Solid state forms of belumosudil and belumosudil salts

Abstract

To solve the problem that there is a need for further solid state forms of Belumosudil and salts thereof, including solvate forms.SOLUTION: The present invention provides Belumosudil, crystalline polymorphs of salts thereof, including Belumosudil mesylate, Belumosudil tosylate, and / or Belumosudil besylate, processes for preparation thereof, and pharmaceutical compositions thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] The present disclosure encompasses solid forms of vemurafenib, in embodiments crystalline polymorphs of vemurafenib or its salts, methods for their preparation, and pharmaceutical compositions thereof.

Background Art

[0002] Vemurafenib, 2-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide, has the following chemical structure:

[0003]

Chem.

[0004] Vemurafenib is a ROCK2 inhibitor and has been developed for the treatment of graft-versus-host disease including chronic graft-versus-host disease, systemic sclerosis including diffuse cutaneous systemic sclerosis, fibrosis including idiopathic pulmonary fibrosis, psoriasis vulgaris, and systemic scleroderma.

[0005] The compound is described in International Publication No. WO 2006 / 105081. The crystalline forms of vemurafenib are disclosed in International Publication No. WO 2021 / 129589.

[0006] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule can give rise to a variety of polymorphs with different crystal structures and physical properties such as melting point, thermal behavior (measured by, for example, thermogravimetric analysis ("TGA") or differential scanning calorimetry ("DSC")), X-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solid ( 13 C) NMR spectrum. One or more of these techniques can be used to distinguish different polymorphic forms of a compound.

[0007] Salts and solid forms (including solvated forms) of pharmaceutical ingredients may have different properties. Such variations in the properties of different salts, solid forms, and solvates can, for example, serve as a basis for improving formulations by facilitating better processing or handling, altering the dissolution profile in a favorable direction, or improving stability (both polymorphic and chemical stability) and shelf life. These variations in the properties of different salts and solid forms can also, for example, lead to improvements in the final dosage form if they help to improve bioavailability. Different salts, solid forms, and solvates of pharmaceutical ingredients can also give rise to the occurrence of various polymorphic or crystalline forms, thereby providing further opportunities to evaluate variations in the properties and characteristics of solid pharmaceutical ingredients.

[0008] By discovering new solid forms and solvates of pharmaceuticals, substances can be obtained that have desirable processing characteristics such as ease of handling, ease of processing, storage stability, and ease of purification, or that are desirable intermediate crystalline forms that facilitate conversion to other polymorphic forms. New solid forms of pharmaceutically useful compounds can also provide opportunities to improve the performance characteristics of pharmaceuticals. This can, for example, expand the repertoire of substances available to formulation scientists for formulation optimization by providing products with different properties including different crystal habits, higher crystallinity, or polymorphic stability, and can provide better processing or handling, improved dissolution profiles, or improved shelf life (chemical / physical stability). For at least these reasons, further solid forms (including solvated forms) of vermostil and vermostil salts are needed.

Prior Art Documents

Patent Documents

[0009]

Patent Document 1

Patent Document 2

Non-Patent Documents

[0010]

Non-Patent Document 1

SUMMARY OF THE INVENTION

MEANS FOR SOLVING THE PROBLEM

[0011] The present disclosure provides the crystalline polymorphs of vemuralsil, and salts thereof including vemuralsil mesylate, vemuralsil tosylate and / or vemuralsil besylate, methods for preparing the same, and pharmaceutical compositions thereof. These crystalline polymorphs can be used for preparing other solid forms of vemuralsil, vemuralsil salts and their solid forms.

[0012] The present disclosure also provides the use of the solid forms of the API or vemuralsil mesylate, vemuralsil tosylate and / or vemuralsil besylate in the preparation of other solid forms of vemuralsil or its salts.

[0013] The present disclosure provides crystalline polymorphs of vemuralsil, or salts thereof including vemuralsil mesylate, vemuralsil tosylate and vemuralsil besylate, for use in medicine, including for the treatment of graft-versus-host disease including chronic graft-versus-host disease, systemic sclerosis including diffuse cutaneous systemic sclerosis, fibrosis including idiopathic pulmonary fibrosis, psoriasis vulgaris, and systemic scleroderma. In particular, the present disclosure provides crystalline polymorphs of vemuralsil, or salts thereof including vemuralsil mesylate, vemuralsil tosylate and vemuralsil besylate, for use in medicine, including for the treatment of chronic graft-versus-host disease and / or systemic sclerosis.

[0014] The present disclosure also encompasses the use of the crystalline polymorphs of vemuralsil of the present disclosure, or salts thereof including vemuralsil mesylate, vemuralsil tosylate and vemuralsil besylate, for the preparation of pharmaceutical compositions and / or formulations.

[0015] In another aspect, the present disclosure provides a pharmaceutical composition comprising a crystalline polymorph of bermodzil according to the present disclosure, or a salt thereof including bermodzil mesylate, bermodzil tosylate, and bermodzil besylate.

[0016] The present disclosure includes a method for preparing the above pharmaceutical composition. The method includes combining any one or a combination of crystalline polymorphs of bermodzil, or salts thereof including bermodzil mesylate, bermodzil tosylate, and bermodzil besylate with at least one pharmaceutically acceptable excipient.

[0017] The crystalline polymorphs of bermodzil, or salts thereof including bermodzil mesylate, bermodzil tosylate, and bermodzil besylate as defined herein, and pharmaceutical compositions or formulations of the crystalline polymorphs of bermodzil, or salts thereof including bermodzil mesylate, bermodzil tosylate, and bermodzil besylate can be used as medicaments, for example, for the treatment of graft-versus-host disease including chronic graft-versus-host disease, systemic sclerosis including diffuse cutaneous systemic sclerosis, fibrosis including idiopathic pulmonary fibrosis, psoriasis vulgaris, and systemic scleroderma. In particular, the crystalline polymorphs of bermodzil, or salts thereof including bermodzil mesylate, bermodzil tosylate, and bermodzil besylate as defined herein, and pharmaceutical compositions or formulations of the crystalline polymorphs of bermodzil, or salts thereof including bermodzil mesylate, bermodzil tosylate, and / or bermodzil besylate can be used as medicaments for the treatment of chronic graft-versus-host disease and / or systemic sclerosis.

[0018] The present disclosure also provides a method for treating graft-versus-host disease including chronic graft-versus-host disease, systemic sclerosis including diffuse cutaneous systemic sclerosis, fibrosis including idiopathic pulmonary fibrosis, psoriasis vulgaris, and systemic scleroderma, by administering to a subject having or in need of treatment for graft-versus-host disease including chronic graft-versus-host disease, systemic sclerosis including diffuse cutaneous systemic sclerosis, fibrosis including idiopathic pulmonary fibrosis, psoriasis vulgaris, and systemic scleroderma, any one or combination of crystalline polymorphs of the belumosudil of the present disclosure, or salts thereof including belumosudil mesylate, belumosudil tosylate, and belumosudil besylate, or at least one therapeutically effective amount of the above pharmaceutical composition. In particular, the present disclosure provides a method for treating chronic graft-versus-host disease and / or systemic sclerosis by administering to a subject having or in need of treatment for chronic graft-versus-host disease and / or systemic sclerosis any one or combination of crystalline polymorphs of the belumosudil of the present disclosure, or salts thereof including belumosudil mesylate, belumosudil tosylate, and belumosudil besylate, or at least one therapeutically effective amount of the above pharmaceutical composition.

[0019] The present disclosure also provides the use of any one or combination of crystalline polymorphs of the belumosudil of the present disclosure, or salts thereof including belumosudil mesylate, belumosudil tosylate, and / or belumosudil besylate, or at least one of the above pharmaceutical compositions, for the manufacture of a medicament for treating graft-versus-host disease including chronic graft-versus-host disease, systemic sclerosis including diffuse cutaneous systemic sclerosis, fibrosis including idiopathic pulmonary fibrosis, psoriasis vulgaris, and systemic scleroderma, particularly for treating chronic graft-versus-host disease and / or systemic sclerosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0020]

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Mode for Carrying Out the Invention

[0021] The present disclosure includes solid forms of vermostil and its salts, methods for preparing the same, and pharmaceutical compositions thereof, which include crystal polymorphs of vermostil and its salts including vermostil mesylate, vermostil tosylate and / or vermostil besylate.

[0022] The solid properties of vermostil, vermostil salts and their crystal polymorphs can be affected by controlling the conditions under which vermostil and vermostil salts and their crystal polymorphs are obtained in solid form.

[0023] Solid forms (or polymorphs) may be referred to herein as being polymorphically pure or substantially free of any other solid (or polymorph) form. As used herein in this context, the expression "substantially free of any other form" means that the solid form contains, for example, by measurement by XRPD, about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other form of the target compound. Thus, a crystalline polymorph of vermoxil or a vermoxil salt described herein as being substantially free of any other solid form is understood to contain greater than about 80% (w / w), greater than about 90% (w / w), greater than about 95% (w / w), greater than about 98% (w / w), greater than about 99% (w / w), or about 100% of the crystalline polymorph of the target vermoxil or vermoxil salt. In some embodiments of the present disclosure, the crystalline polymorph of the vermoxil or vermoxil salt described may contain from about 1% to about 20% (w / w), from about 5% to about 20% (w / w), or from about 5% to about 10% (w / w) of one or more other crystalline polymorphs of the same vermoxil or vermoxil salt. Similarly, a crystalline polymorph of a vermoxil salt (e.g., vermoxil mesylate, vermoxil tosylate, or vermoxil besylate) described herein as being substantially free of any other solid form is understood to contain greater than about 80% (w / w), greater than about 90% (w / w), greater than about 95% (w / w), greater than about 98% (w / w), greater than about 99% (w / w), or about 100% of the crystalline polymorph of the target vermoxil salt (e.g., vermoxil mesylate, vermoxil tosylate, or vermoxil besylate). In some embodiments of the present disclosure, the crystalline polymorph of the vermoxil salt (e.g., vermoxil mesylate, vermoxil tosylate, or vermoxil besylate) described may contain from about 1% to about 20% (w / w), from about 5% to about 20% (w / w), or from about 5% to about 10% (w / w) of one or more other crystalline polymorphs of the same vermoxil salt (e.g., vermoxil mesylate, vermoxil tosylate, or vermoxil besylate).

[0024] Depending on which other crystal polymorphs are compared, the crystal polymorphs of the vermoxil and vermoxil salts (e.g., vermoxil mesylate, vermoxil tosylate or vermoxil besylate) of the present disclosure can have advantageous properties selected from at least one of the following: chemical purity, fluidity, solubility, dissolution rate, morphology or crystal habit, stability, e.g., chemical stability, and thermal and mechanical stability with respect to polymorphic transformation, stability to dehydration and / or storage stability, low content of residual solvents, lower degree of hygroscopicity, fluidity, and advantageous processing and handleability such as compressibility and bulk density.

[0025] Solid forms such as crystalline or amorphous forms may be referred to herein as being characterized by graph data "as shown in" or "substantially as shown in" the figures. Such data includes, for example, powder X-ray diffraction patterns and solid NMR spectra. As is well known in the art, graph data potentially provides additional technical information (so-called "fingerprints") for further defining each solid form that cannot necessarily be explained by just numerical or peak position references. In any case, one of ordinary skill in the art will understand that such graphical representations of data are subject to small variations in peak relative intensity and peak position due to certain factors such as, but not limited to, variations in instrument response well known to those of ordinary skill in the art, as well as variations in sample concentration and purity. Nevertheless, one of ordinary skill in the art can readily compare the graph data in the figures herein with graph data generated for an unknown crystal form and determine whether the two sets of graph data characterize the same crystal form or two different crystal forms. Thus, it is understood that the crystal forms of vermoxil or vermoxil salts referred to herein as being characterized by graph data "as shown in" or "substantially as shown in" the figures include any crystal form of vermoxil or vermoxil salts characterized by graph data having small variations as would be well known to one of ordinary skill in the art compared to the figures.

[0026] As used herein, unless otherwise specified, the term "anhydrous" in relation to a crystalline form of vermoxil, vermoxil mesylate, vermoxil tosylate, and / or vermoxil besylate relates to a crystalline form of vermoxil or a vermoxil salt that does not contain a stoichiometric amount of water of crystallization (or other solvent) within the crystal. Further, the "anhydrous" form generally contains no more than 1% (w / w) of either water or an organic solvent, as measured, for example, by TGA.

[0027] As used herein, unless otherwise indicated, the term "solvate" refers to a crystalline form in which a solvent is incorporated into the crystal structure. When the solvent is water, the solvate is often referred to as a "hydrate". The solvent in the solvate may be present in either a stoichiometric or non-stoichiometric amount.

[0028] As used herein, unless otherwise specified, the term "isolated" in relation to a crystalline polymorph of vermoxil or a vermoxil salt (e.g., vermoxil mesylate, vermoxil tosylate, and / or vermoxil besylate) of the present disclosure corresponds to a crystalline polymorph of vermoxil or a vermoxil salt that is physically separated from the reaction mixture in which it is formed.

[0029] As used herein, unless otherwise specified, XRPD measurements are performed using copper Kα radiation with a wavelength of 1.5418 Å. The XRPD peaks reported herein are typically measured at a temperature of 25 ± 3 °C using CuKα radiation, λ = 1.5418 Å.

[0030] As used herein, 13 The 13C NMR spectrum is preferably measured at 125 MHz with a magic angle spinning (MAS) frequency ωr / 2π = 11 kHz.

[0031] As used herein, unless otherwise specified, TGA analysis is preferably performed using a nitrogen flow rate of 40 ml / min at a heating rate of 10 °C / min up to 250 °C.

[0032] An object, for example a reaction mixture, may be characterized herein as being at or brought to "room temperature" or "ambient temperature", often abbreviated as "RT". This means that the temperature of the object is close to or the same as the temperature of the space in which the object is located, such as a room or a fume hood. Typically, room temperature is about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.

[0033] The amount of solvent used in a chemical process, such as a reaction or crystallization, may be referred to herein as a number of "volumes" or "vol" or "V". For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10 V) of solvent. In this context, this expression is understood to mean milliliters of solvent per gram of the suspended material, and thus suspending 5 grams of material in 10 volumes of solvent means that the solvent is used in an amount of 10 milliliters of solvent per gram of the suspended material, or 50 mL of solvent in this example. In another context, the term "v / v" may be used to indicate the number of volumes of solvent added to a liquid mixture based on the volume of that mixture. For example, adding solvent X (1.5 v / v) to 100 ml of a reaction mixture indicates that 150 mL of solvent X has been added.

[0034] A method or process may be referred to herein as being carried out "overnight". This refers to a time interval that spans the nighttime hours when, for example, the method or process may not be actively observed. This time interval is about 8 to about 20 hours, or about 10 to 18 hours, and in some cases about 16 hours.

[0035] As used herein, the term "reduced pressure" refers to a pressure lower than atmospheric pressure. For example, reduced pressure is about 10 mbar to about 50 mbar.

[0036] As used herein, unless otherwise indicated, the term "ambient conditions" refers to atmospheric pressure and a temperature of 22 - 24°C.

[0037] This disclosure includes a crystalline polymorph of vermoxil designated as Form B1. The crystalline form B1 of vermoxil may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 2, an X-ray powder diffraction pattern having peaks at 3.5, 6.9, 10.5, 24.9 and 25.7 degrees two-theta ± 0.2 degrees two-theta, and combinations of these data.

[0038] The crystalline form B1 of vermoxil may further be characterized by an X-ray powder diffraction pattern having peaks at 3.5, 6.9, 10.5, 24.9 and 25.7 degrees two-theta ± 0.2 degrees two-theta and further having any 1, 2, 3, 4 or 5 additional peaks selected from 9.4, 12.5, 15.7, 18.9 and 19.7 degrees two-theta ± 0.2 degrees two-theta.

[0039] Alternatively, the crystalline form B1 of vermoxil may be characterized by an X-ray powder diffraction pattern having peaks at 3.5, 6.9, 9.4, 10.5, 12.5, 15.7, 18.9, 19.7, 24.9, and 25.7 degrees two-theta ± 0.2 degrees two-theta.

[0040] In one embodiment of the present disclosure, the crystalline form B1 of vermoxil is isolated.

[0041] The crystalline form B1 of vermoxil may be characterized by each individual / all possible combinations of the above characteristics, for example, an XRPD pattern having peaks at 3.5, 6.9, 10.5, 24.9 and 25.7 degrees two-theta ± 0.2 degrees two-theta, an XRPD pattern as shown in Figure 2, and combinations thereof.

[0042] The present disclosure includes a crystalline polymorph of vermoxil designated as Form B2. The crystalline Form B2 of vermoxil may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 3, an X-ray powder diffraction pattern having peaks at 3.8, 5.7, 7.6, 9.6 and 25.9 degrees 2 theta ± 0.2 degrees 2 theta, and combinations of these data.

[0043] The crystalline Form B2 of vermoxil may further be characterized by an X-ray powder diffraction pattern having peaks at 3.8, 5.7, 7.6, 9.6 and 25.9 degrees 2 theta ± 0.2 degrees 2 theta and further having any 1, 2, 3, 4 or 5 additional peaks selected from 10.7, 15.4, 16.6, 17.8 and 19.3 degrees 2 theta ± 0.2 degrees 2 theta.

[0044] Alternatively, the crystalline Form B2 of vermoxil may be characterized by an X-ray powder diffraction pattern having peaks at 3.8, 5.7, 7.6, 9.6, 10.7, 15.4, 16.6, 17.8, 19.3 and 25.9 degrees 2 theta ± 0.2 degrees 2 theta.

[0045] In one embodiment of the present disclosure, the crystalline Form B2 of vermoxil is isolated.

[0046] The crystalline Form B2 of vermoxil may be characterized by each individual / all possible combinations of the above characteristics, for example, an XRPD pattern having peaks at 3.8, 5.7, 7.6, 9.6 and 25.9 degrees 2 theta ± 0.2 degrees 2 theta, an XRPD pattern substantially as shown in Figure 3, and combinations of these data.

[0047] The present disclosure includes a crystalline polymorph of vermoxil designated as Form B3. The crystalline Form B3 of vermoxil may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 4, an X-ray powder diffraction pattern having peaks at 6.5, 8.4, 12.2, 19.6 and 26.3 degrees 2 theta ± 0.2 degrees 2 theta, and combinations of these data.

[0048] The crystalline form B3 of vermostil has peaks at 6.5, 8.4, 12.2, 19.6 and 26.3 degrees two-theta ± 0.2 degrees two-theta, and may further be characterized by an X-ray powder diffraction pattern having any 1, 2, 3, 4 or 5 additional peaks selected from 14.7, 15.4, 16.4, 18.8 and 22.5 degrees two-theta ± 0.2 degrees two-theta.

[0049] Alternatively, the crystalline form B3 of vermostil may be characterized by an X-ray powder diffraction pattern having peaks at 6.5, 8.4, 12.2, 14.7, 15.4, 16.4, 18.8, 19.6, 22.5 and 26.3 degrees two-theta ± 0.2 degrees two-theta.

[0050] In one embodiment of the present disclosure, the crystalline form B3 of vermostil is isolated.

[0051] The crystalline form B3 of vermostil may be characterized by each of the above features alone / or all possible combinations, for example, an XRPD pattern having peaks at 6.5, 8.4, 12.2, 19.6 and 26.3 degrees two-theta ± 0.2 degrees two-theta, an XRPD pattern as shown in FIG. 4, and combinations thereof.

[0052] The present disclosure includes a crystalline polymorph of vermostil designated as form B4. The crystalline form B4 of vermostil may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in FIG. 6, an X-ray powder diffraction pattern having peaks at 8.3, 9.3, 11.9, 16.7 and 17.2 degrees two-theta ± 0.2 degrees two-theta, and combinations of these data.

[0053] The crystalline form B4 of vermostil has peaks at 8.3, 9.3, 11.9, 16.7 and 17.2 degrees two-theta ± 0.2 degrees two-theta, and may further be characterized by an X-ray powder diffraction pattern having any 1, 2, 3, 4 or 5 additional peaks selected from 15.2, 18.7, 24.1, 25.6 and 26.2 degrees two-theta ± 0.2 degrees two-theta.

[0054] The crystalline form B4 of vermostil has peaks at 8.3, 9.3, 11.9, 16.7 and 17.2 degrees 2 theta ± 0.2 degrees 2 theta, and may further be characterized by an X-ray powder diffraction pattern having any 1, 2, 3, 4 or 5 additional peaks selected from 15.2, 18.7, 24.1, 25.6 and 26.2 degrees 2 theta ± 0.2 degrees 2 theta.

[0055] Alternatively, the crystalline form B4 of vermostil may be characterized by an X-ray powder diffraction pattern having peaks at 8.3, 9.3, 11.9, 15.2, 16.7, 17.2, 18.7, 24.1, 25.6 and 26.2 degrees 2 theta ± 0.2 degrees 2 theta.

[0056] In one embodiment of the present disclosure, the crystalline form B4 of vermostil is isolated.

[0057] The crystalline form B4 of vermostil may be characterized by each individual / all possible combinations of the above features, for example, an XRPD pattern having peaks at 8.3, 9.3, 11.9, 16.7 and 17.2 degrees 2 theta ± 0.2 degrees 2 theta, an XRPD pattern as shown in Figure 6, and combinations thereof.

[0058] The present disclosure includes a crystalline polymorph of vermostil designated as form B5. The crystalline form B5 of vermostil may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 9, an X-ray powder diffraction pattern having peaks at 6.1, 12.9, 16.2, 16.8 and 19.2 degrees 2 theta ± 0.2 degrees 2 theta, and combinations of these data.

[0059] The crystalline form B5 of vermostil has peaks at 6.1, 12.9, 16.2, 16.8 and 19.2 degrees 2 theta ± 0.2 degrees 2 theta, and may further be characterized by an X-ray powder diffraction pattern having any 1, 2, 3, 4 or 5 additional peaks selected from 3.7, 9.4, 9.8, 12.4 and 18.4 degrees 2 theta ± 0.2 degrees 2 theta.

[0060] The crystalline form B5 of vermostil may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 3.7, 6.1, 9.4, 9.8, 12.4, 12.9, 16.2, 16.8, 18.4 and 19.2 degrees 2 theta ± 0.2 degrees 2 theta.

[0061] In one embodiment of the present disclosure, the crystalline form B5 of vermostil is isolated.

[0062] The crystalline form B5 of vermostil may be characterized by each individual / all possible combinations of the above features, for example, an XRPD pattern having peaks at 6.1, 12.9, 16.2, 16.8 and 19.2 degrees 2 theta ± 0.2 degrees 2 theta, an XRPD pattern as shown in FIG. 9, and combinations thereof.

[0063] The present disclosure includes a crystalline polymorph of vermostil mesylate designated as form M1. The crystalline form M1 of vermostil mesylate may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in FIG. 5, an X-ray powder diffraction pattern having peaks at 7.1, 17.2, 20.3, 21.5 and 25.5 degrees 2 theta ± 0.2 degrees 2 theta, a solid 13 C NMR spectrum having characteristic peaks at 137.8, 133.8, 122.5, 118.3 and 111.6 ppm ± 0.2 ppm, the following absolute differences in chemical shift from a reference peak of 167.2 ppm ± 1 ppm: a solid having 29.4, 33.4, 44.7, 4,8.9 and 55.6 ppm ± 0.1 ppm 13 C NMR spectrum, a solid substantially as shown in any of FIGS. 16, 17 and 18 13 C NMR spectrum, and combinations of these data.

[0064] The crystalline form M1 of velmosdil mesylate has peaks at 7.1, 17.2, 20.3, 21.5 and 25.5 degrees two-theta ± 0.2 degrees two-theta, and may further be characterized by an X-ray powder diffraction pattern having any 1, 2, 3, 4 or 5 additional peaks selected from 8.4, 15.5, 16.8, 19.5 and 22.1 degrees two-theta ± 0.2 degrees two-theta.

[0065] Alternatively, the crystalline form M1 of velmosdil mesylate may be characterized by an X-ray powder diffraction pattern having peaks at 7.1, 8.4, 15.5, 16.8, 17.2, 19.5, 20.3, 21.5, 22.1 and 25.5 degrees two-theta ± 0.2 degrees two-theta.

[0066] According to any aspect or embodiment described herein, the crystalline form M1 of velmosdil mesylate may be an anhydrous form as determined by TGA. According to any aspect or embodiment described herein, the crystalline form M1 of velmosdil mesylate may contain 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less of total residual solvents. The residual solvents may be one or more polar solvents, preferably water, alcohol (especially C 1~4 alcohol, especially methanol, ethanol, isopropanol, 1-propanol or n-butanol) or halogenated solvents (especially 2,2,2-trifluoroethanol or dichloromethane), or DMSO or mixtures thereof. In particular, the crystalline form M1 of velmosdil mesylate according to any aspect or embodiment of the present disclosure may contain 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less of total residual solvents, where the residual solvents are ethanol, water, or DMSO, or a combination of ethanol, water and DMSO and water, or a combination of ethanol and DMSO. Alternatively, the crystalline form M1 of velmosdil mesylate according to any aspect or embodiment of the present disclosure may contain 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less of ethanol, or 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less of a mixture of ethanol and DMSO.

[0067] In one embodiment of the present disclosure, the crystalline form M1 of bermodzil mesylate is isolated. In particular, the crystalline form M1 of bermodzil mesylate according to any aspect or embodiment of the present disclosure can be isolated.

[0068] According to any aspect or embodiment of the present disclosure, the crystalline form M1 of bermodzil mesylate is non-hygroscopic. In particular, the form M1 of bermodzil mesylate according to any aspect or embodiment is polymorphically stable at room temperature with up to 100% relative humidity for at least 7 days.

[0069] The crystalline form M1 of bermodzil mesylate may be characterized by each individual / or all possible combinations of the above features, for example, an XRPD pattern having peaks at 7.1, 17.2, 20.3, 21.5, and 25.5 degrees 2 theta ± 0.2 degrees 2 theta, an XRPD pattern as shown in FIG. 5, and combinations thereof.

[0070] The crystalline form M1 of bermodzil mesylate may be prepared by crystallization from a mixture comprising bermodzil mesylate and one or more polar solvents, preferably polar organic solvents, in particular polar solvents that are alcohols or halogenated solvents, or mixtures thereof. Examples of suitable solvents include, but are not limited to, methanol, ethanol, isopropanol, 1-propanol, n-butanol, dichloromethane, and combinations thereof, preferably ethanol, isopropanol, n-butanol, or 1-propanol. In any aspect or embodiment of the present disclosure for preparing form M1, the method comprises (a) preparing a mixture of bermodzil mesylate in at least one polar solvent while heating if necessary, (b) heating the mixture if necessary and stirring the mixture if necessary, (c) cooling the mixture if necessary, preferably to room temperature, (d) stirring the cooled mixture if necessary, and (e) Optionally, isolating the crystalline form M1 of belumosudil mesylate from the mixture may be included.

[0071] The mixture of step (a) (i) preparing a mixture of the free base of belumosudil in a polar solvent, (ii) combining the mixture with methanesulfonic acid, (iii) optionally heating the mixture, and (iv) optionally adding a further polar solvent can be prepared by.

[0072] Preferably, the method for preparing form M1 of belumosudil mesylate according to any embodiment described herein is carried out in the absence or substantial absence of water, particularly with water of 2 wt% or less, 1 wt% or less, 0.5 wt% or less, 0.2 wt% or less, or 0.1 wt% or less.

[0073] According to any embodiment of the method for preparing form M1, the solvent in step (i) is preferably an organic solvent containing in particular an alcohol, a halogenated solvent, or a mixture thereof. Preferably, the solvent is selected from the group consisting of methanol, ethanol, isopropanol, 1-propanol, n-butanol, and dichloromethane or mixtures thereof, particularly ethanol, isopropanol, 1-propanol, n-butanol.

[0074] In step (i), the ratio of the solvent to belumosudil is about 10 to about 40 ml per gram of belumosudil, about 14 to about 35 ml per gram of belumosudil, or about 16 to about 20 to about 32 ml per gram of belumosudil, or about 18 to about 24 ml per gram of belumosudil, and may optionally be about 20 ml per gram of belumosudil. The mixture of step (i) may be a solution or a slurry.

[0075] In step (ii) of the method for preparing Form M1, the step of combining methanesulfonic acid with vermostil may be in any order. Preferably, methanesulfonic acid may be added to the mixture of vermostil in a solvent. The addition may be carried out in small portions or dropwise. Methanesulfonic acid is added in an amount of about 0.7 to about 1.5 molar equivalents, about 0.9 to about 1.3 molar equivalents, about 1.0 to about 1.2 molar equivalents, or about 1.1 molar equivalents, relative to vermostil, as needed. Preferably, step (ii) includes the step of adding methanesulfonic acid to the mixture of vermostil and a solvent.

[0076] In step (iii) of the method for preparing Form M1, the mixture may be heated as needed. The heating may be up to a temperature of about 30 °C to about 70 °C, about 40 °C to about 60 °C, about 45 °C to about 55 °C, or about 50 °C.

[0077] In step (iv), an additional polar solvent may be added to the reaction mixture. The additional solvent may be any solvent that is a poor solvent for vermostil mesylate, i.e., a solvent in which vermostil mesylate has low solubility. The additional polar solvent may be the same as or different from the one used in step (i). Preferably, the additional solvent is selected from the group consisting of methanol, ethanol, isopropanol, 1-propanol, n-butanol, and dichloromethane or mixtures thereof. Preferably, the additional polar solvent in step (iv) is selected from methanol, ethanol, isopropanol, 1-propanol, and n-butanol. More preferably, the additional polar solvent in step (iv) is ethanol. The additional polar solvent in step (iv) may be added in any suitable amount. Preferably, the v / v ratio of the additional polar solvent to the solvent in step (i) may be about 5:1 to about 1:5, or about 2:1 to about 1:2, or about 1.5:1 to about 1:1.5, or about 1.3:1 to about 1:1.3, preferably about 1:1.3.

[0078] Alternatively, according to any embodiment of the method for preparing Form M1, the mixture of step (a) is (i-a) Optionally forming a solution by combining belumosudil mesylate with a polar solvent while heating, and optionally (ii-a) adding an organic poor solvent may be prepared by.

[0079] The polar solvent in step (i-a) is preferably an organic solvent, more preferably selected from the group consisting of 2,2,2-trifluoroethanol (TFE) and DMSO or mixtures thereof. In particular, the solvent is selected from the group consisting of TFE and DMSO. In step (i-a), the ratio of the solvent to belumosudil mesylate may be about 5 to about 50 ml, about 7 to about 40 ml, about 9 to about 35 ml, or about 10 V to about 30 ml per gram of belumosudil mesylate.

[0080] The organic poor solvent in step (ii-a) may be any organic solvent in which belumosudil mesylate is poorly soluble. Preferably, the organic poor solvent in step (ii-a) is selected from the group consisting of acetonitrile, dioxane, methyl ethyl ketone, methyl t-butyl ketone, ethanol, isopropanol, l-propanol, n-butanol, and more particularly ethanol.

[0081] In any embodiment of the method for preparing Form M1, the mixture of step (a) may be a solution or a slurry. The mixture in step (a) is preferably in the form of a slurry. The mixture in step (a) may be at room temperature or heated. The heating may be up to a temperature of about 30°C to about 70°C, about 40°C to about 60°C, about 45°C to about 55°C, or about 50°C. Alternatively, the mixture may be at room temperature.

[0082] In any embodiment of the method for preparing Form M1, step (b) is preferably carried out by stirring at a temperature of about 30 °C to about 70 °C, about 40 °C to about 60 °C, about 45 °C to about 55 °C, or about 50 °C. Alternatively, step (b) may be carried out at room temperature. Stirring may be carried out for any suitable time. Typically, stirring may be carried out over a period of about 10 minutes to about 2 hours, about 20 minutes to about 1 hour, or about 45 minutes.

[0083] In any embodiment of the method for preparing Form M1, step (c) is carried out. Preferably, the cooling is to room temperature. After cooling, step (d) is preferably carried out by stirring the cooled mixture for a suitable time to prepare the belumosudil mesylate Form M1. Stirring may be carried out for any suitable time, preferably about 6 to about 96 hours, about 20 to about 80 hours, about 30 to about 50 hours, or about 40 hours.

[0084] In any embodiment of the method, step (e) can be carried out by any suitable method, such as filtration, decantation, or centrifugation. Preferably, the isolation of the solid is by filtration or centrifugation, more preferably by centrifugation.

[0085] In any embodiment, the method may further include a washing and / or drying step.

[0086] The present disclosure includes a crystalline polymorph of belumosudil mesylate designated as Form M2. The crystalline form M2 of belumosudil mesylate may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in FIG. 7, an X-ray powder diffraction pattern having peaks at 6.3, 12.8, 15.8, 19.3 and 26.5 degrees 2 theta ± 0.2 degrees 2 theta, a solid having characteristic peaks at 156.1, 132.7, 135.5, 119.8 and 110.9 ppm ± 0.2 ppm 13 13C NMR spectrum, absolute differences in chemical shifts from a reference peak of 166.9 ppm ± 1 ppm: a solid having 10.8, 34.2, 36.4, 47.1 and 56.0 ppm ± 0.1 ppm13 13C NMR spectrum, a solid substantially as shown in any of FIGS. 19, 20 and 21 13 13C NMR spectrum, and combinations of these data.

[0087] The crystalline form M2 of bermodzil mesylate has peaks at 6.3, 12.8, 15.8, 19.3 and 26.5 degrees 2 theta ± 0.2 degrees 2 theta, and further has an X-ray powder diffraction pattern having any 1, 2, 3, 4 or 5 additional peaks selected from 7.8, 20.4, 23.7, 25.1 and 27.4 degrees 2 theta ± 0.2 degrees 2 theta.

[0088] The crystalline form M2 of bermodzil mesylate may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 6.3, 7.8, 12.8, 15.8, 19.3, 20.4, 23.7, 25.1, 26.5 and 27.4 degrees 2 theta ± 0.2 degrees 2 theta.

[0089] According to any aspect or embodiment of the present disclosure, the crystalline form M2 of bermodzil mesylate may be a hydrate, preferably a dihydrate. Alternatively, according to any aspect or embodiment of the present disclosure, the crystalline form M2 of bermodzil mesylate may contain from about 1 wt% to about 7 wt% water, preferably from about 1.5 wt% to about 6.1 wt% water.

[0090] In one embodiment of the present disclosure, the crystalline form M2 of bermodzil mesylate is isolated. In particular, the crystalline form M2 of bermodzil mesylate according to any aspect or embodiment of the present disclosure can be isolated.

[0091] According to any aspect or embodiment of the present disclosure, the crystalline form M2 of bermodzil mesylate is non-hygroscopic. In particular, the form M2 of bermodzil mesylate according to any aspect or embodiment is polymorphically stable at room temperature and up to 100% relative humidity for at least 7 days.

[0092] The crystalline form M2 of belumosudil mesylate may be characterized by each or all possible combinations of the above features, for example, an XRPD pattern having peaks at 6.3, 12.8, 15.8, 19.3 and 26.5 degrees two-theta ± 0.2 degrees two-theta, an XRPD pattern as shown in Figure 7, and combinations thereof.

[0093] The crystalline form M2 of belumosudil mesylate can be prepared by crystallization from a mixture comprising belumosudil mesylate and water and, optionally, one or more polar organic solvents, preferably an alcohol or a mixture thereof. Examples of suitable solvents include, but are not limited to, methanol, isopropanol, l-propanol, n-butanol. Water may be present in an amount of about 1 to about 60 ml per mmol of belumosudil. In any embodiment, the method (a) preparing a mixture of belumosudil mesylate in water and, optionally, one or more polar organic solvents, with heating if necessary; (b) heating the mixture if necessary and stirring the mixture if necessary; (c) cooling the mixture if necessary; (d) stirring the cooled mixture if necessary, and (e) isolating the crystalline form M2 of belumosudil mesylate from the mixture if necessary comprises.

[0094] In any of the embodiments of the method, the mixture of step (a) (i) preparing a mixture of the free base of belumosudil in water or a mixture of water and at least one polar organic solvent; (ii) combining the mixture with methanesulfonic acid, and (iii) heating the mixture if necessary can be prepared by.

[0095] According to any embodiment of the method for preparing form M2 of bermodzil mesylate, the polar organic solvent in step (i) may preferably contain alcohol or a mixture thereof. Preferably, the polar organic solvent in step (i) is selected from methanol, isopropanol, 1-propanol and n-butanol, or a mixture thereof, more preferably the polar organic solvent in step (i) is methanol, ethanol, isopropanol, 1-propanol or n-butanol, and most preferably ethanol.

[0096] According to any embodiment of the method for preparing form M2 of bermodzil mesylate, the ratio of the solvent to bermodzil in step (i) is about 10 to about 40 ml per gram of bermodzil, about 14 to about 35 ml per gram of bermodzil, or about 16 to about 28 ml per gram of bermodzil, or about 18 to about 24 ml per gram of bermodzil, and may optionally be about 20 ml per gram of bermodzil. The mixture of step (i) may be a solution or a slurry.

[0097] According to any embodiment of the method for preparing form M2 of bermodzil mesylate, the step of combining methanesulfonic acid with bermodzil in step (ii) may be in any order. Preferably, methanesulfonic acid may be added to the mixture of bermodzil in the solvent. The addition may be carried out in small portions or dropwise. Methanesulfonic acid is added in an amount of about 0.7 to about 1.5 molar equivalents, about 0.9 to about 1.3 molar equivalents, about 1.0 to about 1.2 molar equivalents, or about 1.1 molar equivalents relative to bermodzil, if necessary. Preferably, step (ii) includes the step of adding methanesulfonic acid to the mixture of bermodzil and the solvent.

[0098] In step (iii) of the method for preparing the berbostil form M2, the mixture may be heated if necessary. The heating may be up to a temperature of about 30°C to about 70°C, about 40°C to about 60°C, about 45°C to about 55°C, or about 50°C. The heating may be carried out for any suitable period of time to form a solution of berbostil mesylate.

[0099] Alternatively, in the method for preparing the berbostil form M2 according to any aspect or embodiment of the present invention, the mixture in step (a) (i-b) forming a solution by combining berbostil mesylate with a polar organic solvent while heating if necessary, and (ii-b) adding water as a poor solvent may be prepared by a method comprising.

[0100] According to any embodiment of the method for preparing the berbostil mesylate form M2, the polar organic solvent in step (i-b) is preferably selected from the group consisting of TFE, DMSO and / or mixtures thereof. In particular, the solvent is selected from the group consisting of TFE and DMSO. The ratio of the polar organic solvent in step (i-b) is preferably about 5 ml to 60 ml, about 7 ml to about 50 ml, about 10 ml to about 45 ml, or about 10 ml to about 40 ml per gram of berbostil mesylate.

[0101] Alternatively, in the method for preparing the berbostil form M2 according to any aspect or embodiment of the present invention, the mixture in step (a) may be prepared by a method comprising (i-c) combining berbostil mesylate with water to form a slurry. Preferably, the berbostil mesylate is in form M1 as described by any aspect or embodiment herein. Preferably, the ratio of water in step (i-c) is preferably about 10 ml to 60 ml, about 20 ml to about 50 ml, about 30 ml to about 45 ml, or about 40 ml per gram of berbostil mesylate.

[0102] In any embodiment of the method, step (b) is carried out. Step (b) is preferably carried out under heating at a temperature of about 30°C to about 80°C, about 40°C to about 75°C, about 45°C to about 70°C, about 45°C to about 65°C, about 45°C to about 65°C, about 48°C to about 62°C, or about 50°C to about 60°C. Stirring can be carried out for any suitable period.

[0103] In any embodiment of the method for preparing Form M2, step (c) is carried out. Step (c) preferably includes the step of cooling the mixture to room temperature.

[0104] In any embodiment of the method for preparing Form M2, step (d) may be carried out. Stirring may be for any suitable time for preparing Form M2.

[0105] In any embodiment of the method for preparing crystalline belumosudil mesylate Form M2, step (e) may be carried out by any suitable method, such as filtration, decantation or centrifugation. Preferably, the isolation of the solid is by filtration or centrifugation, more preferably by centrifugation.

[0106] In any embodiment, the method may further include a washing and / or drying step.

[0107] The present disclosure includes a crystalline polymorph of belumosudil mesylate designated as Form M3. The crystalline form M3 of belumosudil mesylate may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 8, an X-ray powder diffraction pattern having peaks at 7.3, 14.6, 16.6, 17.5 and 19.6 degrees 2 theta ± 0.2 degrees 2 theta, and combinations of these data.

[0108] The crystalline form M3 of belumosudil mesylate has peaks at 7.3, 14.6, 16.6, 17.5 and 19.6 degrees 2 theta ± 0.2 degrees 2 theta, and may further be characterized by an X-ray powder diffraction pattern having any 1, 2, 3, 4 or 5 additional peaks selected from 12.9, 13.7, 19.0, 20.6 and 26.0 degrees 2 theta ± 0.2 degrees 2 theta.

[0109] Alternatively, the crystalline form M3 of belumosudil mesylate may be characterized by an X-ray powder diffraction pattern having peaks at 7.3, 12.9, 13.7, 14.6, 16.6, 17.5, 19.0, 19.6, 20.6 and 26.0 degrees 2 theta ± 0.2 degrees 2 theta.

[0110] In one embodiment of the present disclosure, the crystalline form M3 of belumosudil mesylate is isolated.

[0111] The crystalline form M3 of belumosudil mesylate may be characterized by each of the above features alone / or all possible combinations, for example, an XRPD pattern having peaks at 7.3, 14.6, 16.6, 17.5 and 19.6 degrees 2 theta ± 0.2 degrees 2 theta, an XRPD pattern as shown in FIG. 8, and combinations thereof.

[0112] The present disclosure includes a crystalline polymorph of belumosudil mesylate designated as form M4. The crystalline form M4 of belumosudil mesylate may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in FIG. 11, an X-ray powder diffraction pattern having peaks at 7.5, 15.0, 17.9, 21.8 and 22.6 degrees 2 theta ± 0.2 degrees 2 theta, and combinations of these data.

[0113] The crystalline form M4 of belumosudil mesylate has peaks at 7.5, 15.0, 17.9, 21.8 and 22.6 degrees 2 theta ± 0.2 degrees 2 theta, and may further be characterized by an X-ray powder diffraction pattern having any 1, 2, 3, 4 or 5 additional peaks selected from 11.3, 17.4, 20.9, 24.2 and 29.2 degrees 2 theta ± 0.2 degrees 2 theta.

[0114] The crystalline form M4 of belumosudil mesylate may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 7.5, 11.3, 15.0, 17.4, 17.9, 20.9, 21.8, 22.6, 24.2 and 29.2 degrees two-theta ± 0.2 degrees two-theta.

[0115] In one embodiment of the present disclosure, the crystalline form M4 of belumosudil mesylate is isolated.

[0116] The crystalline form M4 of belumosudil mesylate may be characterized by each individual / or all possible combinations of the above characteristics, for example, an XRPD pattern having peaks at 7.5, 15.0, 17.9, 21.8 and 22.6 degrees two-theta ± 0.2 degrees two-theta, an XRPD pattern as shown in FIG. 11, and combinations thereof.

[0117] The present disclosure includes a crystalline polymorph of belumosudil mesylate designated as form M5. The crystalline form M5 of belumosudil mesylate may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in FIG. 12, an X-ray powder diffraction pattern having peaks at 6.2, 15.7, 18.4, 19.2 and 25.1 degrees two-theta ± 0.2 degrees two-theta, and combinations of these data.

[0118] The crystalline form M5 of belumosudil mesylate may further be characterized by an X-ray powder diffraction pattern having peaks at 6.2, 15.7, 18.4, 19.2 and 25.1 degrees two-theta ± 0.2 degrees two-theta and further having any 1, 2, 3, 4 or 5 additional peaks selected from 17.8, 21.6, 21.9, 24.7, 25.9 degrees two-theta ± 0.2 degrees two-theta.

[0119] The crystalline form M5 of belumosudil mesylate may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 6.2, 15.7, 17.8, 18.4, 19.2, 21.6, 21.9, 24.7, 25.1 and 25.9 degrees two-theta ± 0.2 degrees two-theta.

[0120] In one embodiment of the present disclosure, the crystalline form M5 of belumosudil besylate is isolated.

[0121] The crystalline form M5 of belumosudil besylate may be characterized by each individual / all possible combinations of the above features, for example, an XRPD pattern having peaks at 6.2, 15.7, 18.4, 19.2 and 25.1 degrees two-theta ± 0.2 degrees two-theta, an XRPD pattern as shown in FIG. 12, and combinations thereof.

[0122] The present disclosure includes a crystalline polymorph of belumosudil besylate designated as form BS1. The crystalline form BS1 of belumosudil besylate may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in FIG. 13, an X-ray powder diffraction pattern having peaks at 6.6, 12.5, 14.9, 17.0 and 20.1 degrees two-theta ± 0.2 degrees two-theta, a solid 13 13C NMR spectrum having characteristic peaks at 158.9, 146.8, 134.3, 121.3 and 117.6 ppm ± 0.2 ppm, an absolute chemical shift difference from a reference peak of 169.6 ppm ± 1 ppm: a solid having 10.7, 22.8, 35.3, 48.3 and 52.0 ppm ± 0.1 ppm 13 13C NMR spectrum, a solid substantially as shown in any of FIGS. 22, 23 and 24 13 13C NMR spectrum, and combinations of these data.

[0123] The crystalline form BS1 of belumosudil besylate may be further characterized by an X-ray powder diffraction pattern having peaks at 6.6, 12.5, 14.9, 17.0 and 20.1 degrees two-theta ± 0.2 degrees two-theta and further having any 1, 2, 3, 4 or 5 additional peaks selected from 11.6, 17.6, 18.2, 21.7 and 25.1 degrees two-theta ± 0.2 degrees two-theta.

[0124] The crystalline form BS1 of belumosudil besylate may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 6.6, 11.6, 12.5, 14.9, 17.0, 17.6, 18.2, 20.1, 21.7 and 25.1 degrees two-theta ± 0.2 degrees two-theta.

[0125] The crystalline form BS1 of belumosudil besylate may be in an anhydrous form as determined by TGA. In certain embodiments, the present disclosure includes the crystalline form BS1 of belumosudil besylate having a total residual solvent of 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less. According to any aspect or embodiment described herein, the crystalline form BS1 of belumosudil besylate may contain a total residual solvent of 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less. The residual organic solvent may be one or more polar solvents, preferably water, alcohol (especially C 1~4 alcohol, especially ethanol, methanol, isopropanol, 1-propanol, or n-butanol), and most preferably the residual organic solvent may be ethanol. In particular, the crystalline form BS1 of belumosudil besylate according to any aspect or embodiment of the present disclosure may contain 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less of ethanol.

[0126] In one embodiment of the present disclosure, the crystalline form BS1 of belumosudil besylate is isolated. In particular, the crystalline form BS1 of belumosudil besylate according to any aspect or embodiment of the present disclosure may be isolated.

[0127] In any aspect or embodiment of the present disclosure, the crystalline form BS1 of belumosudil mesylate is non-hygroscopic. In particular, the form BS1 of belumosudil mesylate according to any aspect or embodiment is polymorphically stable at room temperature with a relative humidity of up to 100% for at least 7 days.

[0128] The crystalline form BS1 of bermostil besylate may be characterized by each or all possible combinations of the above features, for example, an XRPD pattern having peaks at 6.6, 12.5, 14.9, 17.0 and 20.1 degrees 2 theta ± 0.2 degrees 2 theta, an XRPD pattern as shown in Figure 13, and combinations thereof.

[0129] The crystalline form BS1 of bermostil besylate may be prepared by crystallization from a mixture containing a polar solvent such as ethanol and bermostil besylate. In any aspect or embodiment, the method comprises (a) preparing a mixture of bermostil besylate in one or more polar solvents, (b) optionally heating and optionally stirring the mixture, (c) optionally cooling the mixture, and (d) optionally isolating the crystalline form BS1 of bermostil mesylate from the mixture and includes.

[0130] In any embodiment of the method for preparing form BS1, the mixture of step (a) is (i) preparing a mixture of the free base of bermostil (preferably form BS1 as described herein) in a polar solvent, and (ii) combining the mixture with benzenesulfonic acid can be prepared by.

[0131] In any embodiment of the method for preparing form BS1, the polar solvent in step (i) is preferably an alcohol (especially C 1~4It is alcohol, particularly ethanol, methanol, isopropanol, 1-propanol, or n-butanol. Preferably, the polar solvent contains ethanol or isopropanol, and more preferably, the polar solvent is ethanol. In step (i), the ratio of the solvent to vermodzil is about 10 to about 40 ml per gram of vermodzil, about 14 to about 35 ml per gram of vermodzil, or about 16 to about 28 ml per gram of vermodzil, or about 18 to about 24 ml per gram of vermodzil, and may be about 20 ml per gram of vermodzil as required. The mixture may be a solution or a slurry.

[0132] In any aspect or embodiment of the method for preparing Form BS1, step (ii) includes the step of combining benzenesulfonic acid with vermodzil. The combining step may be in any order. Preferably, the benzenesulfonic acid may be added to the mixture of vermodzil in a solvent. The addition may be carried out in small portions or dropwise. The benzenesulfonic acid is added in an amount of about 0.7 to about 1.5 molar equivalents, about 0.9 to about 1.3 molar equivalents, about 1.0 to about 1.2 molar equivalents, or about 1.1 molar equivalents with respect to vermodzil as required. Preferably, step (ii) includes the step of adding benzenesulfonic acid to a mixture of vermodzil and a polar solvent.

[0133] Alternatively, in any of the embodiments of the method for preparing Form BS1, the mixture in step (a) may be prepared by combining vermodzil besylate with a polar solvent. Preferably, the polar solvent is alcohol (particularly C 1~4 alcohol, particularly ethanol, methanol, isopropanol, 1-propanol, or n-butanol), and most preferably, the polar solvent is ethanol.

[0134] In any embodiment of the method for preparing Form BS1, step (b) is preferably carried out at room temperature, more preferably at a temperature of about 30 °C to about 70 °C, about 40 °C to about 60 °C, about 45 °C to about 55 °C, or about 50 °C by stirring. Preferably, the stirring is carried out at a certain temperature. The stirring may be carried out for any suitable time to form the berbamozyl tosylate Form BS1. Typically, the stirring may be carried out over a period of about 10 minutes to about 2 hours, about 20 minutes to about 1 hour, or about 45 minutes.

[0135] In any embodiment of the method for preparing Form BS1, step (c) is carried out, and preferably the cooling is to room temperature.

[0136] In any embodiment of the method for preparing Form BS1, step (d) may be carried out by any suitable method, such as filtration, decantation or centrifugation. Preferably, the isolation of the solid is by filtration or centrifugation, more preferably by centrifugation.

[0137] In any embodiment, the method for preparing from BS1 may further include a washing and / or drying step.

[0138] The present disclosure includes a crystalline polymorph of berbamozyl tosylate designated as Form T1. The crystalline form T1 of berbamozyl tosylate may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in FIG. 14, an X-ray powder diffraction pattern having peaks at 6.2, 12.3, 14.1, 17.7 and 18.4 degrees 2 theta ± 0.2 degrees 2 theta, a solid having characteristic peaks at 152.6, 143.4, 132.3, 125.3 and 119.8 ppm ± 0.2 ppm 13 C NMR spectrum, absolute chemical shift differences from a reference peak of 168.6 ppm ± 1 ppm: a solid having 16.0, 25.2, 36.3, 43.3 and 48.8 ppm ± 0.1 ppm 13 C NMR spectrum, a solid substantially as shown in any of FIGS. 26, 27 and 28 1313C NMR spectra, and combinations of these data.

[0139] The crystalline form T1 of vermostisiltosylate has peaks at 6.2, 12.3, 14.1, 17.7 and 18.4 degrees 2 theta ± 0.2 degrees 2 theta, and may further be characterized by an X-ray powder diffraction pattern having any 1, 2, 3, 4 or 5 additional peaks selected from 9.9, 14.5, 16.7, 21.5 and 24.6 degrees 2 theta ± 0.2 degrees 2 theta.

[0140] Alternatively, the crystalline form T1 of vermostisiltosylate may be characterized by an X-ray powder diffraction pattern having peaks at 6.2, 9.9, 12.3, 14.1, 14.5, 16.7, 17.7, 18.4, 21.5 and 24.6 degrees 2 theta ± 0.2 degrees 2 theta.

[0141] The crystalline form T1 of vermostisiltosylate may be in an anhydrous form as determined by TGA. In certain embodiments, the present disclosure includes the crystalline form T1 of vermostisiltosylate having a total residual solvent of 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less. The residual solvent may be one or more polar solvents, preferably water and / or alcohol (especially C 1~4 alcohol, especially ethanol, methanol, isopropanol, 1-propanol, or n-butanol), and most preferably, the residual organic solvent may be methanol. In particular, the crystalline form T1 of vermostisiltosylate according to any aspect or embodiment of the present disclosure may contain methanol at 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less.

[0142] In one embodiment of the present disclosure, the crystalline form T1 of vermostisiltosylate is isolated. In particular, the crystalline form T1 of vermostisiltosylate according to any aspect or embodiment of the present disclosure may be isolated.

[0143] In any aspect or embodiment of the present disclosure, the crystalline form T1 of belumosudil mesylate is non-hygroscopic. In particular, the form T1 of belumosudil mesylate according to any aspect or embodiment is polymorphically stable at room temperature with up to 100% relative humidity for at least 7 days.

[0144] The crystalline form T1 of belumosudil tosylate may be characterized by any one or all possible combinations of the above features, for example, an XRPD pattern having peaks at 6.2, 12.3, 14.1, 17.7, and 18.4 degrees 2 theta ± 0.2 degrees 2 theta, an XRPD pattern as shown in FIG. 14, and combinations thereof.

[0145] The crystalline form T1 of belumosudil tosylate may be prepared by crystallization from a mixture containing belumosudil tosylate and one or more polar solvents such as alcohol. Preferably, the solvent is methanol. In any embodiment, the method (a) preparing a mixture of belumosudil tosylate in one or more polar solvents, preferably including methanol; (b) heating the mixture if necessary and stirring the mixture if necessary; (c) cooling the mixture if necessary; and (d) isolating the crystalline form T1 of belumosudil tosylate from the mixture if necessary including.

[0146] In any of the method embodiments, the mixture of step (a) (i) preparing a mixture of belumosudil free base in a polar solvent; and (ii) combining the mixture with toluenesulfonic acid can be prepared by.

[0147] Preferably, the method for preparing the form T1 of belumosudil tosylate according to any embodiment described herein is carried out in the absence or substantial absence of water, particularly at 2% wt% or less, 1 wt% or less, 0.5% wt% or less, 0.2% wt% or less, or 0.1 wt% of water.

[0148] In any embodiment or implementation of the method for preparing Form T1, the polar solvent is preferably an alcohol (especially a C 1~4 alcohol, especially ethanol, methanol, isopropanol, 1-propanol, or n-butanol), and most preferably, the polar solvent is methanol. In step (i), the ratio of the solvent to bermostil is about 10 to about 40 ml per gram of bermostil, about 14 to about 35 ml per gram of bermostil, or about 16 to about 28 ml per gram of bermostil, or about 18 to about 24 ml per gram of bermostil, and optionally about 20 ml per gram of bermostil. The mixture may be a solution or a slurry.

[0149] In step (ii), the step of combining toluenesulfonic acid with bermostil may be in any order. Preferably, the toluenesulfonic acid may be added to the mixture of bermostil in the solvent. The addition may be carried out in small portions or dropwise. The toluenesulfonic acid is added in an amount of about 0.7 to about 1.5 molar equivalents, about 0.9 to about 1.3 molar equivalents, about 1.0 to about 1.2 molar equivalents, or about 1.1 molar equivalents relative to bermostil, as required. Preferably, step (ii) includes the step of adding toluenesulfonic acid to the mixture of bermostil and the solvent.

[0150] Alternatively, in any of the embodiments of the method for preparing Form T1, the mixture of step (a) may be prepared by combining bermostil tosylate with a polar solvent. Preferably, the polar solvent is an alcohol (especially a C 1~4 alcohol, especially ethanol, methanol, isopropanol, 1-propanol, or n-butanol), and most preferably, the polar solvent is methanol.

[0151] In any embodiment of the method for preparing Form T1, step (b) is preferably carried out by stirring at a temperature of about 30 °C to about 70 °C, about 40 °C to about 60 °C, about 45 °C to about 55 °C, or about 50 °C. The stirring may be carried out for any suitable time.

[0152] In any embodiment of the method for preparing Form T1, step (c) is carried out, and preferably the cooling is to room temperature.

[0153] In any embodiment of the method for preparing Form T1, step (d) can be carried out by any suitable method, such as filtration, decantation or centrifugation. Preferably, the isolation of the solid is by filtration or centrifugation, more preferably by centrifugation.

[0154] In any embodiment of the method for preparing Form T1, the method may further comprise a washing and / or drying step.

[0155] This disclosure includes a crystalline polymorph of vermostil tosylate designated as Form T2. The crystalline form T2 of vermostil tosylate may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 15, an X-ray powder diffraction pattern having peaks at 5.1, 15.7, 16.4, 19.7 and 23.7 degrees 2 theta ± 0.2 degrees 2 theta, a solid having characteristic peaks at 141.7, 140.2, 131.1, 125.9 and 124.2 ppm ± 0.2 ppm 13 13C NMR spectrum, absolute chemical shift differences from a reference peak of 166.3 ppm: a solid having 24.6, 26.1, 35.2, 40.4 and 42.1 ppm ± 0.1 ppm 13 13C NMR spectrum, a solid substantially as shown in any of Figures 30, 31 and 32 13 13C NMR spectrum, as well as combinations of these data.

[0156] The crystalline form T2 of vermostilsylate has peaks at 5.1, 15.7, 16.4, 19.7 and 23.7 degrees two-theta ± 0.2 degrees two-theta, and may further be characterized by an X-ray powder diffraction pattern having any 1, 2, 3, 4 or 5 additional peaks selected from 13.7, 14.2, 14.6, 19.1 and 23.0 degrees two-theta ± 0.2 degrees two-theta.

[0157] Alternatively, the crystalline form T2 of vermostilsylate may be characterized by an X-ray powder diffraction pattern having peaks at 5.1, 13.7, 14.2, 14.6, 15.7, 16.4, 19.1, 19.7, 23.0 and 23.7 degrees two-theta ± 0.2 degrees two-theta.

[0158] The crystalline form T2 of vermostilsylate may be in the anhydrous form as determined by TGA. In certain embodiments, the present disclosure includes the crystalline form T2 of vermostilsylate having total residual solvents of 1% w / w or less, or 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less. The residual solvent may be one or more polar solvents, preferably water or alcohol (especially C 1~4 alcohol, especially ethanol, methanol, isopropanol, 1-propanol or n-butanol), and most preferably the residual organic solvent may be water and / or ethanol. In particular, the crystalline form T2 of vermostilsylate according to any aspect or embodiment of the present disclosure may contain 0.5% w / w or less, or 0.2% w / w or less, or 0.1 wt% or less of ethanol. In one embodiment of the present disclosure, the crystalline form T2 of vermostilsylate is isolated. In particular, the crystalline form T2 of vermostilsylate according to any aspect or embodiment of the present disclosure may be isolated.

[0159] In any aspect or embodiment of the present disclosure, the crystalline form T2 of vermostildimesylate is non-hygroscopic. In particular, the form T2 of vermostildimesylate according to any aspect or embodiment is polymorphically stable at room temperature and up to 100% relative humidity for at least 7 days.

[0160] The crystalline form T2 of vermost dihydrochloride may be characterized by each or all possible combinations of the above features, for example, an XRPD pattern having peaks at 5.1, 15.7, 16.4, 19.7, and 23.7 degrees two-theta ± 0.2 degrees two-theta, an XRPD pattern as shown in Figure 15, and combinations thereof.

[0161] The crystalline form T2 of vermost dihydrochloride may be prepared by crystallization from a mixture containing vermost dihydrochloride and one or more polar solvents such as water. In any embodiment, the method (a) preparing a mixture of vermost dihydrochloride in one or more polar solvents, (b) optionally heating and optionally stirring the mixture, (c) optionally cooling to room temperature, and (d) optionally isolating the crystalline form T2 of vermost mesylate from the mixture is included.

[0162] In any of the embodiments of the method for preparing form T2, the mixture in step (a) (i) preferably preparing a mixture of the free base of vermost (preferably form B1 described herein) in a polar solvent containing water and / or ethanol, and (ii) optionally combining the mixture with toluenesulfonic acid at an elevated temperature, and (iii) optionally adding a polar solvent may be prepared by.

[0163] In any aspect or embodiment of the method for preparing Form T2, the polar solvent in step (i) preferably contains water, and more preferably, the polar solvent in step (i) contains water. In step (i), the ratio of the solvent to vermostilbene is about 10 to about 40 ml per gram of vermostilbene, about 14 to about 35 ml per gram of vermostilbene, or about 16 to about 28 ml per gram of vermostilbene, or about 18 to about 24 ml per gram of vermostilbene, about 20 to about 30 per gram of vermostilbene, and may optionally be about 20 ml. The mixture may be a solution or a slurry.

[0164] In any aspect or embodiment of the method for preparing Form T2, step (ii) includes the step of combining toluenesulfonic acid with vermostilbene in any order. Preferably, toluenesulfonic acid may be added to the mixture of vermostilbene in the solvent. The addition may be carried out in small portions or dropwise. Toluenesulfonic acid is added in an amount of about 0.7 to about 1.5 molar equivalents, about 0.9 to about 1.3 molar equivalents, about 1.0 to about 1.2 molar equivalents, or about 1.1 molar equivalents with respect to vermostilbene, if necessary. Preferably, step (ii) includes adding toluenesulfonic acid to the mixture of vermostilbene and the solvent.

[0165] In any aspect or embodiment of the method for preparing Form T2, in step (iii), the polar solvent is preferably selected from the group consisting of methanol, ethanol, isopropanol, 1-propanol, and n-butanol. More preferably, the polar solvent in step (iii) is ethanol. In step (iii), the ratio of the total solvent to vermostilbene may be about 20 to about 50 ml per gram of vermostilbene, about 20 to about 40 ml per gram of vermostilbene, about 22 to about 35 ml per gram of vermostilbene, or about 25 ml.

[0166] Alternatively, in any of the embodiments of the method for preparing Form T2, the mixture in step (a) may be prepared by combining vermostilbene tosylate with one or more polar solvents. Preferably, the polar solvent is water and / or alcohol (especially C1~4 is an alcohol, particularly ethanol, methanol, isopropanol, 1-propanol, or n-butanol). Preferably, the polar solvent is water and ethanol.

[0167] In any embodiment of the method for preparing Form T2, step (b) is preferably carried out by stirring at a temperature of about 30 °C to about 70 °C, about 40 °C to about 60 °C, about 45 °C to about 55 °C, or about 50 °C. The stirring may be carried out for any suitable time. Typically, the stirring may be carried out over a period of about 10 minutes to about 2 hours, about 20 minutes to about 1 hour, or about 50 minutes.

[0168] In any embodiment of the method for preparing Form T2, the mixture may preferably be cooled to room temperature, and step (d) may be carried out by any suitable method, such as filtration, decantation or centrifugation. Preferably, the isolation of the solid is by filtration or centrifugation, more preferably by centrifugation.

[0169] In any embodiment, the method may further comprise a washing and / or drying step.

[0170] The crystalline polymorphs of the above-mentioned vermoxdil, or salts thereof including vermoxdil mesylate, vermoxdil tosylate and / or vermoxdil besylate can be used in the preparation of other crystalline polymorphs of vermoxdil, vermoxdil salts and their solid forms.

[0171] The present disclosure includes methods for preparing belumosudil, belumosudil salts, and other solid forms of such salts in their solid forms. The method includes the steps of preparing any one of the solid forms of belumosudil or its salts by the method of the present disclosure and converting the salt into the other belumosudil salts. The conversion can be carried out, for example, by basifying any one or a combination of the above-mentioned salts such as belumosudil mesylate, belumosudil tosylate, and / or belumosudil besylate, and / or their solid forms, and reacting the obtained belumosudil base with an appropriate acid to obtain the corresponding salt. Alternatively, the conversion can be carried out by salt exchange, that is, reacting the belumosudil acid addition salt with an acid having a pKa lower than that of the acid of the first belumosudil acid addition salt.

[0172] The present disclosure provides the above-mentioned crystalline polymorphs of salts of belumosudil or belumosudil mesylate, belumosudil tosylate, and / or belumosudil besylate for use in the preparation of pharmaceutical compositions comprising belumosudil, its salts, and / or its crystalline polymorphs.

[0173] The present disclosure also encompasses the use of the crystalline polymorphs of belumosudil or its salts of the present disclosure, such as the crystalline forms of belumosudil mesylate, belumosudil tosylate, and / or belumosudil besylate, for the preparation of pharmaceutical compositions of crystalline polymorphs of belumosudil or its salts, including, for example, belumosudil mesylate, belumosudil tosylate, and / or belumosudil besylate and / or their crystalline polymorphs.

[0174] In any aspect or embodiment of the present disclosure, any of the solid forms of velmosdil, velmosdil mesylate, velmosdil tosylate, and / or velmosdil besylate described herein may be polymorphically pure or may substantially exclude any other solid form of the subject compound (i.e., velmosdil, velmosdil mesylate, velmosdil tosylate, and / or velmosdil besylate, respectively). In any aspect or embodiment of the present disclosure, any of the solid forms of velmosdil, velmosdil mesylate, velmosdil tosylate, and / or velmosdil besylate may preferably contain, as measured by XRPD, about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, about 0.5% (w / w) or less, about 0.2% (w / w) or less, about 0.1% (w / w) or less, or about 0% of any other solid form of the subject compound. Thus, any of the disclosed crystalline forms of velmosdil, velmosdil mesylate, velmosdil tosylate, and / or velmosdil besylate described herein may be substantially free of any other solid form of the subject compound and may contain greater than about 80% (w / w), greater than about 90% (w / w), greater than about 95% (w / w), greater than about 98% (w / w), greater than about 99% (w / w), or about 100% of the solid form of velmosdil, velmosdil mesylate, velmosdil tosylate, and / or velmosdil besylate.

[0175] The present disclosure includes methods for preparing the pharmaceutical compositions described above. The methods include combining any one or combination of crystalline polymorphs of velmosdil or a salt thereof of the present disclosure with at least one pharmaceutically acceptable excipient.

[0176] The pharmaceutical combination or formulation of the present disclosure contains any one or combination of the solid forms of velmosdil or a salt thereof of the present disclosure. In addition to the active ingredient, the pharmaceutical formulation of the present disclosure may contain one or more excipients. Excipients are added to the formulation for various purposes. Preferably, the pharmaceutical composition or formulation according to any aspect or embodiment of the present disclosure is in the form of a tablet or capsule, more preferably a tablet.

[0177] The diluent can increase the bulk of the solid pharmaceutical composition and make the pharmaceutical dosage form containing the composition easy to handle for patients and caregivers. Examples of diluents for solid compositions include microcrystalline cellulose (e.g., Avicel (registered trademark)), fine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrate, dextrin, dextrose, dibasic calcium phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylate (e.g., Eudragit (registered trademark)), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0178] The solid pharmaceutical composition that is densified into dosage forms such as tablets may contain excipients that function to assist in the binding of the active ingredient and other excipients after compression. Examples of binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g., carbopol), sodium carboxymethyl cellulose, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., Klucel (registered trademark)), hydroxypropyl methylcellulose (e.g., Methocel (registered trademark)), liquid glucose, magnesium aluminum silicate, maltodextrin, methyl cellulose, polymethacrylate, povidone (e.g., Kollidon (registered trademark), Plasdone (registered trademark)), pregelatinized starch, sodium alginate, and starch.

[0179] The dissolution rate of a compacted solid pharmaceutical composition in the stomach of a patient can be increased by adding a disintegrant to the composition. Examples of disintegrants include alginic acid, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose (e.g., Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, potassium polyacrylate, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab®), and starch.

[0180] A lubricant can be added to improve the fluidity of the non-compacted solid composition and the accuracy of dosing. Excipients that can function as lubricants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tricalcium phosphate.

[0181] When a dosage form such as a tablet is produced by compacting a powdered composition, the composition is subjected to pressure from a pestle and a die. Some excipients and active ingredients tend to adhere to the surfaces of the pestle and the die, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and facilitate the release of the product from the die. Examples of lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.

[0182] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceuticals that may be included in the compositions of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0183] Solid and liquid compositions can also be dyed using any pharmaceutically acceptable coloring agent to improve the appearance and / or facilitate the identification of the product and unit dosage levels by the patient.

[0184] In the liquid pharmaceutical composition of the present invention, vermoxyl and any other solid excipient can be dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[0185] The liquid pharmaceutical composition can contain an emulsifier to uniformly disperse an active ingredient or other excipient that is not soluble in the liquid carrier throughout the composition. Emulsifiers that may be useful in the liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, hornbeam, pectin, methylcellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[0186] The liquid pharmaceutical composition of the present invention may contain a viscosity enhancer to improve the mouthfeel of the product and / or coat the inner membrane of the gastrointestinal tract. Such agents include acacia, bentonite alginate, carbomer, calcium or sodium carboxymethylcellulose, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin gum arabic, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, xanthan gum, and combinations thereof.

[0187] To improve the taste, sweeteners such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added.

[0188] To improve the storage stability, preservatives and chelating agents such as alcohol, sodium benzoate, butylhydroxytoluene, butylhydroxyanisole, and ethylenediaminetetraacetic acid can be added at levels safe for ingestion.

[0189] According to the present disclosure, the liquid composition may also contain a buffering agent such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. The selection and amount of the excipient can be readily determined by a formulation scientist based on experience and consideration of standard procedures and references in the art.

[0190] The solid compositions of the present disclosure include powders, granules, aggregates, and compacted compositions. Dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalation, and ophthalmic administration. The most suitable administration in any given case depends on the nature and severity of the condition being treated, but in embodiments, the route of administration is oral. Dosages can be conveniently presented in unit dosage forms and can be prepared by any of the methods well known in the pharmaceutical art.

[0191] Dosage forms include solid dosage forms such as tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.

[0192] The dosage forms of the present disclosure may be capsules containing a composition such as the powdery or granular solid composition of the present disclosure in either a hard or soft shell. The shell may be made of gelatin and may contain plasticizers such as glycerin and / or sorbitol, opacifying agents, and / or coloring agents as needed.

[0193] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[0194] Compositions for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredient and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, to agglomerate the powder into granules. The granulated material is screened and / or milled and dried, and then screened and / or milled to the desired particle size. The granulated material may then be tabletted, or other excipients, such as lubricants and / or glidants, may be added prior to tableting.

[0195] Tableting compositions can be prepared by conventional methods by dry blending. For example, a blend composition of the active agent and excipients can be compacted into slugs or sheets and then crushed into compacted granules. Thereafter, the compacted granules may be compressed into tablets.

[0196] As an alternative to dry granulation, direct compression technology can be used to directly compress the blend composition into a compacted dosage form. Direct compression produces more uniform tablets that do not contain granules. Excipients that are particularly well-suited for direct compression tableting include microcrystalline cellulose, spray-dried lactose, calcium hydrogen phosphate dihydrate, and colloidal silica. The appropriate use of these and other excipients in direct compression tableting is known to those skilled in the art with experience and skill in the specific formulation challenges of direct compression tableting.

[0197] The capsule fillings of the present disclosure can include any of the aforementioned blends and granulated materials described in relation to tableting, but they are not subjected to the final tableting step.

[0198] Pharmaceutical formulations of bermostil can be administered. Bermostil may be formulated for administration to mammals, in embodiments humans, by injection. Bermostil can be formulated, for example, as a viscous liquid solution or suspension such as a clear solution for injection. The formulation may contain one or more solvents. Suitable solvents can be selected considering the physical and chemical stability, viscosity (which enables injectability), fluidity, boiling point, miscibility, and purity of the solvent at various pH levels. Suitable solvents include Alcohol USP, Benzyl Alcohol NF, Benzyl Benzoate USP, and Castor Oil USP. Additional substances, such as, among others, buffers, solubilizers, and antioxidants can be added to the formulation. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition.

[0199] The crystalline polymorphs of bermostil of the present disclosure, as well as the pharmaceutical compositions and / or formulations of bermostil, can be used as a medicament, in embodiments for the treatment of graft-versus-host disease including chronic graft-versus-host disease, systemic sclerosis including diffuse cutaneous systemic sclerosis, fibrosis including idiopathic pulmonary fibrosis, psoriasis vulgaris, systemic scleroderma, particularly chronic graft-versus-host disease and / or systemic sclerosis.

[0200] The present disclosure also provides a method for treating graft-versus-host disease including chronic graft-versus-host disease, systemic sclerosis including diffuse cutaneous systemic sclerosis, fibrosis including idiopathic pulmonary fibrosis, psoriasis vulgaris, systemic scleroderma, particularly chronic graft-versus-host disease and / or systemic sclerosis, by administering to a subject in need thereof at least a therapeutically effective amount of any one or a combination of the crystalline polymorphs of bermostil of the present disclosure, or at least one of the above pharmaceutical compositions and / or formulations.

[0201] Thus, while the present disclosure has been described with reference to specific preferred embodiments and examples, those skilled in the art will recognize modifications to the disclosed embodiments and examples that do not depart from the spirit and scope of the disclosure herein. The examples are provided to aid in understanding the disclosure but are not intended to limit the scope of the disclosure in any way and should not be construed as limiting.

[0202] Powder X-ray diffraction (``XRPD'') method For Examples 1-9 and 12-15: XRPD analysis was performed on an ARL (SCINTAG) powder X-ray diffractometer model X'TRA equipped with a solid detector. Copper radiation of 1.5418 Å was used. Scanning parameters: range: 2-40 degrees 2 theta, scan mode: continuous scan, step size: 0.05°, and rate: 3 deg / min.

[0203] For Examples 10 and 11: XRPD analysis was performed on a Bruker powder X-ray diffractometer model D8 ADVANCE equipped with a solid detector. Copper radiation of 1.54060 Å was used. Scanning parameters: range: 2-40 degrees 2 theta, scan mode, step size: 0.05°.

[0204] The position of the peak was corrected with respect to the silicon theoretical peak at 28.45 degrees 2 theta.

[0205] Solid 13 C-NMR method Solid 13 13C NMR spectra were recorded using a BRUKER AvanceII+ spectrometer operating at 125 MHz and a temperature controlled at 0 °C, with variable amplitude cross polarization, magic angle spinning, and high power proton decoupling. A probe using a 4 mm o.d. zirconia rotor was utilized. The operating conditions were contact time: 2 ms, waiting time: 5 s, 1024 scans, and spinning rate 11 kHz. Chemical shifts were referenced by a substituted sample of glycine (chemical shift of carboxyl carbon assigned as 176.03 ppm relative to the signal of tetramethylsilane).

[0206] TGA method Thermogravimetric analysis was performed using a TGA / DSC manufactured by Mettler Toledo with the following scanning parameters. Heat from 25 to 250 °C. Heating rate: 10 °C / min. Purge with a N2 flow of 40 ml / min. Sample mass: 7 - 15 mg. Crucible: 150 μL alumina crucible with a standard aluminum lid.

[0207] SEM method SEM micrographs were taken using a Phenom Pro scanning microscope at 10 kV and low current. Gold was sputtered onto the samples using a Desk V sputter coater manufactured by Denton.

Example

[0208] Preparation of starting materials Bermosil can be prepared according to methods known from the literature, for example according to International Publication No. WO 2006 / 105081.

[0209] (Example 1) Preparation of amorphous bermosil Procedure A Methanol (90 ml, 90 V) was added to bermosil (1 gram, 2.21 mmol) to obtain a slurry. The slurry was magnetically stirred at 62 °C for 15 minutes to obtain a clear solution, which was then mechanically filtered. After cooling the solution to room temperature, it was dried in a spray dryer at Tin = 140 °C (Tout = 78 °C). The resulting solid was analyzed by X-ray powder diffraction, and the XRPD pattern is shown in Figure 1.

[0210] Procedure B Methanol (3.5 ml, 70 V) was added to bermosil (50 mg, 0.11 mmol) to obtain a slurry. The slurry was magnetically stirred at 60 °C for 15 minutes to obtain a clear solution, which was then mechanically filtered. The resulting clear mother liquor was evaporated at 50 °C / 300 - 35 mbar to obtain a solid. The resulting solid was characterized as amorphous bermosil by X-ray powder diffraction.

[0211] (Example 2) Preparation of the crystalline form B1 of vermostil Procedure A Acetone (7.5 ml, 250 V) was added to vermostil (30 mg, 0.066 mmol) to obtain a clear solution. Next, the solution was mechanically filtered at room temperature and slowly evaporated over 6 days at this temperature. The obtained solid was analyzed by X-ray powder diffraction to obtain the crystalline form B1 of vermostil. The XRPD pattern is shown in Figure 2.

[0212] Procedure B Ethanol (0.6 ml, 20 V) was added to amorphous vermostil (30 mg, 0.066 mmol) to obtain a slurry. The slurry was magnetically stirred at 50 °C for 5 hours. The solid was separated by centrifugation and dried in a vacuum oven at 45 °C for 20 hours to obtain an off-white solid, which was identified as the crystalline form B1 of vermostil.

[0213] (Example 3) Preparation of the crystalline form B2 of vermostil Procedure A Acetonitrile (12 ml, 400 V) was added to amorphous vermostil (30 mg, 0.066 mmol) at 80 °C to obtain a clear solution. Next, the solution was mechanically filtered at room temperature and slowly evaporated over 5 days at this temperature. The obtained solid was analyzed by XRPD and characterized as the crystalline form B2 of vermostil. The XRPD pattern is shown in Figure 3.

[0214] Procedure B Amorphous vermostil (30 mg, 0.066 mmol) was heated to 160 °C by TGA over 0.5 hour. The obtained solid was analyzed by X-ray powder diffraction and identified as the crystalline form B2 of vermostil.

[0215] Procedure C Methanol (12 ml, 400 V) was added to amorphous vermostil (30 mg, 0.066 mmol) at room temperature to obtain a slurry. The slurry was magnetically stirred at 50 °C for 5 hours. The solid was separated by centrifugation and dried in a vacuum oven at 45 °C for 20 hours. The resulting off-white solid was analyzed by X-ray powder diffraction and characterized as vermostil crystal form B2.

[0216] (Example 4) Preparation of vermostil crystal form B3 Tetrahydrofuran (5 ml, 50 V) was added to vermostil (100 mg, 0.22 mmol) at 40 °C and stirred for 10 minutes to obtain a clear solution. Next, the solution was mechanically filtered, cooled to room temperature, and stirred for 14 hours to obtain a wet solid. The solid was separated by centrifugation. The resulting wet solid was analyzed by XRPD and characterized as vermostil crystal form B3. The XRPD pattern is shown in Figure 4.

[0217] (Example 5) Preparation of vermostil mesylate crystal form M1 Procedure A Ethanol (4 ml, 20 V) was added to vermostil (200 mg, 0.44 mmol) at room temperature to obtain a slurry. Next, methanesulfonic acid (31 μL, 1.1 equivalents) was added dropwise to obtain a clear solution. The solution was heated to 50 °C and precipitation was observed. Ethanol (3 ml, 15 V) was added to the resulting lumpy precipitate, and then magnetically stirred at 50 °C for 30 minutes. Next, the precipitate was naturally cooled to room temperature. The solid was separated by centrifugation. The resulting solid was washed twice with ethanol (400 μL, 2 V) and dried in a vacuum oven at 45 °C for 16 hours to obtain a yellow solid. The resulting solid was analyzed by X-ray powder diffraction and characterized as vermostil mesylate crystal form M1. The XRPD pattern is shown in Figure 5.

[0218] Procedure B DMSO (0.9 ml, 30 V) was added to vermostil mesylate (30 mg, 0.06 mmol) to obtain a slurry. The slurry was heated to 50 °C for 10 minutes to obtain complete dissolution, and then hot mechanical filtration was performed. Next, ethanol (2.7 ml, 100 V) was added dropwise as a poor solvent to obtain a solid precipitate. Next, the slurry was magnetically stirred at room temperature for 40 hours. Thereafter, the solid was isolated by centrifugation. The obtained wet solid was analyzed by X-ray powder diffraction and identified as the vermostil mesylate crystal form M1.

[0219] Procedure C Isopropyl alcohol (2 ml, 20 V) was added to vermostil (100 mg, 0.2 mmol) at room temperature to obtain a slurry. Next, methanesulfonic acid (161 μL, 1.1 equivalents) was added dropwise to obtain a clear solution. The solution was heated to 50 °C, precipitation was observed, and it was magnetically stirred at 50 °C for 30 minutes. Next, the precipitate was naturally cooled to room temperature. The solid was separated by centrifugation. The obtained solid was washed twice with IPA (200 μL, 2 V) to obtain a yellow solid. The obtained solid was analyzed by X-ray powder diffraction and identified as the vermostil mesylate crystal form M1.

[0220] Procedure D n-Butanol (2 ml, 20 V) was added to vermostil (100 mg, 0.2 mmol) at room temperature to obtain a slurry. Next, methanesulfonic acid (161 μL, 1.1 equivalents) was added dropwise to obtain a clear solution. The solution was heated to 50 °C, precipitation was observed, and it was magnetically stirred at 50 °C for 30 minutes. Next, the precipitate was naturally cooled to room temperature. The solid was separated by centrifugation. The obtained solid was washed twice with n-butanol (200 μL, 2 V) to obtain a yellow solid. The obtained solid was analyzed by X-ray powder diffraction and identified as the vermostil mesylate crystal form M1.

[0221] Procedure E 1-Propanol (2 ml, 20 V) was added to vermostil (100 mg, 0.2 mmol) at room temperature to obtain a slurry. Next, methanesulfonic acid (161 μL, 1.1 eq) was added dropwise to obtain a clear solution. The solution was heated to 50 °C, precipitation was observed, and it was magnetically stirred at 50 °C for 30 minutes. Next, the precipitate was naturally cooled to room temperature. The solid was separated by centrifugation. The obtained solid was washed twice with 1-propanol (200 μL, 2 V) to obtain a yellow solid. The obtained solid was analyzed by X-ray powder diffraction and identified as the vermostil mesylate crystal form M1.

[0222] Procedure F 2,2,2-Trifluoroethanol (0.3 ml, 10 V) was added to vermostil mesylate (30 mg, 0.06 mmol) to obtain a slurry. The slurry was heated to 60 °C for 10 minutes to obtain complete dissolution, and then hot mechanical filtration was performed. Next, ethanol (1.2 ml, 40 V) was added dropwise as a poor solvent to obtain a solid precipitate. Next, the slurry was magnetically stirred at room temperature for 17 hours. Then, the solid was isolated by centrifugation. The obtained wet solid was analyzed by X-ray powder diffraction and identified as the vermostil mesylate crystal form M1.

[0223] (Example 6) Preparation of the crystal form B4 of vermostil Procedure A Methanol (0.6 ml, 20 V) was added to vermostil form B1 (30 mg, 0.066 mmol) to obtain a slurry. Next, the slurry was magnetically stirred at 50 °C for 5 hours. Next, the slurry was cooled to room temperature and magnetically stirred for 16 hours. Then, the solid was isolated at room temperature by centrifugation. The obtained wet solid was dried in a vacuum oven at 45 °C for 18 hours to obtain an off-white solid, which was characterized by X-ray powder diffraction, and the XRPD pattern is shown in Figure 6.

[0224] Procedure B Acetonitrile:MeOH (0.75 ml, 25 V, 1:1 equivalent) was added to B1 (50 mg, 0.11 mmol) to obtain a slurry. The slurry was magnetically stirred at room temperature for 1 week. Thereafter, the solid was isolated at room temperature by centrifugation. The obtained wet solid was characterized as the vermostil crystalline form B4 by X-ray powder diffraction.

[0225] (Example 7) Preparation of the crystalline form M2 of vermostil mesylate Procedure A Water (2 ml, 20 V) was added to form B1 (100 mg, 0.22 mmol) at room temperature to obtain a slurry. Next, methanesulfonic acid (16 μL, 1.1 equivalents) was added dropwise to obtain a slurry. The slurry was heated to 50 °C over 45 minutes to obtain a clear solution. Next, the solution was allowed to cool naturally to room temperature, and a precipitate was observed. The obtained solid was isolated using centrifugation. The isolated solid was washed twice with water (0.2 ml, 2 V) and dried in a vacuum oven at 45 °C for 18 hours to obtain a yellow solid. The obtained solid was analyzed by X-ray powder diffraction, and the XRPD pattern is shown in Figure 7.

[0226] Procedure B A water:ethanol (2 ml, 20 V, 1:3) mixture was added to form B1 (100 mg, 0.22 mmol) at room temperature to obtain a slurry. Next, methanesulfonic acid (16 μL, 1.1 equivalents) was added dropwise to obtain a slurry. The slurry was heated to 50 °C over 45 minutes to obtain a clear solution. Next, the solution was allowed to cool naturally to room temperature, and a precipitate was observed. The obtained solid was isolated using centrifugation. The isolated solid was washed twice with water:ethanol (2.2 ml, 22 V, 1:3) and dried in a vacuum oven at 45 °C for 18 hours to obtain a yellow solid. The obtained solid was analyzed by X-ray powder diffraction and identified as the vermostil mesylate crystalline form M2.

[0227] Procedure C Water (2 ml, 40 V) was added to vermostil mesylate form M1 (50 mg, 0.11 mmol) to obtain a slurry. The slurry was magnetically stirred at 60 °C for 1 week. Thereafter, the solid was isolated at room temperature by centrifugation. The obtained wet solid was analyzed by X-ray powder diffraction and identified as vermostil mesylate crystal form M2.

[0228] Procedure D DMSO (2 ml, 40 V) was added to vermostil mesylate form M1 (50 mg, 0.11 mmol) to obtain a slurry. The slurry was heated to 50 °C for 10 minutes to obtain complete dissolution, and then hot mechanical filtration was performed. The solution was allowed to cool naturally to room temperature and magnetically stirred for 5 days. Next, cold water (5 ml, 100 V, 4 °C) was added dropwise as a poor solvent to obtain a solid precipitate. Next, the slurry was magnetically stirred at room temperature for 18 hours. Thereafter, the solid was isolated by centrifugation. The obtained wet solid was analyzed by X-ray powder diffraction and identified as vermostil mesylate crystal form M2.

[0229] Procedure E 2,2,2-Trifluoroethanol (0.3 ml, 10 V) was added to vermostil mesylate (30 mg, 0.06 mmol) to obtain a slurry. The slurry was heated to 60 °C for 10 minutes to obtain complete dissolution, and then hot mechanical filtration was performed. Next, water (1.2 ml, 40 V) was added dropwise as a poor solvent to obtain a solid precipitate. Next, the slurry was magnetically stirred at room temperature for 17 hours. Thereafter, the solid was isolated by centrifugation. The obtained wet solid was analyzed by X-ray powder diffraction and identified as vermostil mesylate crystal form M2.

[0230] (Example 8) Preparation of Vermostil Mesylate Crystal Form M3 Procedure A Vermostil mesylate form M2 (prepared according to the procedure of Example 7) was dried in a vacuum oven at 200 °C for 4 hours to obtain a yellow solid. The obtained solid was characterized as vermostil mesylate crystal form M3 by X-ray powder diffraction.

[0231] (Example 9) Preparation of the Crystal Form B5 of Berlmoszil Procedure A 2,2,2-Trifluoroethanol (TFE) (0.6 ml, 50 V) was added to Berlmoszil (12.5 mg, 0.03 mmol) to obtain a clear solution. Next, the solution was magnetically stirred at 70 °C for 1 hour. Then, the solution was cooled to 4 °C at a rate of 20 °C every 10 minutes, and a massive precipitate was observed. Further, TFE (0.1 ml, 10 V) was added to obtain a slurry. Next, the solid was isolated using centrifugation. Then, the mother liquor was left at 4 °C for 20 days to crystallize slowly. The obtained wet solid was filtered with a Buchner funnel, and the solid was characterized as Berlmoszil crystal form B5 by X-ray powder diffraction. The XRPD pattern is shown in Figure 9.

[0232] (Example 10) Preparation of Amorphous Berlmoszil Mesylate Procedure A Methanol (286 ml, 220 V) was added to Berlmoszil mesylate form M1 (1.3 grams, 2.4 mmol) to obtain a slurry. The slurry was magnetically stirred at 62 °C for 45 minutes, and after obtaining a clear solution, it was mechanically filtered. After the solution was cooled to room temperature, it was dried in a spray dryer at Tin = 140 °C (Tout = 63 °C). The obtained solid was analyzed by X-ray powder diffraction and identified as amorphous Berlmoszil mesylate. The XRPD pattern is shown in Figure 10.

[0233] (Example 11) Preparation of the Form M4 of Berlmoszil Mesylate Procedure A 2,2,2-Trifluoroethanol (TFE) (0.7 ml, 7 V) was added to vermox mesylate form M1 (100 mg, 0.2 mmol) to obtain a clear solution. The clear solution was mechanically filtered and added to heptane (0.8 ml, 8 V) pre-cooled to 4 °C to obtain two phases. The solution was stirred at 4 °C for 4 days. Next, the mixture was seeded with vermox mesylate M3 (about 1 wt%), stirred for 1 day, and a solid precipitate was obtained. The precipitate was then isolated by centrifugation and dried in a vacuum oven at 45 °C for 18 hours to obtain a yellow solid. The obtained solid was analyzed by X-ray powder diffraction, and the XRPD pattern is shown in Figure 11.

[0234] Procedure B TFE (0.7 ml, 7 V) was added to vermox mesylate form M1 (100 mg, 0.2 mmol) to obtain a clear solution. The clear solution was mechanically filtered and added to heptane (0.8 ml, 8 V) pre-cooled to 4 °C to obtain two phases. Next, the mixture was seeded with vermox mesylate form M4 (about 1 wt%), stirred for 1 day, and a solid precipitate was obtained. The precipitate was then isolated by centrifugation and dried in a vacuum oven at 45 °C for 18 hours to obtain a yellow solid. The obtained solid was analyzed by X-ray powder diffraction and identified as vermox mesylate crystal form M4.

[0235] Procedure C TFE (0.7 ml, 7 V) was added to vermox mesylate form M1 (100 mg, 0.2 mmol) to obtain a clear solution. The clear solution was mechanically filtered and added to cyclopentyl methyl ether (0.8 ml, 8 V) pre-cooled to 4 °C. Next, the mixture was seeded with vermox mesylate form M4 (about 1 wt%), stirred for 18 hours, and a solid precipitate was obtained. The precipitate was then isolated by centrifugation and dried in a vacuum oven at 45 °C for 18 hours to obtain a yellow solid. The obtained solid was analyzed by X-ray powder diffraction and identified as vermox mesylate crystal form M4.

[0236] Procedure D TFE (0.7 ml, 7 V) was added to vermox mesylate form M1 (100 mg, 0.2 mmol) to obtain a clear solution. The clear solution was added to cyclopentyl methyl ether (0.8 ml, 8 V) pre-cooled to 4 °C to obtain a lumpy slurry. Next, cyclopentyl methyl ether (0.4 ml, 4 V) was added to obtain a slurry. Next, NaCl (about 1 wt%) was seeded into the mixture, and after stirring for 1 hour, a precipitate was obtained. Next, the precipitate was isolated by centrifugation and dried in a vacuum oven at 45 °C for 18 hours to obtain a yellow solid. The obtained solid was analyzed by X-ray powder diffraction and identified as vermox mesylate crystal form M4.

[0237] (Example 12) Preparation of Form M5 of Vermox Mesylate Procedure A DMSO (9 ml, 30 V) was added to vermox mesylate form M1 (300 mg, 0.6 mmol) to obtain a clear solution. Next, the clear solution was added to cyclopentyl methyl ether (9 ml, 30 V) containing seeds (about 1 wt%) of vermox mesylate form M4 pre-cooled to about 4 °C, and additional cyclopentyl methyl ether (18 ml, 60 V) and seeds (about 1 wt%) of vermox mesylate form M4 were added. Some precipitate was observed after 10 minutes. The mixture was stirred at about 4 °C for 18 hours to obtain a lumpy precipitate. Next, the precipitate was separated by centrifugation and dried in a vacuum oven at 45 °C for 18 hours to obtain a yellow solid. The obtained solid was analyzed by X-ray powder diffraction, and the XRPD pattern is shown in Figure 12.

[0238] (Example 13) Preparation of Form BS1 of Vermox Besylate Procedure A Ethanol (10 ml, 20 V) was added to vermostil form B1 (500 mg, 1.1 mmol) at room temperature to obtain a slurry. Next, benzenesulfonic acid (192.3 mg, 1.1 equiv) was added, and the slurry was heated to 50 °C over 45 minutes with stirring. Next, the slurry was allowed to cool naturally to room temperature, and the solid obtained using centrifugation was isolated. The isolated solid was dried in a vacuum oven at 45 °C for 18 hours to obtain a yellow solid. The obtained solid was analyzed by X-ray powder diffraction, and the XRPD pattern is shown in Figure 13.

[0239] (Example 14) Preparation of vermostil tosylate form T1 Procedure A Methanol (2 ml, 20 V) was added to vermostil form B1 (100 mg, 0.22 mmol), and the mixture was heated to 50 °C to obtain a slurry. Next, p-toluenesulfonic acid (46.2 mg, 1.1 equiv) was added to obtain a clear solution. After stirring at 50 °C for 10 minutes, precipitation was observed. The solution was stirred at 50 °C for 45 minutes. Next, the solution was allowed to cool naturally to room temperature, and massive precipitation was observed. The solid obtained using centrifugation was isolated and washed once with methanol (200 μL, 2 V). The solid was dried in a vacuum oven at 45 °C for 18 hours to obtain a yellow solid. The obtained solid was analyzed by X-ray powder diffraction, and the XRPD pattern is shown in Figure 14.

[0240] (Example 15) Preparation of vermostil tosylate form T2 Procedure A Water (1 ml, 20 V) was added to vermostil form B1 (50 mg, 0.11 mmol), and the mixture was heated to 50 °C to obtain a slurry. Next, p-toluenesulfonic acid (23.1 mg, 1.1 eq) was added, and the sticky slurry was stirred at 50 °C for 20 minutes. Then, ethanol (250 μl, 5 V) was added to obtain a slurry. The slurry was stirred at 50 °C for 50 minutes. Next, the slurry was allowed to cool naturally to room temperature, and the solid obtained using centrifugation was isolated. The isolated solid was washed once with water:ethanol (1 ml, 2 V, 4:1) and dried in a vacuum oven at 45 °C for 18 hours to obtain a yellow solid. The obtained solid was analyzed by X-ray powder diffraction, and the XRPD pattern is shown in Figure 15.

Claims

1. A crystalline form of belumosudil mesylate designated as Form M3, characterized by an XRPD pattern having peaks at 7.3, 14.6, 16.6, 17.5 and 19.6 degrees 2 theta ± 0.2 degrees 2 theta.

2. The following: (i) An XRPD pattern having peaks at 7.3, 14.6, 16.6, 17.5 and 19.6 degrees 2 theta ± 0.2 degrees 2 theta and further having any 1, 2, 3, 4 or 5 additional peaks selected from 12.9, 13.7, 19.0, 20.6 and 26.0 degrees 2 theta ± 0.2 degrees 2 theta, (ii) An X-ray powder diffraction pattern having peaks at 7.3, 12.9, 13.7, 14.6, 16.6, 17.5, 19.0, 19.6, 20.6 and 26.0 degrees 2 theta ± 0.2 degrees 2 theta, and (iii) An XRPD pattern substantially as shown in Figure 8 characterized by one or more of the above, the crystalline form according to Claim 1.

3. A crystalline form of belumosudil mesylate designated as Form M4, characterized by an XRPD pattern having peaks at 7.5, 15.0, 17.9, 21.8 and 22.6 degrees 2 theta ± 0.2 degrees 2 theta.

4. The following: (i) An XRPD pattern having peaks at 7.5, 15.0, 17.9, 21.8 and 22.6 degrees 2 theta ± 0.2 degrees 2 theta and further having any 1, 2, 3, 4 or 5 additional peaks selected from 11.3, 17.4, 20.9, 24.2 and 29.2 degrees 2 theta ± 0.2 degrees 2 theta, (ii) An X-ray powder diffraction pattern having peaks at 7.5, 11.3, 15.0, 17.4, 17.9, 20.9, 21.8, 22.6, 24.2 and 29.2 degrees 2 theta ± 0.2 degrees 2 theta, and (iii) An XRPD pattern substantially as shown in Figure 11 characterized by one or more of the above, the crystalline form according to Claim 3.

5. A crystalline form of belumosudil mesylate designated as Form M5, characterized by an XRPD pattern having peaks at 6.2, 15.7, 18.4, 19.2 and 25.1 degrees 2 theta ± 0.2 degrees 2 theta.

6. The following: (i) An XRPD pattern having peaks at 6.2, 15.7, 18.4, 19.2 and 25.1 degrees 2-theta ± 0.2 degrees 2-theta, and further having any 1, 2, 3, 4 or 5 additional peaks selected from 17.8, 21.6, 21.9, 24.7, 25.9 degrees 2-theta ± 0.2 degrees 2-theta, (ii) An X-ray powder diffraction pattern having peaks at 6.2, 15.7, 17.8, 18.4, 19.2, 21.6, 21.9, 24.7, 25.1 and 25.9 degrees 2-theta ± 0.2 degrees 2-theta, and (iii) An XRPD pattern substantially as shown in Figure 12 The crystalline form according to claim 5, characterized by one or more of the above.

7. Containing 20% or less, 10% or less, 5% or less, 2% or less, 1% or less or about 0% of any other crystalline form of belumosudil mesylate, and / or containing 20% or less, 10% or less, 5% or less, 2% or less, 1% or less or about 0% of amorphous belumosudil mesylate, the crystalline product according to any one of claims 1 to 6.

8. The crystalline product according to any one of claims 1 to 7, which is non-hygroscopic and preferably polymorphically stable at room temperature with a relative humidity of up to 100% for at least 7 days.

9. The isolated crystalline product according to any one of claims 1 to 8.

10. Use of the crystalline product according to any one of claims 1 to 9 for the preparation of a pharmaceutical composition.

11. A pharmaceutical composition comprising the crystalline product according to any one of claims 1 to 9 and at least one pharmaceutically acceptable excipient.

12. A method for preparing the pharmaceutical composition according to claim 11, comprising the step of combining the crystalline form according to any one of claims 1 to 9 with at least one pharmaceutically acceptable excipient.

13. For use as a medicament, optionally for the treatment of graft-versus-host disease including chronic graft-versus-host disease, systemic sclerosis including diffuse cutaneous systemic sclerosis, fibrosis including idiopathic pulmonary fibrosis, psoriasis vulgaris, systemic scleroderma, particularly chronic graft-versus-host disease and systemic sclerosis, the crystalline product according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 11.

14. Use of the crystalline product according to any one of claims 1 to 9 in the preparation of another solid form of belumosudil, or another salt of belumosudil or its solid form.

15. A method for preparing a berberine salt or a solid form thereof, comprising the step of preparing the crystalline product according to any one of claims 1 to 9 and converting it into another solid form of berberine or another salt or a solid form thereof.

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