slurried in the non-aqueous binary solvent system of 2-propanol / tetrahydrofuran (THF) for 11 days, as described in Table 5. In brief, excess form B was added to 2-propanol / tetrahydrofuran (THF) mixture until saturated. The obtained suspension was stirred at ambient temperature for eleven days. The solid was vacuum filtered and analyzed by XRD to determine that form E1 was prepared. In order to avoid possible desolvation or physical changes after separation, the sample was not further dried before X-ray analysis.These data demonstrate that Form E1 is more stable than Form B in many solvent systems and support Form E1 as a relatively stable polymorph of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride compared to Form B.

[0161] Example 5: [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone salt Polymorphs prepared by competitive slurry experiments of acid salts

[0162] In addition to solvent recrystallization and non-competitive slurry experiments, competitive slurry experiments were performed to prepare novel polymorphs and determine the most stable polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride. The experiments rely on the solubility differences of different polymorphic forms. Therefore, only polymorphic forms (and solvates) with lower solubility (more stable) than the initially dissolved form can be produced from competitive slurry experiments. In essence, when a solid is dissolved in a (slurry) solvent, a saturated solution is eventually produced. The solution is saturated with respect to the dissolved polymorphic forms. However, for any polymorphic form that is more stable (the more stable form has a lower solubility) than the initially dissolved polymorphic form, the solution is supersaturated. Therefore, any more stable polymorphic form can nucleate and precipitate out of solution. In addition, competitive slurry experiments are generally helpful in identifying solvents that form solvates with active pharmaceutical ingredients (APIs).

[0163] Slurry experiments were performed by exposing excess material of both (polymorphic) forms to a small volume 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. To avoid possible desolvation or physical changes after separation, the samples were not dried before X-ray analysis. Table 6 contains the results of these competitive slurry experiments.

[0164]

[0165] When Form B and Form D were co-incubated in 1-propanol for about 2 weeks, Form E was prepared, which shows the relative stability of Form E relative to Form B or Form D (Table 6, row 5). In short, excess Form B and Form D were added to pure 1-propanol until saturated. The resulting suspension was stirred at ambient temperature for about two weeks. The solid was vacuum filtered and analyzed by XRD to determine that Form E was prepared. In order to avoid possible desolvation or physical changes after separation, the sample was not further dried before X-ray analysis. When Form A and Form B were co-incubated in 1-propanol for about 2 weeks, Form E was also prepared (Table 6, row 9). In short, excess Form A and Form B were added to pure 1-propanol until saturated. The resulting suspension was stirred at ambient temperature for about two weeks. The solid was vacuum filtered and analyzed by XRD to determine that Form E was prepared. In order to avoid possible desolvation or physical changes after separation, the sample was not further dried before X-ray analysis. This data shows that Form E is relatively stable compared to Form A, Form B and Form D. This is consistent with data from recrystallization experiments, in which Form E (and Form El) were generated from various solvent systems, and non-competitive slurry experiments, in which Form El was generated from Form B in various binary solvent systems.

[0166] Form E1 differs slightly from Form E only in some peaks in the 10-12° 2θ region of their XRD patterns, which indicates that they have very similar physical properties. The data in this example indicate that Form E1 has higher stability than Form E, but their physical properties are expected to be similar. As described in Table 6, rows 7 and 10-12, Form E1 was generated from a competitive slurry experiment involving Form A, Form B, Form C, and Form E1. H The binary combination of Form C, Form D and Form E (Example 5) shows that Form E1 is relatively stable compared to these other forms. H Form E1 was prepared when Form C and Form B were co-incubated in 1-propanol for about 2 weeks (Table 6, row 7). HThe obtained suspension was stirred at ambient temperature for about two weeks. The solid was vacuum filtered and analyzed by XRD to determine that Form E1 was prepared. In order to avoid possible desolvation or physical changes after separation, the sample was not further dried before X-ray analysis. When Form A and Form D were co-incubated in 1-propanol for about 2 weeks, Form E1 was also prepared (Table 6, row 10). In short, excess Form A and Form D were added to pure 1-propanol until saturation. The obtained suspension was stirred at ambient temperature for about two weeks. The solid was vacuum filtered and analyzed by XRD to determine that Form E1 was prepared. In order to avoid possible desolvation or physical changes after separation, the sample was not further dried before X-ray analysis. When Form B and Form E were co-incubated in 1-propanol for about 2 weeks, Form E1 was also prepared (Table 6, row 11). In short, excess Form B and Form E were added to pure 1-propanol until saturation. The obtained suspension was stirred at ambient temperature for about two weeks. The solid was vacuum filtered and analyzed by XRD to determine that Form E1 was prepared. In order to avoid possible desolvation or physical changes after separation, the sample was not further dried before X-ray analysis. When Form D and Form E were co-incubated in 1-propanol for about 2 weeks, Form E1 was also prepared (Table 6, row 12). In short, excess Form D and Form E were added to pure 1-propanol until saturated. The resulting suspension was stirred at ambient temperature for about two weeks. The solid was vacuum filtered and analyzed by XRD to determine that Form E1 was prepared. In order to avoid possible desolvation or physical changes after separation, the sample was not further dried before X-ray analysis.

[0167] Recrystallization (Example 3) and non-competitive slurry (Example 4) polymorph screening experiments showed that Form E and Form E1 were the most stable forms in these experiments. However, Form E or Form E1 samples stored under ambient conditions converted to Form H, indicating that Form H is more stable than Form E or Form E1. To test this hypothesis, competitive slurry experiments (Example 5) were performed to demonstrate that Form H rapidly and completely converted to Form E and Form H.

[0168] Form H is synthesized by competitive slurrying of Form E and Form H in 2-butanol or 2-propanol for 1 day (Table 6, rows 13 and 14). In one embodiment, when Form E and Form H are co-incubated in 2-propanol for 1 day, Form H is produced (Table 6, row 13). In brief, excess Form E and Form H are added to pure 2-propanol until saturated. The resulting suspension is stirred at ambient temperature for 1 day. The solid is vacuum filtered and analyzed by XRD to determine that Form H is prepared. In order to avoid possible desolvation or physical changes after separation, the sample is not further dried before X-ray analysis. In another experiment, when Form E and Form H are co-incubated in 2-butanol for 1 day, Form H is produced (Table 6, row 14). In brief, excess Form E and Form H are added to pure 2-butanol until saturated. The resulting suspension is stirred at ambient temperature for 1 day. The solid is vacuum filtered and analyzed by XRD to determine that Form H is prepared. To avoid possible desolvation or physical changes after isolation, the samples were not further dried prior to X-ray analysis. These rapid 1-day conversions to Form H in Table 6, compared to other slurry conversions of 11 days or approximately 14 days, indicate that Form H is relatively stable compared to Form E. From the initial slurry experiments (all samples except the last two samples in Table 6), it appeared that Form E or E1 was the most stable form observed during the study and that their physical properties were similar. However, competitive slurries of Form E and Form H in two different solvents showed that Form H was more stable than Form E (and possibly Form E1 as well). Further evidence supporting that Form H is more stable than Form E or Form E1 is presented in Example 6, where the differential scanning calorimetry (DSC) thermogram exhibits a broad melting onset endotherm compared to Form E and Form E1 (at approximately 239.5°C and 243.2°C, respectively), and a relatively low melting enthalpy, followed by immediate decomposition (see Table 6, respectively). Fig.32 and Fig.34 )), Form H has a higher melting point (a pronounced high enthalpy endotherm with an onset at 247.4 °C, a peak maximum at 250.1 °C, and a melting enthalpy of 158.0 J / g ( Fig.45 )). Further, large-scale Form H is produced by adding a small amount of Form H to the process used to prepare Form E. Based on competitive slurry experiments and DSC experiments, Form H is expected to be the thermodynamically stable form.

[0169] Embodiment 6: The polymorphs of the HCl salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone were characterized by XRD, DSC, TGA, DVS, etc.

[0170] This section of the report summarizes the polymorphs produced during 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 entity 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 work was to screen [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride for polymorphic behavior. The screening was aimed at preparing as many new crystalline forms as possible and characterizing these polymorphs for use in drug products. The screening was performed using solvent recrystallization under different conditions and competitive and non-competitive slurry experiments to control the solid state form of the test material.

[0171] Samples produced 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 studies revealed that [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride is polymorphic, and several solid-state forms were prepared and characterized. Among them, the initially prepared stable form was Form E1, which is very similar to Form E. These are generally identical except for minor changes in the diffraction pattern and DSC thermogram. Form H was prepared from Form E or Form E1 samples stored under ambient conditions. Form H was characterized as a stable crystalline polymorph and was more stable than Form E in competitive slurry experiments. Subsequently, when Form E and / or Form E1 were prepared on a kilogram scale, due to the presence of gram amounts of Form H seed crystals (Example 7), rapid and complete conversion of Form E or Form E1 to Form H was observed, supporting 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.

[0172] Based on 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 a polymorph as various polymorphic forms were prepared and characterized as described below. Form A, Form B, Form C of the HCl salt were prepared. H , Form D, Form E, Form E1, Form F H , Form G H, Form H and Form I, and they are characterized and summarized in Table 7 below. Based on diffraction behavior, each polymorphic form was studied to determine the differences. The characterization of each hydrochloride polymorph form began with the X-ray powder diffraction (XRD) data comparison of each form with the other forms. DSC and TGA analysis were usually performed subsequently. Table 7 below summarizes the different forms prepared during the study.

[0173]

[0174]

[0175] Form A and Form B were prepared by recrystallization as described in Example 3. Form D, Form E, Form El and Form H were prepared 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 prepared from samples stored at room temperature. The method for preparing Form H involves competitive slurrying of Form E in 2-butanol or 2-propanol as discussed in Example 5, or seeding Form H crystals into the synthesis of other polymorphic forms of the HCl salt, including Form E and Form El (Example 7).

[0176] [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 by the procedure of Panel 4 in 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 saturated concentration at 25°C, heated to 45-50°C to dissolve the solid, and rapidly evaporated at 40°C under a flow of 1.5 psi of N2 to produce solid Form A. Fig.35 As shown, the XRD pattern of Form A indicates that it has a reproducible powder pattern and is crystalline. Form A is characterized by an XRD pattern having peaks at approximately 9.6, 12.0, 19.2, 23.6, and 24.4 2θ ± 0.2 2θ. Form A is further characterized by an XRD pattern having peaks at 16.3, 18.1, and 28.9 2θ ± 0.2 2θ. TGA demonstrates that Form A is free of volatiles from 25°C to 150°C, with a weight loss of approximately 0.04%, as shown in Table 1. Fig.36 As shown. Fig.37As shown, the DSC thermogram of Form A exhibits a melting onset endotherm with an average onset of approximately 250.3° C. These thermal events are attributed to the melting and decomposition behavior of the form. The dynamic vapor sorption (DVS) graph of Form A illustrates that the material is very hydrophobic and does not appear to readily form hydrates. A total weight gain of approximately 0.4% was observed at 90% RH (not shown).

[0177] [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 by the procedure of Panel 4 in 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 saturated concentration at 25° C., heated to 45-50° C. to dissolve any solids, and flash evaporated at 40° C. under a flow of 1.5 psi N2 to produce Form B. Form B was stable (i.e., unchanged) in non-competitive slurry experiments (Example 4, Tables 4 and 5), indicating that it was stable in many single solvents, including tetrahydrofuran (THF), ethyl acetate, dichloromethane, toluene, and heptane, as well as in trifluoroethanol (TFE) / dichloromethane (DCM) binary solvent mixtures. Only in acetone or acetonitrile, in non-competitive slurry experiments, did Form B transform to Form D (Table 4). Further, as described in Table 6 (row 4) of Example 5, Form C was converted to Form D by the reaction mixture. H Form B was prepared by competitive slurrying of Form C and Form B in ethyl acetate, which showed that Form C H The relative stability compared to Form B. Briefly, an 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 about two weeks. The solid was vacuum filtered and analyzed by XRD to confirm that Form B was prepared. In order to avoid possible desolvation or physical changes after isolation, the sample was not further dried before X-ray analysis. Form B has diffraction characteristics different from other polymorphic forms. Fig.18 As shown, the XRD pattern of Form B indicates that it has a reproducible powder pattern and is crystalline. Form B is characterized by an XRD pattern having peaks at approximately 9.5, 12.1, 18.0, 18.9, and 23.0 2θ ± 0.2 2θ. Form B is further characterized by an XRD pattern having peaks at 19.2, 28.5, 29.5, and 31.8 2θ ± 0.2 2θ. Fig.19 As shown, the TGA thermogram demonstrates that the average weight loss of Form B at 150°C is less than 0.05%. Fig. 20As shown, the DSC thermogram of Form B exhibits a distinct melting onset endotherm with an average onset of approximately 247.4°C. These thermal events are 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 appears to be a metastable form of the HCl salt.

[0178] [2-(1H-Indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride Form C H The hydrate (Form C) was prepared from samples stored at room temperature. H ).like Fig. 22 As shown, Form C H The XRD pattern of Form C indicates crystallinity. H 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 Form C is further characterized by an XRD pattern having peaks at 10.3, 18.0, 23.7, 28.7, and 29.7 2θ ± 0.2 2θ. TGA demonstrates that Form C H The weight loss at 150 °C is about 5.3%, which is approximately equivalent to the loss of one mole of water from the lattice, such as Fig.23 As shown. Form C H The DSC thermogram exhibits a large broad endotherm starting at approximately 152.7 °C, which may be due to the loss of residual water. Fig.24 This was followed by a broad exotherm at about 200°C and an extrapolated broad endothermic melt onset at 233.8°C, followed by decomposition. H The DVS scan shows the water adsorption-desorption isotherm and kinetic curve. [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride form C H Very low water sorption uptake is shown, which is believed to be because the drying portion of the DVS scan was insufficient to remove the original molar water found in the crystalline structure (not shown). The monohydrate sample absorbed up to 0.95 wt% at high humidity and then recovered to its original mass after the scan was completed (not shown).

[0179] [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 in which Form B was slurried in non-aqueous solvents acetone or acetonitrile for 14 days, as described in Table 4 of Example 4. A method for preparing Form D was observed in these non-competitive slurry experiments in which Form B was slurried in a non-aqueous solvent acetone for 14 days, as described in Table 4 of Example 4. Briefly, an excess of Form B was added to pure acetone until saturated. The resulting suspension was stirred at ambient temperature for fourteen 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 before X-ray analysis. Another method for preparing Form D was observed in these non-competitive slurry experiments in which Form B was slurried in a non-aqueous solvent acetonitrile for 14 days, as described in Table 4 of Example 4. Briefly, an excess of Form B was added to neat acetonitrile until saturated. The resulting suspension was stirred at ambient temperature for fourteen 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 before X-ray analysis. These observations provide a method by which Form D of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride can be prepared. The data indicate that in some solvent systems, Form D is more stable than Form B. As Fig.25 As shown, the XRD pattern of Form D indicates a distinct crystalline powder pattern. Form D is characterized by an XRD pattern having peaks at approximately 9.4, 15.1, 17.3, 22.1, and 23.2 2θ ± 0.2 2θ. Form D is further characterized by an XRD pattern having peaks at 10.5, 18.1, 22.8, 24.8, and 30.3 2θ ± 0.2 2θ. Fig.26 As shown, the TGA thermogram indicates a loss of about 0.13 wt% at 150°C, with continued weight loss at higher temperatures. Fig. 27 As shown, the DSC thermogram of Form D exhibits a small and broad solid-solid phase transition endotherm with an onset of approximately 144.2°C, a peak temperature of approximately 156°C, and an enthalpy of approximately 8.1 J / g, followed by a melting endotherm with an extrapolated onset of 244.6°C, a peak temperature of 250.7°C, and subsequent decomposition. The solid-state FT-IR spectrum of Form D of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride is shown in Fig.28 Displayed in.

[0180] [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride Form E (Form E) and E1 (Form E1) are relatively stable forms, as shown by their synthesis in competitive slurry experiments starting from Form B (Table 6, Example 5). In one embodiment, Form E is prepared when Form B and Form D are co-incubated in 1-propanol for about 2 weeks, which shows the relative stability of Form E relative to Form B and Form D (Table 6, row 5). Briefly, excess Form B and Form D are added to pure 1-propanol until saturated. The resulting suspension is stirred at ambient temperature for about two weeks. The solid is vacuum filtered and analyzed by XRD to determine that Form E is prepared. To avoid possible desolvation or physical changes after separation, the sample was not further dried before X-ray analysis. In another embodiment, Form E is prepared when Form A and Form B are co-incubated in 1-propanol for about 2 weeks (Table 6, row 9). In brief, excess Form A and Form B are added to pure 1-propanol until saturated. The resulting suspension is stirred at ambient temperature for about two weeks. The solid is vacuum filtered and analyzed by XRD to determine that Form E has been prepared. In order to avoid possible desolvation or physical changes after separation, the sample is not further dried before X-ray analysis. Cumulatively, this data shows that compared with Form A, Form B and Form D, Form E is relatively stable. This is consistent with the data of the recrystallization experiment, in which Form E (and Form E1) is from a variety of solvent systems.

[0181] Form E was also prepared by three different recrystallization methods, including 2-propanol, 1-propanol / 1-dioxane mixtures, or ethanol. In one embodiment, Form E was prepared by recrystallization from 2-propanol by the procedure of Panel 1 in 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 at saturation concentration at 25°C, heated to 45-50°C to dissolve the solids, and rapidly evaporated at ambient temperature under a flow of N2 at 1.5 psi to produce Form E. In another embodiment, Form E was prepared by recrystallization from a 1-propanol / dioxane binary solvent mixture by the procedure of Panel 3 in 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 saturated concentration at 25° C., and the solvent was slowly evaporated at ambient temperature to prepare Form E. In another embodiment, Form E was prepared by recrystallization from ethanol by the procedure of Panel 4 in 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 saturated concentration at 25° C., heated to 45-50° C. to dissolve any solids, and the solvent was rapidly evaporated at 40° C. under a flow of 1.5 psi of N2 to prepare Form E.

[0182] Form E1 differs slightly from Form E only in some peaks in the 10-12° 2θ region of their XRD patterns, indicating that they have very similar physical properties. H Form E1 is relatively stable compared to Form B, Form D, and Form E, as confirmed by the results of non-competitive (Form B only) and competitive (all forms) slurry experiments.

[0183] Form E1 was prepared by two different recrystallization methods from 2-propanol / dichloromethane and 2-propanol / chloroform. In one embodiment, Form E1 was prepared by recrystallization from a 2-propanol / dichloromethane binary solvent mixture by the procedure of Panel 4 in 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 saturated concentration at 25°C, heated to 45-50°C to dissolve the solid, and rapidly evaporated at 40°C under a N2 flow of 1.5 psi to prepare Form E1. In another embodiment, Form E1 was prepared by recrystallization from a 2-propanol / chloroform binary solvent mixture by the procedure of Panel 4 in 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 / chloroform at saturated concentration at 25°C, heated to 45-50°C to dissolve the solid, and flash evaporated at 40°C under a flow of 1.5 psi of N2 to prepare Form E1.

[0184] Form E1 is obtained from a non-competitive slurry experiment starting from Form B incubated in five different binary solvent systems (see Table 5, rows 3, 5 and 7-9 of Example 4). In one embodiment, Form E1 is prepared by a non-competitive slurry experiment, wherein Form B is slurried in a non-aqueous binary solvent system of ethanol / toluene for 11 days. In brief, an excess of Form B is added to the ethanol / toluene mixture until saturated. The resulting suspension is stirred at ambient temperature for eleven days. The solid is vacuum filtered and analyzed by XRD to determine that Form E1 has been prepared. In order to avoid possible desolvation or physical changes after separation, the sample is not further dried before X-ray analysis. In another embodiment, Form E1 is prepared by a non-competitive slurry experiment, wherein Form B is slurried in a non-aqueous binary solvent system of acetonitrile (ACN) / acetone for 11 days. In brief, an excess of Form B is added to an acetonitrile (ACN) / acetone mixture until saturated. The resulting suspension is stirred at ambient temperature for eleven days. The solid is vacuum filtered and analyzed by XRD to determine that Form E1 has been prepared. In order to avoid possible desolvation or physical changes after separation, the sample was not further dried before X-ray analysis. In another embodiment, Form E1 is prepared by non-competitive slurrying experiments, wherein Form B is slurried in a non-aqueous binary solvent system of ethanol / acetonitrile for 11 days. In short, an excess of Form B is added to an ethanol / acetonitrile mixture until saturated. The resulting suspension is stirred at ambient temperature for eleven days. The solid is vacuum filtered and analyzed by XRD to determine that Form E1 has been prepared. In order to avoid possible desolvation or physical changes after separation, the sample was not further dried before X-ray analysis. In another embodiment, Form E1 is prepared by non-competitive slurrying experiments, wherein Form B is slurried in a non-aqueous binary solvent system of 1-propanol / ethyl acetate (EtOAc) for 11 days. In short, an excess of Form B is added to a 1-propanol / ethyl acetate (EtOAc) mixture until saturated. The resulting suspension is stirred at ambient temperature for eleven days. The solid is vacuum filtered and analyzed by XRD to determine that Form E1 has been prepared. In order to avoid possible desolvation or physical changes after separation, the sample was not further dried before X-ray analysis. In another embodiment, Form E1 is prepared by non-competitive slurrying experiment, wherein Form B is slurried in the non-aqueous binary solvent system of 2-propanol / tetrahydrofuran (THF) for 11 days. In brief, excess Form B is added to the 2-propanol / tetrahydrofuran (THF) mixture until saturated. The resulting suspension is stirred at ambient temperature for 11 days. The solid is vacuum filtered and analyzed by XRD to determine that Form E1 is prepared. In order to avoid possible desolvation or physical changes after separation, the sample was not further dried before X-ray analysis.These data in Example 4 demonstrate that Form E1 is more stable than Form B in many binary solvent systems and support Form E1 as a relatively stable polymorph of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride compared to Form B.

[0185] Form E1 was also prepared by four different competitive slurry experiments involving co-incubation of Form A, Form B, Form C, and Form E1 in 1-propanol for about two weeks as described in Table 6, rows 7 and 10-12 of Example 5. H , Form D and Form E. This data demonstrates the increased stability of Form E1 relative to these other forms. In one embodiment, when Form C H Form E1 was prepared when Form C and Form B were co-incubated in 1-propanol for about 2 weeks (Table 6, row 7). HThe obtained suspension was stirred at ambient temperature for about two weeks. The solid was vacuum filtered and analyzed by XRD to determine that Form E1 was prepared. In order to avoid possible desolvation or physical changes after separation, the sample was not further dried before X-ray analysis. In another embodiment, when Form A and Form D were co-incubated in 1-propanol for about 2 weeks, Form E1 (Table 6, row 10) was prepared. In short, excess Form A and Form D were added to pure 1-propanol until saturation. The obtained suspension was stirred at ambient temperature for about two weeks. The solid was vacuum filtered and analyzed by XRD to determine that Form E1 was prepared. In order to avoid possible desolvation or physical changes after separation, the sample was not further dried before X-ray analysis. In another embodiment, when Form B and Form E were co-incubated in 1-propanol for about 2 weeks, Form E1 (Table 6, row 11) was prepared. In short, excess Form B and Form E were added to pure 1-propanol until saturation. The obtained suspension was stirred at ambient temperature for about two weeks. The solid is vacuum filtered and analyzed by XRD to determine that Form E1 is prepared. In order to avoid possible desolvation or physical changes after separation, the sample is not further dried before X-ray analysis. In another embodiment, when Form D and Form E are co-incubated in 1-propanol for about 2 weeks, Form E1 is prepared (Table 6, row 12). In short, excess Form D and Form E are added to pure 1-propanol until saturated. The resulting suspension is stirred at ambient temperature for about two weeks. The solid is vacuum filtered and analyzed by XRD to determine that Form E1 is prepared. In order to avoid possible desolvation or physical changes after separation, the sample is not further dried before X-ray analysis. In some embodiments, Form E and Form E1 are discussed together as significantly stable polymorphs. The data in this embodiment can be interpreted as Form E1 having higher stability than Form E, but their physical properties are expected to be roughly similar. There is no data to support that Form E or Form E1 is more stable than Form H, and Form H is considered to be the most stable polymorph.

[0186] The XRD patterns of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride Forms E and E1 show crystallinity and are Fig.29 and Fig.30. Except for a slight difference between the two diffraction patterns in the 10-12° 2θ region, the two patterns appear very similar. Form E is characterized by an XRD pattern having peaks at approximately 9.4, 17.3, 22.1, 23.4, and 24.8 2θ ± 0.2 2θ. Form E is further characterized by an XRD pattern having peaks at 12.9, 15.0, 18.1, 21.0, and 30.3 2θ ± 0.2 2θ. Form E1 is characterized by an XRD pattern having peaks at approximately 9.4, 10.9, 17.3, 22.1, and 23.2 2θ ± 0.2 2θ. Form E1 is further characterized by an XRD pattern having peaks at 13.0, 15.1, 18.1, 20.9, and 24.8 2θ ± 0.2 2θ. As Fig.31 As shown, the TGA thermogram of Form E exhibits a weight loss of approximately 0.66% at 150°C. Fig.32 As shown, the DSC thermogram of Form E exhibits a melting onset endotherm at approximately 239.6°C, followed by extensive decomposition. The solid-state FT-IR spectrum of Form E is shown in FIG. Fig.33 As shown. Fig.34 As shown, the DSC thermogram of Form E1 exhibits a melting onset endotherm at approximately 243.2° C., followed by extensive decomposition with an unstable baseline. The slightly higher endothermic temperature of Form E1 relative to Form E also indicates that Form E1 is slightly more stable, which is consistent with the above slurry experiment.

[0187] [2-(1H-Indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride Form F H (Form F H ) has diffraction characteristics different from the other polymorphic forms and was prepared from samples stored at room temperature. Form F was not observed in the polymorph screening work H .like Fig.38 As shown, form F H The XRD pattern of Form F showed that it had a reproducible powder pattern, was crystalline and was a hydrate. H 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 Form F is further characterized by an XRD pattern having peaks at 12.9, 20.9 and 26.14 2θ ± 0.2 2θ. H The DSC thermogram exhibits a large split endotherm starting at about 90.8°C with a peak maximum at 99.7°C. Form F H The moisture content of KF was 14 wt% (not shown). Form F HThe solution NMR spectrum of was consistent with the proposed structure of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride (not shown).

[0188] [2-(1H-Indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride Form G H (Form G H ) has diffraction characteristics different from the other polymorphic forms and was prepared from samples stored at room temperature and was assigned as a hydrate. Fig.40 As shown, form G H The XRD pattern of Form G showed that it had a reproducible powder pattern and was moderately crystalline. H 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. Form G H The compound is further characterized by an XRD pattern having peaks at 10.4, 22.3, 24.7 and 25.3 2θ ± 0.2 2θ. Fig.41 As shown, the TGA thermogram demonstrates that Form G H The average weight loss at 150°C was shown to be 4.8%. Form G H The DSC thermogram exhibits two endotherms with extrapolated onsets at 140.5 °C and 246.5 °C, as Fig.42 As shown. Form G H The moisture content of KF was 4.4 wt% (not shown).

[0189] [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride Form H (Form H) was prepared from samples of Form E and Form E1 stored at room temperature and was designated as a dry polymorphic form. Form H was also prepared by competitive slurrying of Form E and Form H in 2-butanol or 2-propanol for 1 day (Table 6 of Example 5, rows 13 and 14), indicating that Form H is relatively stable compared to Form E. In one embodiment, Form H is prepared when Form E and Form H are co-incubated in 2-propanol for 1 day (Table 6, row 13). Briefly, excess Form E and Form H are added to pure 2-propanol until saturated. The resulting suspension is stirred at ambient temperature for 1 day. The solid is vacuum filtered and analyzed by XRD to determine that Form H is prepared. To avoid possible desolvation or physical changes after separation, the sample was not further dried before X-ray analysis. In another embodiment, Form H is prepared when Form E and Form H are co-incubated in 2-butanol for 1 day (Table 6, row 14). Briefly, excess Form E and Form H are added to pure 2-butanol until saturated. The resulting suspension is stirred at ambient temperature for 1 day. The solid is vacuum filtered and analyzed by XRD to determine that Form H has been prepared. To avoid possible desolvation or physical changes after separation, the samples were not further dried before X-ray analysis. From the initial competitive slurry experiments (all samples except the last two samples in Table 6), it appears that Form E or Form E1 is the most stable form observed during the study. However, competitive slurrying of Form E and Form H in two different solvents showed that Form H is more stable than Form E. Based on these slurry experiments, large-scale seeding (Example 7) and DSC thermograms, Form H is expected to be the thermodynamically stable form. As Fig.43 As shown, the XRD pattern of Form H indicates a crystalline powder pattern. The XRD pattern of Form H shows that it is highly crystalline. Form H is characterized by an XRD pattern having peaks at approximately 11.8, 20.1, 23.6, 25.0, and 26.5 2θ ± 0.2 2θ. Form H is further characterized by an XRD pattern having peaks at 8.6, 12.5, 18.6, 21.2, and 28.1 2θ ± 0.2 2θ. Fig.44 As shown, the TGA thermogram indicates a loss of about 0.03 wt % at 150°C. Fig.45 As shown, the DSC thermogram of Form H exhibits a melting onset endotherm starting at 247.5° C., with a peak maximum of 250.1° C., and a melting enthalpy of 158.0 J / g. The KF moisture content of Form H is 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).

[0190] [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride Form I (Form I) was prepared after slurrying in 1:1 ethanol / ethyl acetate (EtOH / EtOAc). After storage at ambient temperature for one month, Form I converted to Form C H The XRD diffraction pattern of Form I is shown in Figure 2. Fig.46 Form I of the HCl salt is characterized by an XRD pattern having peaks at about 10.0, 10.6, 16.6, 23.7, and 25.7 2θ ± 0.2 2θ. Form I is further characterized by Fig.46 XRD pattern depicted in with peaks at 11.8, 15.9, 26.7 and 27.6 2θ ± 0.22θ.

[0191] In general, Form E / E1 was initially observed in a number of recrystallization and slurry experiments, indicating that it was the most stable form observed in these early studies. However, additional work indicates that Form H is more stable than Form E and possibly Form E1 (which shares many of the same physical properties with Form E). Based on the above data, Form H is considered to be the thermodynamically stable form of the compound. Forms A, B, D, and I appear to be metastable polymorphs, and Form C is more stable than Form E and Form E1. H , Form F H and form G H It is a hydrate. Fig.47 Provided are forms A, B, and C of the HCl salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone H , D, E, F H , G H Comparison of the XRD patterns of , H and I, as described in detail above.

[0192] Example 7: Large-scale synthesis of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone HCl (API HCl) Form H from intermediate C-5.

[0193] The following kilogram-scale method for preparing [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride (API HCl) initially produces Form E or Form E1 of API HCl. Form E and Form E1 preparations convert to Form H under ambient conditions, indicating the relative stability of Form H. Further, characterization as in Examples 5 and 6 confirms that Form H is the most stable of the polymorphic forms of API HCl. Importantly, no conversion of Form H to any other polymorphic form was observed. Therefore, the kilogram-scale synthetic method below, in Step 2 and Step 17, uses Form H seed crystals to quickly and completely convert the crude API HCl product to obtain only pure API HCl in Form H. This product is suitable for pharmaceutical products.

[0194] Step 1 - Pre-processing preparation

[0195] Prior to the addition of any reagents, the reaction vessel is verified to be acceptably clean, dry, and in the proper operating configuration. Prior to the first batch, the critical process instrumentation that will be used on the reactor has been verified to be calibrated and functioning properly. Pressurize the reaction system with nitrogen to a pressure of at least 25-psig. Perform a pressure check with nitrogen on each section of the system and any interconnecting piping. Included in the pressure check is all lines connected to the last valve. Hold the system for at least 30 minutes with no more than a 1-psig pressure loss. Repair any leaks and retest as necessary. Upon completion, release the pressure to vent the site. Pressurize the reactor again with nitrogen to a pressure of at least 25-psig. Perform a pressure check with nitrogen on each section of the system and any interconnecting piping. Included in the pressure check is all lines connected to the last valve. Hold the vessel for at least 30 minutes with no more than a 1-psig pressure loss. Repair any leaks and retest as necessary. Upon completion, release the pressure to vent the site. Vacuum check the filter drier to 27" Hg or less. Once at or below 27" Hg vacuum, isolate and hold for at least 30 minutes. If there is no loss of 2" Hg or more for at least 30 minutes, the filter drier is passing. Repair any leaks as necessary and retest.

[0196] Step 2 - [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride (API HCl) reaction steps:

[0197]

[0198] Verify that the reactor data acquisition system is on and that the date and time are correct. Start cooling the water in the top condenser of the reactor. Inertize the reactor with nitrogen and reach atmospheric pressure at the end of the inertization process. Isolate the reactor from the condenser, start the cooling medium of the reactor jacket, and adjust the jacket set temperature to 22°C. Charge the reactor with 1 kg of intermediate C5 (as shown above), taking care not to bury the agitator. Slowly inertize the reactor with nitrogen and place it under vacuum at the end of the inertization process. Charge the reactor with 9.152 kg of ethanol, set the reactor agitator speed to the lowest setting, start the agitator, adjust the agitation to 100 RPM, and stir the mixture for at least 10 minutes. The temperature is then maintained at 20-25°C. Charge the reactor with 1.600 kg of concentrated HCl and configure the reactor for the reaction by confirming the flow of cooling water through the reactor condenser, exhausting the reactor through the condenser, and starting a nitrogen purge on the reactor exhaust port. Adjust the reactor batch temperature to between 74°C and 78°C. The reaction was maintained between 74°C and 78°C for 1 hour, and the batch was cooled to 20-25°C over a period of 1 to 2 hours. During this cooling period, once the batch was 65-70°C, a 1 oz reactor contents sample was collected for analysis by HPLC. The reactor was charged with approximately 0.010 kg (10 grams) of API HCl Form H seed crystals, taking care not to bury the agitator, and then the batch was cooled to 20-25°C and maintained at 20-25°C for at least 12 hours. The batch was then further cooled to 0-5°C and maintained at 0-5°C for at least 2 hours.

[0199] Step 3 - API HCl Filtration

[0200] Prepare the filter dryer for filtration by making the filter dryer inert with nitrogen, ensuring that a pressure relief cartridge is installed, ensuring that the filter dryer is grounded, and ensuring that the agitator in the filter dryer is turned off and raised to the highest position. Filter the slurry in the reactor through the filter dryer and collect the filtrate in a new cartridge. Initially fill the slurry slowly in small increments to allow the filter cake to form. Near the beginning of the filtration, collect a sample of the filtrate and confirm that it contains no solids. Check the reactor for residual solids and rinse any residue in the filter dryer with ethanol. Charge 1.263 kg of ethyl acetate into the reactor to rinse the reactor and cool the rinse to 0-5°C. Drain and level the wet cake, then drain the solvent in the reactor into the filter dryer and drain the filter dryer into a new cartridge. Drain the wet cake.

[0201] Step 4 - Drying of crude API HCl

[0202] Prepare the APOVAC vacuum system by starting the condenser flow, ensuring that the annular liquid fills the overflow line and ensuring that the distillate receiver is empty. The operating parameters are as follows: (1) Cooling medium: cooling water or ethylene glycol at 2-8°C; (2) Precondenser cooling medium: chilled water or ethylene glycol at 2-8°C; annular liquid cooler: 5 gpm (minimum); exhaust condenser: 2 gpm (minimum); charge annular liquid (new or additional if required): potable water. Slowly open the vacuum shutoff valve and pull to full vacuum (less than 27" Hg vacuum) on the filter dryer, then flow tempered water at 52-58°C through the filter dryer jacket, checking the filter dryer every 4 hours (+ / - 30 minutes). Continue to dry the product (jacket inlet temperature 52-58°C, vacuum, nitrogen purge), and after drying for at least 12 hours, test the filter dryer contents for volatiles by loss on drying using a TGA unit (105°C). Continue to sample the dryer contents every approximately 8 hours until the residual volatiles content is less than or equal to 1 wt%. Once the wet cake is partially dry, begin agitation on the filter dryer to aid in the drying process, and cool completely on the filter dryer and bring the dryer to atmospheric pressure using nitrogen. Maintain the dryer at 25-30°C for at least 30 minutes before sampling for HPLC analysis. Drain the crude API HCl from the filter dryer into a 15 L A 1 oz sample was submitted for HPLC to detect any chemical impurities and for XRPD analysis to ensure the proper polymorphic form (Form H is desired). Residual solvent was also measured.

[0203] If impurities are found, additional processing steps are performed to bring the batch to target specifications. For example, acetone grinding (up to 2; steps 5-10), ethanol:ethyl acetate grinding (steps 11-13) or water grinding (steps 14-16); and crystal form correction (steps 17-19) for any polymorphic crystal form other than Form H of API HCl. If no impurities and pure polymorph Form H of API HCl (according to XRPD) are obtained, no additional processing is required. That is, optional steps 5-19 can be omitted.

[0204] Desired goal:

[0205] Any unknown impurities: ≤0.10%

[0206] Total impurities: ≤1.50%

[0207] ROI: ≤0.1%

[0208] Ethanol <5000PPM

[0209] Ethyl acetate <5000PPM

[0210] Step 5 - Optional Acetone Grinding of Crude API HCl (If Impurities Are Present)

[0211] Impurities persisted, and steps 5-7 were performed and completed. Begin cooling the water in the reactor overhead condenser, inertize the reactor with nitrogen, and reach atmospheric pressure at the end of the inertization process. The reactor was then isolated from the condenser, the reactor jacket cooling medium was started, and the jacket set temperature was adjusted to 22°C. All of the API HCl crude in step 4 was charged to the reactor, taking care not to bury the agitator, and the reactor was slowly inertized with nitrogen to avoid solid dusting. 11.887 kg of acetone was added to the reactor for each kg of crude API HCl charged. Set the reactor agitator speed to the lowest setting, start the agitator, adjust the agitation to 100 RPM, and stir the mixture for at least 10 minutes. The reactor batch temperature was adjusted to between 54°C and 58°C, and the batch temperature was maintained between 54°C and 58°C for at least 12 hours. The batch was cooled to 20-24°C and the batch was mixed at 20-24°C for 15 minutes.

[0212] Step 6 - Filtration of the Grinded API

[0213] Prepare for filtration in the filter dryer by making the dryer inertable with nitrogen, ensuring a pressure relief cartridge is installed, ensuring the filter dryer is grounded, and ensuring the dryer agitator is off and raised to its highest position. Then filter the slurry in the reactor through the dryer and collect the filtrate in the cartridge. Initially fill the slurry slowly in small increments to allow the filter cake to form. Near the start of the filtration, collect a sample of the filtrate and confirm that it contains no solids. Check the reactor for solids and, if so, rinse into the dryer. Drain and level the wet cake in the dryer, then drain the solvent from the reactor into the dryer and drain the solvent from the dryer into a new cartridge (labeled Crude API HCl Acetone Rinse). Drain the wet cake.

[0214] Step 7 - Drying of the ground API

[0215] Prepare the APOVAC vacuum system by starting the condenser flow, ensuring that the annular liquid fills the overflow line and ensuring that the distillate receiver is empty. The operating parameters are as follows: (1) Cooling medium: cooling water or ethylene glycol at 2-8°C; Precondenser cooling medium: chilled water or ethylene glycol at 2-8°C; Annular liquid cooler: 5 gpm (minimum); Exhaust condenser: 2 gpm (minimum); Annular liquid (if new or additional is required): potable water. Slowly open the vacuum shutoff valve and pull to full vacuum (less than 27" Hg vacuum) on the dryer and flow tempered water at 47-53°C through the dryer jacket. Check the dryer at 4 hour (+ / - 30 minute) intervals. Continue to dry the product (jacket inlet temperature of 47-53°C, vacuum, nitrogen purge) and after drying for at least 12 hours, sample the filter dryer contents and test the sample for volatiles by loss on drying using a TGA unit (105°C). Continue to sample the dryer contents every ≥8 hours until the residual volatiles content is less than or equal to 1 wt%. Once the wet cake is partially dry, begin stirring on the dryer to aid in the drying process. When the control during drying meets the necessary requirements, fully cool the dryer and bring the dryer to atmospheric pressure using nitrogen and maintain the dryer at 25-30°C for at least 30 minutes before sampling. From API A 1 oz sample is collected in a desiccator of HCl for HPLC analysis for purity testing, appropriate polymorphic form testing by XRPD, and residual solvent testing. The crude API HCl is discharged from the desiccator into a 15 L Curtec keg. When reviewing the results and target ranges specified at the end of Step 4, additional processing is sometimes required in this batch record. If all results are within the purity specifications and only polymorphic forms of API HCl are obtained (according to XRPD), no additional processing is required. Otherwise, Form H can be obtained by removing impurities through an optional second acetone grind (steps 8-10), an optional ethanol / ethyl acetate grind (steps 11-13), or an optional deionized water grind (steps 14-16), or an optional API HCl form correction (steps 17-19).

[0216] Step 8 - Optional Second Acetone Grinding (If Impurities Are Present)

[0217] If impurities persist, perform and complete steps 8-10. As before, clean the reactor and filter dryer, start cooling the water in the reactor overhead condenser, inertize the reactor with nitrogen, and bring the reactor to atmospheric pressure at the end of the inertization process. Isolate the reactor from the condenser, start the cooling medium for the reactor jacket, and adjust the jacket set temperature to 22°C. Charge all the crude API HCl from step 7 or any other drying step into the reactor, taking care not to bury the agitator. Slowly inertize the reactor with nitrogen to avoid dusting of solids. Charge the reactor with 11.887 kg of acetone per kg of crude API HCl, set the reactor agitator speed to the lowest setting, start the agitator, adjust the agitation to 100 RPM, and stir the mixture for at least 10 minutes. Then adjust the reactor batch temperature to between 54°C and 58°C and maintain this temperature for at least 12 hours. Cool the batch to 20-24°C and mix the batch at 20-24°C for 15 minutes.

[0218] Step 9 - Filtration of the Grinded API

[0219] Prepare for filtration in the filter-dryer by making the dryer inertable with nitrogen, ensuring a pressure relief cartridge is installed, ensuring the filter-dryer is grounded, and ensuring the dryer agitator is off and raised to its highest position. Filter the slurry from the reactor through the dryer and collect the filtrate in a new cartridge. Initially fill the slurry slowly in small increments to allow the filter cake to form. Near the start of filtration, collect a sample of the filtrate and confirm that it contains no solids. If solids remain in the filtrate, refilter. Check the reactor for solids and if a large amount of solids remain, recycle the filtrate and charge more acetone rinse to remove. Strip and level the wet cake in the filter-dryer. Drain the solvent from the reactor into the dryer, and then drain the solvent from the dryer into a new cartridge. Strip the wet cake.

[0220] Step 10 - Drying of the ground API

[0221] Prepare the APOVAC vacuum system by starting flow to the condenser; ensuring that the annular liquid fills the overflow line; and ensuring that the distillate receiver is empty. The operating parameters are as follows: Cooling medium: cooling water or glycol at 2-8°C; Precondenser cooling medium: chilled water or glycol at 2-8°C; Annular liquid cooler: 5 gpm (minimum); Exhaust condenser: 2 gpm (minimum); and Annular liquid (if new or additional is required): potable water. Slowly open the vacuum shutoff valve and pull to full vacuum (less than 27" Hg vacuum) on the dryer, flow tempered water at 47-53°C through the dryer jacket, and begin monitoring the dryer every 4 hours (+ / - 30 minutes). Continue to dry the product (jacket inlet temperature of 47-53°C, vacuum, nitrogen purge), and after drying for at least 12 hours, sample the contents of the filter dryer and test the volatiles of the filter dryer contents by loss on drying using a TGA unit (105°C). Continue to sample the dryer contents every ≥8 hours until the residual volatiles content is less than or equal to 1 wt%. Once the wet cake is partially dry, begin agitation on the dryer to aid in the drying process. When the control during drying meets the necessary requirements, fully cool the dryer, bring the dryer to atmospheric pressure using nitrogen, and maintain the dryer at 25-30°C for at least 30 minutes before sampling. Collect a 1 oz sample from the API HCl dryer for HPLC analysis. Drain the API HCl from the dryer into a 15L Curtec keg. Submit 1 oz sample for HPLC purity testing, XRPD testing of desired polymorph Form H, and residual solvent testing. If all results are within specification and the polymorphic form of API HCl is obtained (according to XRPD), no additional processing is required. Otherwise, Form H can be prepared by optional ethanol / ethyl acetate grinding (steps 11-13) and / or optional deionized water grinding (steps 14-16) to remove impurities, or optional API HCl form correction (steps 17-19).

[0222] Step 11 - Optional ethanol / ethyl acetate trituration (if impurities present)

[0223] If impurities persist, perform and complete steps 11-13. As before, clean the reactor and filter dryer, start cooling the water in the reactor overhead condenser, inertize the reactor with nitrogen, and bring the reactor to atmospheric pressure at the end of the inertization process. Isolate the reactor from the condenser, start the cooling medium of the reactor jacket, and adjust the jacket set temperature to 22°C. Charge all the crude API HCl from step 10 or any other drying step into the reactor, taking care not to bury the agitator. Slowly inertize the reactor with nitrogen to avoid solid dusting. Charge the reactor with 4.500 kg of ethyl acetate per kg of crude API HCl, set the reactor agitator speed to the lowest setting, start the agitator, adjust the agitation to 100 RPM, and stir the mixture for at least 10 minutes. Adjust the reactor batch temperature to between 58°C and 62°C, and maintain the batch temperature between 58°C and 62°C for at least 24 hours. Cool the batch to 20-25°C and mix the batch at 20-24°C for 15 minutes.

[0224] Step 12 - Filtration of the Grinded API

[0225] Prepare for filtration in the filter dryer by: inerting the dryer with nitrogen, ensuring that a pressure relief cartridge is installed, ensuring that the filter dryer is grounded, and ensuring that the dryer agitator is off and raised to the highest position. Filter the slurry in the reactor through the dryer and collect the filtrate in a new cartridge. Initially fill the slurry slowly in small increments to allow the filter cake to form. Near the beginning of the filtration, collect a sample of the filtrate and confirm that it contains no solids. If solids remain in the filtrate, refilter. Check the reactor for solids and recover the filtrate if a large amount of solids remain. Then rinse by adding 0.900 kg of ethyl acetate per kg of crude API HCl and 0.790 kg of ethanol per kg of crude API HCl to the reactor. Then set the reactor agitator speed to its lowest setting, start the agitator, and adjust the agitation speed to 100 RPM. Adjust the reactor contents to between 2°C and 8°C. Deliquify and level the wet cake in the dryer, drain the solvent in the reactor into the dryer, and then drain the solvent in the dryer into a new cartridge. Again, the wet cake is deliquified.

[0226] Step 13 - Drying of the ground API

[0227] Prepare the APOVAC vacuum system by starting flow to the condenser; ensuring that the annular liquid fills the overflow line; and ensuring that the distillate receiver is empty. The operating parameters are as follows: Cooling medium: cooling water or glycol at 2-8°C; Precondenser cooling medium: chilled water or glycol at 2-8°C; Annular liquid cooler: 5 gpm (minimum); Exhaust condenser: 2 gpm (minimum); and Annular liquid (if new or additional is required): potable water. Slowly open the vacuum shutoff valve and pull to full vacuum (less than 27" Hg vacuum) on the dryer, flow tempered water at 52-58°C through the dryer jacket, and begin monitoring drying every 4 hours (+ / - 30 minutes). Continue drying the product (jacket inlet temperature of 52-58°C, vacuum, nitrogen purge), and after drying for at least 12 hours, sample the contents of the filter dryer and test the volatiles of the filter dryer contents by loss on drying using a TGA unit (105°C). Continue sampling the dryer contents every ≥8 hours until the residual volatiles content is less than or equal to 1 wt%. Once the wet cake is partially dry, begin stirring on the dryer to aid in the drying process. When the control during drying meets the necessary requirements, fully cool the dryer and bring the dryer to atmospheric pressure using nitrogen and maintain the dryer at 25-30°C for at least 30 minutes before sampling. Collect a 1 oz sample from the dryer of API HCl for HPLC testing, XRPD testing, and residual solvent testing. HCl is discharged from the dryer into a 15L Curtec keg. If all results are within specification and only polymorphic forms of API HCl are obtained (according to XRPD), no additional processing is required. Otherwise, impurities can be removed by optional deionized water grinding (steps 14-16), or Form H can be prepared by optional API HCl form correction (steps 17-19).

[0228] Step 14 - Optional DI Water Grinding (if impurities present)

[0229] If impurities persist, perform and complete steps 14-16. As previously described, clean the reactor and filter dryer, start cooling the water in the reactor overhead condenser, inertize the reactor with nitrogen, and bring the reactor to atmospheric pressure at the end of the inertization process. Isolate the reactor from the condenser, start the cooling medium of the reactor jacket, and adjust the jacket set temperature to 22°C. Charge all the crude API HCl from step 13 or any other drying step into the reactor, taking care not to bury the agitator. Slowly inertize the reactor with nitrogen to avoid solid dusting. Fill the reactor with 10kg WFI (water for injection) quality water per kg of crude API HCl charged, set the reactor agitator speed to the lowest setting, start the agitator, adjust the agitation to 100RPM, and stir the mixture for at least 10 minutes. Adjust the reactor batch temperature to between 58°C and 62°C, and maintain the batch temperature between 58°C and 62°C for at least 4 hours. Cool the batch to 20-24°C in at least one hour.

[0230] Step 15 - Filtration of the Grinded API

[0231] Prepare for filtration in the filter dryer by making the dryer inertable with nitrogen, ensuring a pressure relief cartridge is installed, ensuring the filter dryer is grounded, and ensuring the dryer agitator is off and raised to the highest position. Filter the slurry in the reactor through the dryer and collect the filtrate in a new cartridge. Initially fill the slurry slowly in small increments to allow the filter cake to form. Near the start of the filtration, collect a filtrate sample and confirm that it contains no solids. If solids remain in the filtrate, refilter. Check the reactor for solids and recover the filtrate if a large amount of solids remain. Then rinse by adding 10 kg WFI mass water per kg crude API HCl to the reactor. Drain the solvent from the reactor into the dryer, and then drain the solvent from the dryer into a new cartridge. Deliquify the wet cake.

[0232] Step 16 - Drying of the ground API

[0233] Prepare the APOVAC vacuum system by starting flow to the condenser; ensuring that the annular liquid fills the overflow line; and ensuring that the distillate receiver is empty. The operating parameters are as follows: Cooling medium: cooling water or glycol at 2-8°C; Precondenser cooling medium: chilled water or glycol at 2-8°C; Annular liquid cooler: 5 gpm (minimum); Exhaust condenser: 2 gpm (minimum); and Annular liquid (if new or additional is required): potable water. Slowly open the vacuum shutoff valve and pull to full vacuum (less than 27" Hg vacuum) on the dryer, flow tempered water at 50-60°C through the dryer jacket, and begin monitoring drying every 4 hours (+ / - 30 minutes). Continue drying the product (jacket inlet temperature 50-60°C, vacuum, nitrogen purge), and after drying for at least 12 hours, sample the contents of the filter dryer and test the volatiles of the filter dryer contents by loss on drying using a TGA unit (105°C). Continue sampling the dryer contents every ≥8 hours until the residual volatiles content is less than or equal to 1 wt%. Once the wet cake is partially dry, begin stirring on the dryer to aid in the drying process. When the control during drying meets the necessary requirements, fully cool the dryer, bring the dryer to atmospheric pressure using nitrogen, and maintain the dryer at 25-30°C for at least 30 minutes before sampling. Collect a 1 oz sample from the dryer of API HCl for HPLC testing, XRPD testing, and residual solvent testing. HCl is discharged from the dryer into a 15L Curtec keg. If all results are within specification and only polymorphic forms of API HCl are obtained (according to XRPD), no additional processing is required. If Form H is not obtained, an optional API HCl form correction is performed (steps 17-19).

[0234] Step 17 - API HCl Form Correction

[0235] If Form H is not observed in step 16 or any of the above drying steps, proceed to steps 17-19. Inertize the reactor with nitrogen and reach atmospheric pressure at the end of the inertization process. Isolate the reactor from the condenser, start the cooling medium of the reactor jacket, and adjust the jacket set temperature to 22°C. Add all the crude API HCl from step 16 or any previously performed grinding to the reactor, taking care not to bury the agitator. Slowly inertize the reactor with nitrogen to avoid dusting of solids. Charge the reactor with 3.945 kg of ethanol per kg of crude API HCl and 4.510 kg of ethyl acetate per kg of crude API HCl, set the reactor agitator speed to the lowest setting, start the agitator, adjust the agitation to 100 RPM, and stir the mixture at 20-25°C for at least 10 minutes. Add 0.010 kg of Form H seed crystals of API HCl to the reactor, taking care not to bury the agitator. After loading is complete, close the loading valve on the reactor and configure the reactor by confirming that cooling water is flowing through the reactor condenser; vent the reactor through the condenser; and begin a nitrogen purge on the reactor vent. Adjust the reactor batch temperature to between 58°C and 62°C and begin monitoring approximately every 2 hours (+ / - 30 minutes) until form conversion is complete. Maintain the reaction between 58°C and 62°C for at least 24 hours. Collect a 1 oz sample of the reactor contents by: (1) placing 5 psig nitrogen pressure on the reactor; (2) collecting a 1 oz sample to flush the sample line; (3) collecting a 1 oz sample of the reactor contents; and (4) venting the reactor to a fixed vent with a slow nitrogen purge on the vent. Analyze a sample of the reactor contents (second sample) by XRPD to confirm that the appropriate polymorph Form H has been obtained. If Form H is not formed within the first 24 hours, the reaction can be maintained at 58°C and 62°C and repeated sampling for up to 2 additional 24 hours until Form H is formed. Once Form H is formed, the batch is cooled to 20-25°C and held for at least 20 minutes.

[0236] Step 18 - API HCl Filtered Form H

[0237] Prepare for filtration in the filter dryer by making the dryer inert with nitrogen, ensuring that a pressure relief cartridge is installed, ensuring that the filter is grounded, and ensuring that the dryer agitator is off and raised to the highest position. Filter the slurry in the reactor through the dryer and collect the filtrate in a new cartridge. Initially fill the slurry slowly in small increments to allow the filter cake to form. Near the beginning of the filtration, collect a filtrate sample and confirm that it contains no solids. If solids remain in the filtrate, refilter. Check the reactor for solids and recover the filtrate if a large amount of solids remains. Then rinse the reactor by adding 0.789 kg of ethanol per kg of crude API HCl and 0.902 kg of ethyl acetate per kg of crude API HCl to the reactor. Cool the rinse to 2-8°C. Drain the wet filter cake and level it. Drain the solvent in the reactor into the dryer, and then drain the solvent in the dryer into a new cartridge. Drain the wet cake again.

[0238] Step 19 - API HCl Form H Drying

[0239] Prepare the APOVAC vacuum system by starting flow to the condenser; ensuring that the annular liquid fills the overflow line; and ensuring that the distillate receiver is empty. The operating parameters are as follows: Cooling medium: cooling water or glycol at 2-8°C; Precondenser cooling medium: chilled water or glycol at 2-8°C; Annular liquid cooler: 5 gpm (minimum); Exhaust condenser: 2 gpm (minimum); and Annular liquid (if new or additional is required): potable water. Slowly open the vacuum shutoff valve and pull full vacuum on the dryer (less than 27" Hg vacuum), flow tempered water at 52-58°C through the dryer jacket, and begin monitoring drying every 4 hours (+ / - 30 minutes). Continue drying the product (jacket inlet temperature 52-58°C, vacuum, nitrogen purge), and after drying for at least 12 hours, sample the contents of the filter dryer and test the volatiles of the filter dryer contents by loss on drying using a TGA unit (105°C). Continue sampling the dryer contents every ≥8 hours until the residual volatiles content is less than or equal to 1 wt%. Once the wet cake is partially dry, begin agitation in the dryer to aid in the drying process. When control during drying meets the necessary requirements, fully cool the dryer and bring the dryer to atmospheric pressure using nitrogen. A 2 oz sample of HCl was collected in a desiccator and analyzed by HPLC, Karl Fischer, Appearance, XRPD, and residual solvent testing. If the GC result for residual solvent was above target, the material was redried for an additional time and retested. The API HCl was drained from the desiccator into a 15 L Curtec keg. If all results were within specification and only polymorphic forms of API HCl were obtained (according to XRPD), no additional processing was required.

[0240] Although certain features of the present invention have been illustrated and described herein, many modifications, substitutions, changes and equivalents will now occur to those skilled in the art. It is therefore to be understood that the appended claims are intended to cover all such modifications and changes as 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 in that An X-ray powder diffraction (XRD) pattern having peaks at 9.6, 12.0, 19.2, 23.6 and 24.4 2θ ± 0.2 2θ.

2. The crystalline polymorph 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 pattern substantially as depicted in Figure 35.

3. The crystalline polymorph 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 polymorph Form B of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized in that An X-ray powder diffraction (XRD) pattern having peaks at 9.5, 12.1, 18.0, 18.9 and 23.0 2θ ± 0.2 2θ.

5. The crystalline polymorph 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 depicted in Figure 18.

6. The crystalline polymorph 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±0.22θ.

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

8. The crystalline polymorph Form C of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 7 H , which is further characterized by an XRD pattern substantially as depicted in Figure 22.

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

10. A crystalline polymorph Form D of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized in that An X-ray powder diffraction (XRD) pattern having peaks at 9.4, 15.1, 17.3, 22.1 and 23.2 2θ ± 0.2 2θ.

11. The crystalline polymorph 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 depicted in Figure 25.

12. The crystalline polymorph 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 polymorph Form E of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized in that 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.

14. The crystalline polymorph 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 depicted in Figure 29.

15. The crystalline polymorph 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 polymorph Form E1 of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride, characterized in that An X-ray powder diffraction (XRD) pattern having peaks at 9.4, 10.9, 17.3, 22.1, 23.4 and 24.8 2θ ± 0.2 2θ.

17. The crystalline polymorph 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 depicted in Figure 30.

18. The crystalline polymorph 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 H , characterized in that X-ray powder diffraction (XRD) pattern with peaks at 9.06, 10.4, 18.85, 25.48 and 27.97 2θ ± 0.2 2θ.

20. The crystalline polymorph Form F of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 19 H , which is further characterized by XRD peaks at 12.9, 20.9 and 26.14 2θ ± 0.22θ.

21. The crystalline polymorph Form F of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 19 H , which is further characterized by XRD pattern substantially as depicted in Figure 38.

22. The crystalline polymorph Form F of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 19 H , which has a differential scanning calorimetry (DSC) thermogram exhibiting a large split endotherm with an onset at approximately 90.8°C and a peak maximum at 99.7°C.

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

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

25. The crystalline polymorph Form G of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 23 H , which is further characterized by An XRD pattern substantially as depicted in FIG. 40 .

26. A crystalline polymorph Form H of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride characterized in that 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.

27. The crystalline polymorph 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. The crystalline polymorph 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 pattern substantially as depicted in Figure 43.

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

30. The crystalline polymorph Form H of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride according to claim 26, which has a differential scanning calorimetry (DSC) thermogram, wherein the melting endotherm of the DSC thermogram starts at 247.5°C, with a peak maximum of 250.1°C.

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

32. The crystalline polymorph 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 ± 0.22θ ± 0.2 2θ.

33. The crystalline polymorph 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 depicted in Figure 46.

34. A hydrochloride salt of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone, characterized in that at least The following polymorphs: Form A, Form B, Form C characterized by an XRD pattern substantially as depicted in FIG. 47 H , Form D, Form E, Form F H , Form G H , Form H and Form I and Form E1 characterized by an XRD pattern substantially as depicted in FIG. 30 .

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) having peaks at 10.8, 15.3, 15.9, 18.6 and 25.9 2θ ± 0.2 2θ.

36. A crystalline polymorph 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 depicted in Figure 1.

37. A crystalline polymorph Form II of the free base of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone according to 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 in that 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.

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 depicted in FIG5 .

40. 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 XRD peaks at 10.5, 14.1, 16.1 and 26.2 2θ ± 0.22θ.

41. A crystalline polymorphic form of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone mesylate characterized in that 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.

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 depicted in FIG15 .

43. 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 XRD peaks at 12.1, 18.8, 21.9, 24.5 and 28.2 2θ ± 0.2 2θ.

44. A method for preparing Form E of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride by recrystallizing any form of the salt from 2-propanol, a 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 depicted in Figure 29.

45. The method of claim 44, whereby the Form E is prepared by adding the salt at a saturated concentration to 2-propanol at 25°C, heating to 45-50°C to dissolve the solid, and flash evaporating at ambient temperature under a flow of 1.5 psi of N2 to produce solid Form E.

46. ​​The method of claim 44, whereby Form E is prepared by adding the salt at saturated 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. A method according to claim 44, whereby the Form E is prepared by adding the salt at a saturated concentration to ethanol at 25°C, heating to 45-50°C to dissolve any solids, and rapidly evaporating the solvent at 40°C under a flow of 1.5 psi of N2 to produce Form E.

48. A method for preparing Form E1 of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride by recrystallizing any form of the salt 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 depicted in Figure 30.

49. The method of claim 48, whereby the Form E1 is prepared by adding the salt at a saturated concentration to a 2-propanol / dichloromethane binary solvent mixture at 25°C, heating to 45-50°C to dissolve the solid, and rapidly evaporating the solvent at 40°C under a N2 flow of 1.5 psi to produce solid Form E1.

50. The method of claim 48, wherein the Form E1 is prepared by adding the salt at a saturated concentration to a 2-propanol / chloroform binary solvent mixture at 25°C, heating to 45-50°C to dissolve the solid, and rapidly evaporating the solvent at 40°C under a N2 flow of 1.5 psi to produce solid Form E1.

51. A method for preparing Form H of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride by incubating Form E or Form El at ambient temperature.

52. A method for preparing Form H of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride by competitively slurrying Form E and Form H in 2-butanol or 2-propanol for 1 day, wherein in order to avoid possible desolvation or physical changes after separation, the sample is not further dried before the obtained Form H is subjected to X-ray analysis, 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 depicted in Figure 29; and wherein 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 is further characterized by an XRD pattern substantially as depicted in FIG. 43 .

53. A method according to claim 52, whereby Form H is synthesized by co-incubating Form E and Form H in 2-butanol for 1 day, wherein the co-incubation involves adding Form E and Form H to pure 2-butanol until saturated, stirring the resulting suspension at ambient temperature for 1 day, and vacuum filtering the solid to produce Form H.

54. A method according to claim 52, whereby Form H is synthesized by co-incubating Form E and Form H in 2-propanol for 1 day, wherein the co-incubation involves adding Form E and Form H to pure 2-propanol until saturated, stirring the resulting suspension at ambient temperature for 1 day, and vacuum filtering the solid to produce Form H.

55. A method for preparing Form H of [2-(1H-indol-3-yl)-1H-imidazol-4-yl](3,4,5-trimethoxyphenyl)methanone hydrochloride by seeding Form H crystals into the synthesis of other polymorphic forms of the salt, wherein 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 is further characterized by an XRD pattern substantially as depicted in Figure 43.

56. The method of claim 55, whereby the other polymorph form is the 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 is further characterized by an XRD pattern substantially as depicted in Figure 29.

57. The method of claim 55, whereby the other polymorph 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 is further characterized by an XRD pattern substantially as depicted in Figure 30.

58. A method of using a specific polymorph of the present invention in a pharmaceutical product for treating a disease.

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

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

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

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

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

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

65. The method of claim 65, wherein the inflammatory lung disease is an infection.

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

67. The method of use according to 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.

Images