Solid forms of belmosdil and belmosdil salts

Abstract

The present disclosure encompasses solid forms of belmosudil, in embodiments crystalline polymorphs of belmosudil or a salt thereof, methods for preparing same, and pharmaceutical compositions thereof.

Description

[Technical Field]

[0001] This disclosure includes the solid form of belmosdil, crystalline polymorphs of belmosdil or its salts in embodiments, methods for preparing the same, and pharmaceutical compositions thereof. [Background technology]

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

[0003] [ka]

[0004] Belmosdil is a ROCK2 inhibitor and is being developed for the treatment of graft-versus-host diseases, including chronic graft-versus-host disease; systemic sclerosis, including diffuse cutaneous systemic sclerosis; fibrosis, including idiopathic pulmonary fibrosis; psoriasis vulgaris; and systemic sclerosis.

[0005] The compound is described in International Publication No. 2006 / 105081. The crystalline form of belmosdil is disclosed in International Publication No. 2021 / 129589.

[0006] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule exhibits polymorphism in its melting point, thermal behavior (e.g., measured by thermogravimetric analysis ("TGA") or differential scanning calorimetry ("DSC")), X-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solid state. 13 C) This can lead to the generation of diverse polymorphs with different crystal structures and physical properties, such as NMR spectra. One or more of these techniques can be used to distinguish between different polymorphic forms of a compound.

[0007] Different salts and solid forms (including solvated forms) of pharmaceutical components may have different properties. Such variations in the properties of different salts, solid forms, and solvates can provide a basis for improving formulations, for example, by promoting better processability or handling, altering the solubility profile in a favorable direction, or improving stability (chemical stability as well as polymorphism) and shelf life. These variations in the properties of different salts and solid forms can also lead to improvements in the final dosage form, for example, if they help improve bioavailability. Different salts, solid forms, and solvates of pharmaceutical components may also result in the generation of various polymorphs or crystalline forms, which in turn can provide further opportunities to evaluate variations in the properties and characteristics of solid pharmaceutical components.

[0008] Discovering novel solid forms and solvates of pharmaceuticals may yield substances with desirable handling properties such as ease of handling, ease of processing, storage stability, and ease of purification, or as desirable intermediate crystalline forms that facilitate conversion to other polymorphic forms. Novel solid forms of pharmaceutically useful compounds can also offer opportunities to improve the performance characteristics of pharmaceuticals. This can 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, resulting in better processability or handling, improved solubility profiles, or improved shelf life (chemical / physical stability). For at least these reasons, further solid forms (including solvated forms) of belmosdil and belmosdil salts are needed. [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] International Publication No. 2006 / 105081 [Patent Document 2] International Publication No. 2021 / 129589 [Non-patent literature]

[0010] [Non-Patent Document 1] Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition [Summary of the Invention] [Means for Solving the Problems]

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

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

[0013] The present disclosure provides crystalline polymorphs of vemurafenib, or salts thereof including vemurafenib mesylate, vemurafenib tosylate and vemurafenib 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 vemurafenib, or salts thereof including vemurafenib mesylate, vemurafenib tosylate and vemurafenib 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 vemurafenib of the present disclosure, or salts thereof including vemurafenib mesylate, vemurafenib tosylate and vemurafenib 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 bermodasil according to the present disclosure, or a salt thereof including bermodasil mesylate, bermodasil tosylate, and bermodasil besylate.

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

[0017] The crystalline polymorphs of bermodasil, or salts thereof including bermodasil mesylate, bermodasil tosylate, and bermodasil besylate, as defined herein, and pharmaceutical compositions or formulations of the crystalline polymorphs of bermodasil, or salts thereof including bermodasil mesylate, bermodasil tosylate, and bermodasil besylate, can be used as a medicine, 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 bermodasil, or salts thereof including bermodasil mesylate, bermodasil tosylate, and bermodasil besylate, as defined herein, and pharmaceutical compositions or formulations of the crystalline polymorphs of bermodasil, or salts thereof including bermodasil mesylate, bermodasil tosylate, and / or bermodasil besylate, can be used as a medicine for the treatment of chronic graft-versus-host disease and / or systemic sclerosis.

[0018] The 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 sclerosis by administering a therapeutically effective amount of any one or combination of crystalline polymorphs thereof, including belmosudil mesylate, belmosudil tosylate, and belmosudil besylate, or at least one of the above pharmaceutical compositions, to subjects suffering from or otherwise requiring 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 sclerosis. In particular, the present disclosure provides a method for treating chronic graft-versus-host disease and / or systemic sclerosis by administering a therapeutically effective amount of belmosdil, or any one or a combination of crystalline polymorphs thereof including belmosdil mesylate, belmosdil tosylate, and belmosdil besylate, or at least one of the above pharmaceutical compositions, to a subject suffering from chronic graft-versus-host disease and / or systemic sclerosis, or otherwise requiring treatment.

[0019] The Disclosure also provides the use of belmosdil or belmosdil mesylate, belmosdil tosylate and / or belmosdil besylate, crystalline polymorphs thereof, or at least one of the above pharmaceutical compositions, for the manufacture of a medicament for treating graft-versus-host diseases, including chronic graft-versus-host disease; systemic sclerosis, including diffuse cutaneous systemic sclerosis; fibrosis, including idiopathic pulmonary fibrosis; psoriasis vulgaris; and systemic sclerosis, particularly for treating chronic graft-versus-host disease and / or systemic sclerosis. [Brief explanation of the drawing]

[0020] [Figure 1] The X-ray powder diffraction (XRPD) pattern of amorphous vermosdil is shown. [Figure 2] This shows the characteristic X-ray powder diffraction (XRPD) pattern of belmosdil morphology B1. [Figure 3] This shows the characteristic X-ray powder diffraction (XRPD) pattern of belmosdil morphology B2. [Figure 4] This shows the characteristic X-ray powder diffraction (XRPD) pattern of belmosdil morphology B3. [Figure 5] This shows the characteristic X-ray powder diffraction (XRPD) pattern of belmosdil mesylate morphology M1. [Figure 6] This shows the characteristic X-ray powder diffraction (XRPD) pattern of belmosdil morphology B4. [Figure 7] This shows the characteristic X-ray powder diffraction (XRPD) pattern of belmosdil mesylate morph M2. [Figure 8] This shows the characteristic X-ray powder diffraction (XRPD) pattern of belmosdil mesylate morphology M3. [Figure 9] This shows the characteristic X-ray powder diffraction (XRPD) pattern of belmosdil morphology B5. [Figure 10] This shows the characteristic X-ray powder diffraction (XRPD) pattern of amorphous vermosdil mesylate. [Figure 11] This shows the characteristic X-ray powder diffraction (XRPD) pattern of belmosdil mesylate morph M4. [Figure 12] This shows the characteristic X-ray powder diffraction (XRPD) pattern of belmosdil mesylate morphology M5. [Figure 13] This shows the characteristic X-ray powder diffraction (XRPD) pattern of bermosdilbesylate morph BS1. [Figure 14] This shows the characteristic X-ray powder diffraction (XRPD) pattern of belmosdil tosylate morph T1. [Figure 15] This shows the characteristic X-ray powder diffraction (XRPD) pattern of belmosdil tosylate morph T2. [Figure 16] This shows the characteristic solid-state 13C NMR spectrum (overall range 200-0 ppm) of morphology M1 of bellmosdyl mesylate. [Figure 17] The characteristic solid-state 13C NMR spectrum (200–100 ppm) of morphology M1 of bellmosdyl mesylate is shown. [Figure 18] The characteristic solid-state 13C NMR spectrum (100–0 ppm) of morphology M1 of bellmosdyl mesylate is shown. [Figure 19] This shows the characteristic solid-state 13C NMR spectrum (overall range 200-0 ppm) of morphology M2 of bellmosdyl mesylate. [Figure 20] The characteristic solid-state 13C NMR spectrum (200–100 ppm) of morphology M2 of bellmosdyl mesylate is shown. [Figure 21] This shows the characteristic solid-state 13C NMR spectrum (100–0 ppm) of morphology M2 of bellmosdyl mesylate. [Figure 22] The characteristic solid-state 13C NMR spectrum (overall range 200-0 ppm) of bermosdylbesylate BS1 is shown. [Figure 23] The characteristic solid-state 13C NMR spectrum (200–100 ppm) of bermosdylbesylate BS1 is shown. [Figure 24] The characteristic solid-state 13C NMR spectrum (100-0 ppm) of bermosdylbesylate BS1 is shown. [Figure 25] This image shows a scanning electron microscope (SEM) image of morphological BS1 particles of bellmosdilbesylate. [Figure 26] This shows the characteristic solid-state 13C NMR spectrum (overall range 200-0 ppm) of morphology T1 of bellmosdil tosylate. [Figure 27] The characteristic solid-state 13C NMR spectrum (200–100 ppm) of morphology T1 of bellmosdil tosylate is shown. [Figure 28] The characteristic solid-state 13C NMR spectrum (100–0 ppm) of morphology T1 of bellmosdil tosylate is shown. [Figure 29] This image shows a scanning electron microscope (SEM) image of morphological T1 particles of belmosdil tosylate. [Figure 30] This shows the characteristic solid-state 13C NMR spectrum (overall range 200-0 ppm) of morphology T2 of bellmosdil tosylate. [Figure 31] The characteristic solid-state 13C NMR spectrum (200–100 ppm) of morphology T2 of bellmosdil tosylate is shown. [Figure 32]The characteristic solid-state 13C NMR spectrum (100–0 ppm) of morphology T2 of bellmosdil tosylate is shown. [Figure 33] This image shows a scanning electron microscope (SEM) image of morphological T2 particles of belmosdil tosylate. [Modes for carrying out the invention]

[0021] This disclosure includes belmosdil and belmosdil salts in solid form, methods for preparing the same, and pharmaceutical compositions thereof, including crystalline polymorphs of belmosdil and salts thereof including belmosdil mesylate, belmosdil tosylate and / or belmosdil besylate.

[0022] The solid-state properties of belmosudil, belmosudil salts, and their crystalline polymorphs can be influenced by controlling the conditions under which belmosudil, belmosudil salts, and their crystalline polymorphs are obtained in solid form.

[0023] A solid form (or polymorph) may be referred to herein as being polymorphically pure or substantially free of any other solid (or polymorph) form. When used herein in this context, the expression “substantially free of any other form” is understood to mean that the solid form contains any other form of the compound in question at a concentration of 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% as measured, for example, by XRPD. Thus, a crystalline polymorph of belmosudil or a belmosudil salt described herein as substantially free of any other solid form is understood to contain about 80% (w / w), about 90% (w / w), about 95% (w / w), about 98% (w / w), about 99% (w / w), or about 100% of the crystalline polymorph of the belmosudil or belmosudil salt in question. In some embodiments of this disclosure, the crystalline polymorphs of belmosudil or belmosudil salt described may contain about 1% to about 20% (w / w), about 5% to about 20% (w / w), or about 5% to about 10% (w / w) of one or more other crystalline polymorphs of the same belmosudil or belmosudil salt. Similarly, the crystalline polymorphs of belmosudil salts (e.g., belmosudil mesylate, belmosudil tosylate, or belmosudil besylate) described herein as substantially free of any other solid forms are understood to contain about 80% (w / w), about 90% (w / w), about 95% (w / w), about 98% (w / w), about 99% (w / w), or about 100% of the crystalline polymorphs of the belmosudil salt in question (e.g., belmosudil mesylate, belmosudil tosylate, or belmosudil besylate). In some embodiments of this disclosure, the crystalline polymorphs of the belmosudil salt described (e.g., belmosudil mesylate, belmosudil tosylate, or belmosudil besylate) may contain about 1% to about 20% (w / w), about 5% to about 20% (w / w), or about 5% to about 10% (w / w) of one or more other crystalline polymorphs of the same belmosudil salt (e.g., belmosudil mesylate, belmosudil tosylate, or belmosudil besylate).

[0024] Depending on which other crystalline polymorphs are being compared, the crystalline polymorphs of belmosdil and belmosdil salts of this disclosure (e.g., belmosdil mesylate, belmosdil tosylate, or belmosdil besylate) may have advantageous properties selected from at least one of the following: chemical purity, fluidity, solubility, dissolution rate, morphology or crystal habit, stability, such as chemical stability, as well as thermal and mechanical stability with respect to polymorph transformation, stability against dehydration and / or storage stability, low residual solvent content, lower degree of hygroscopicity, fluidity, and advantageous processability and handling properties such as compressibility and bulk density.

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

[0026] As used herein, unless otherwise specified, the term “anhydrous” relating to the crystalline form of belmosudil, belmosudil mesylate, belmosudil tosylate, and / or belmosudil besylate refers to the crystalline form of belmosudil or belmosudil salt that does not contain a specified stoichiometric amount of crystal water (or other solvent) within the crystal. Furthermore, the “anhydrous” form generally does not contain more than 1% (w / w) of water or 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 crystalline 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 stoichiometric or non-stoichiometric amounts.

[0028] As used herein, the term “isolated” in relation to the crystalline polymorphs of belmosudil or belmosudil salts (e.g., belmosudil mesylate, belmosudil tosylate, and / or belmosudil besylate) in this disclosure corresponds to the crystalline polymorphs of belmosudil or belmosudil salt that are physically separated from the reaction mixture in which they are formed.

[0029] Where used herein, unless otherwise specified, XRPD measurements are performed using copper Kα radiation at 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] When used in this specification, 13 The 13C NMR spectrum is preferably measured at 125 MHz with a magic angle rotation (MAS) frequency ωr / 2π = 11 kHz.

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

[0032] A substance, such as a reaction mixture, may be characterized herein as being at or being brought to "room temperature" or "ambient temperature," often abbreviated as "RT." This means that the temperature of the substance is close to or equal to the temperature of the space in which it is located, such as a room or 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,” “vol,” or “V.” For example, it may be said that a material is 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 suspended material, and therefore 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 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 reaction mixture means 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, for example, to a time interval that spans the nighttime hours during which the method or process may not be actively observed. This time interval is approximately 8 to 20 hours, or approximately 10 to 18 hours, and in some cases approximately 16 hours.

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

[0036] As used herein, unless otherwise specified, the term “ambient conditions” refers to atmospheric pressure and a temperature of 22–24°C.

[0037] This disclosure includes a crystalline polymorph of belmosudil designated as morph B1. Crystalline morph B1 of belmosudil 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 2-theta ± 0.2 degrees 2-theta, and a combination of these data.

[0038] The crystalline form B1 of belmosdil 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 2-theta ± 0.2 degrees 2-theta, and any one, two, three, four, or five additional peaks selected from 9.4, 12.5, 15.7, 18.9, and 19.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0039] Alternatively, the crystalline form B1 of belmosdil 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 2-theta ± 0.2 degrees 2-theta.

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

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

[0042] This disclosure includes a crystalline polymorph of belmosudil designated as morph B2. Crystalline morph B2 of belmosudil 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 a combination of these data.

[0043] The crystalline form B2 of belmosdil 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 any one, two, three, four, or five 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 belmosdil 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, crystalline form B2 of belmosdil is isolated.

[0046] The crystalline form B2 of belmoszil may be characterized by each of the above features individually or in any possible combination thereof, 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 as shown in Figure 3, and combinations of these data.

[0047] This disclosure includes a crystalline polymorph of belmosdil designated as morph B3. Crystalline morph B3 of belmosdil 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 a combination of these data.

[0048] The crystalline form B3 of belmosdil may further be characterized by 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 any one, two, three, four, or five additional peaks selected from 14.7, 15.4, 16.4, 18.8 and 22.5 degrees 2-theta ± 0.2 degrees 2-theta.

[0049] Alternatively, crystalline morphology B3 of belmosdil 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 2-theta ± 0.2 degrees 2-theta.

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

[0051] The crystalline form B3 of belmoszil may be characterized by each of the above features individually or in all possible combinations thereof, for example, an XRPD pattern having peaks at 6.5, 8.4, 12.2, 19.6 and 26.3 degrees 2-theta ± 0.2 degrees 2-theta, an XRPD pattern as shown in Figure 4, and combinations thereof.

[0052] This disclosure includes a crystalline polymorph of belmosudil designated as morph B4. Crystalline morph B4 of belmosudil may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 6, an X-ray powder diffraction pattern having peaks at 8.3, 9.3, 11.9, 16.7 and 17.2 degrees 2-theta ± 0.2 degrees 2-theta, and a combination of these data.

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

[0054] The crystalline form B4 of belmosdil may further be characterized by an X-ray powder diffraction pattern having peaks at 8.3, 9.3, 11.9, 16.7, and 17.2 degrees 2-theta ± 0.2 degrees 2-theta, and any one, two, three, four, or five 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, crystalline form B4 of belmosdil 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, crystalline form B4 of belmosdil is isolated.

[0057] The crystalline form B4 of belmoszil may be characterized by each of the above features individually or in all possible combinations thereof, 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] This disclosure includes a crystalline polymorph of belmosdil designated as morph B5. Crystalline morph B5 of belmosdil 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 a combination of these data.

[0059] The crystalline form B5 of belmosdil may further be characterized by 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 any one, two, three, four, or five additional peaks selected from 3.7, 9.4, 9.8, 12.4, and 18.4 degrees 2-theta ± 0.2 degrees 2-theta.

[0060] Alternatively, the crystalline form B5 of belmosdil may 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, crystalline form B5 of belmosdil is isolated.

[0062] The crystalline form B5 of belmoszil may be characterized by each of the above features individually or in all possible combinations thereof, 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 Figure 9, and combinations thereof.

[0063] This disclosure includes a crystalline polymorph of belmosdyl mesylate designated as morph M1. Crystalline morph M1 of belmosdyl 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 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; and a solid having characteristic peaks at 137.8, 133.8, 122.5, 118.3 and 111.6 ppm ± 0.2 ppm. 13 Solids with the following absolute differences in chemical shifts from a reference peak of 167.2 ppm ± 1 ppm in their 13C NMR spectra: 29.4, 33.4, 44.7, 48.9, and 55.6 ppm ± 0.1 ppm. 13 ¹³C NMR spectrum, essentially as shown in any of Figures 16, 17, and 18 of the solid-state model. 13 13C NMR spectra, and combinations of these data.

[0064] The crystalline form M1 of bellmosdil mesylate may further be characterized by 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, and any one, two, three, four, or five additional peaks selected from 8.4, 15.5, 16.8, 19.5, and 22.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0065] Alternatively, the crystalline form M1 of bellmosdil 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 2-theta ± 0.2 degrees 2-theta.

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

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

[0068] According to any aspect or embodiment of this disclosure, the crystalline form M1 of belmosdil mesylate is nonhygroscopic. In particular, form M1 of belmosdil mesylate according to any aspect or embodiment is polymorphically stable at room temperature and a maximum relative humidity of 100% for at least 7 days.

[0069] The crystalline form M1 of bellmosdil mesylate may be characterized by each of the above features individually or in all possible combinations thereof, 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 Figure 5, and combinations thereof.

[0070] Crystallized form M1 of bellmosdyl mesylate may be prepared by crystallizing bellmosdyl mesylate from one or more polar solvents, preferably polar organic solvents, particularly 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 is as follows: (a) A step of preparing a mixture of bermosdil mesylate in at least one polar solvent, while heating as necessary. (b) A step of stirring the mixture, raising the temperature as necessary, (c) If necessary, preferably a step of cooling the mixture to room temperature, (d) a step of stirring the cooled mixture as necessary, and (e) If necessary, the step of isolating crystalline form M1 of bellmosdil mesylate from the mixture. It may include.

[0071] The mixture in step (a) is (i) A step of preparing a mixture of free bermosdil base in a polar solvent, (ii) A step of combining the mixture with methanesulfonic acid, (iii) A step of heating the increased amount as needed, and (iv) Adding further polar solvents as needed. It can be prepared by [method].

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

[0073] According to any embodiment of the method for preparing form M1, the solvent in step (i) is preferably an organic solvent, particularly 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 a mixture thereof, particularly ethanol, isopropanol, 1-propanol, and n-butanol.

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

[0075] In step (ii) of the method for preparing morphology M1, the step of combining methanesulfonic acid with belmosdil may be in any order. Preferably, methanesulfonic acid may be added to the mixture of belmosdil in the solvent. The addition may be carried out in small amounts or dropwise. Methanesulfonic acid is added as needed in amounts 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 belmosdil. Preferably, step (ii) includes the step of adding methanesulfonic acid to the mixture of belmosdil and solvent.

[0076] In step (iii) of the method for preparing morphology M1, the mixture may be heated as necessary. The heating may be 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 up to 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 bermosudil mesylate, i.e., a solvent in which bermosudil mesylate has low solubility. The additional polar solvent may be the same solvent as the one used in step (i), or it may be different. 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 appropriate 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 in step (a) is (ia) A step of combining bermosdil mesylate with a polar solvent while heating as needed to form a solution, and as needed (ii-a) Step of adding an organic poor solvent It may be prepared by

[0079] The polar solvent in step (ia) 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 (ia), the ratio of solvent to bermosdil mesylate may be about 5 to about 50 ml, about 7 to about 40 ml, about 9 to about 35 ml, or about 10 to about 30 ml per gram of bermosdil mesylate.

[0080] The organic poor solvent in step (ii-a) may be any organic solvent in which bermosdyl 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, and n-butanol, and more specifically ethanol.

[0081] In any embodiment of the method for preparing form M1, the mixture in 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 may be heated. The heating may be 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 morphology M1, step (b) is carried out by stirring at a temperature preferably between about 30°C and about 70°C, about 40°C and about 60°C, about 45°C and about 55°C, or about 50°C. Alternatively, step (b) may be carried out at room temperature. 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 45 minutes.

[0083] In any embodiment of the method for preparing form M1, step (c) is performed. Preferably, cooling is to room temperature. After cooling, step (d) can be performed, preferably by stirring the cooled mixture for an appropriate time, to prepare vermosdil mesylate form M1. Stirring may be performed for any appropriate 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) 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, and more preferably by centrifugation.

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

[0086] This disclosure includes a crystalline polymorph of belmosdyl mesylate designated as morph M2. Crystalline morph M2 of belmosdyl 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 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; and a solid having characteristic peaks at 156.1, 132.7, 135.5, 119.8 and 110.9 ppm ± 0.2 ppm. 13 Solids with the following absolute differences in chemical shifts from a reference peak of 166.9 ppm ± 1 ppm in their 13C NMR spectra: 10.8, 34.2, 36.4, 47.1, and 56.0 ppm ± 0.1 ppm.13 A solid 13C NMR spectrum 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 belsomrazil 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 optionally has 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, and may be further characterized by an X-ray powder diffraction pattern.

[0088] Alternatively, the crystalline form M2 of belsomrazil mesylate may 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 belsomrazil mesylate may be a hydrate, preferably a dihydrate. Alternatively, according to any aspect or embodiment of the present disclosure, the crystalline form M2 of belsomrazil mesylate may contain from about 1% to about 7% by weight of water, preferably from about 1.5% to about 6.1% by weight of water.

[0090] In one embodiment of the present disclosure, the crystalline form M2 of belsomrazil mesylate is isolated. In particular, the crystalline form M2 of belsomrazil 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 belsomrazil mesylate is non-hygroscopic. In particular, the form M2 of belsomrazil 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 bellmosdil mesylate may be characterized by each of the above features individually or in all possible combinations thereof, for example, an XRPD pattern having peaks at 6.3, 12.8, 15.8, 19.3 and 26.5 degrees 2-theta ± 0.2 degrees 2-theta, an XRPD pattern as shown in Figure 7, and combinations thereof.

[0093] The crystalline form M2 of belmosudil mesylate can be prepared by crystallization from a mixture containing belmosudil mesylate and water, and optionally one or more polar organic solvents, preferably alcohols or mixtures thereof. Suitable solvents include, but are not limited to, methanol, isopropanol, l-propanol, and n-butanol. Water may be present in an amount of about 1 to about 60 ml per 1 mmol of belmosudil. In any embodiment, the method is (a) A step of preparing a mixture of water and, if necessary, one or more polar organic solvents containing vermosdil mesylate, while heating as necessary. (b) A step of stirring the mixture, raising the temperature as necessary, (c) A step of cooling the mixture as necessary, (d) a step of stirring the cooled mixture as necessary, and (e) If necessary, the step of isolating crystalline form M2 of bellmosdil mesylate from the mixture. Includes.

[0094] In any embodiment of the method, the mixture of step (a) is (i) A step of preparing a mixture of vermosdil free base in water or a mixture of water and at least one polar organic solvent, (ii) The step of combining the mixture with methanesulfonic acid, (iii) Heating the mixture as needed. It can be prepared by [method].

[0095] According to any embodiment of the method for preparing form M2 of bellmosdil mesylate, the polar organic solvent in step (i) may preferably include an 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, and more preferably the polar organic solvent in step (i) is methanol, ethanol, isopropanol, 1-propanol, or n-butanol, most preferably ethanol.

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

[0097] According to any embodiment of the method for preparing form M2 of belmosudil mesylate, the step of combining methanesulfonic acid with belmosudil in step (ii) may be in any order. Preferably, methanesulfonic acid may be added to the mixture of belmosudil in the solvent. The addition may be carried out in small amounts or dropwise. The methanesulfonic acid is added as needed in amounts 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 belmosudil. Preferably, step (ii) includes the step of adding methanesulfonic acid to the mixture of belmosudil and the solvent.

[0098] In step (iii) of the method for preparing belmosdil form M2, the mixture may be heated as necessary. The heating may be 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 belmosdil mesylate.

[0099] Alternatively, in a method for preparing belmosdil form M2 according to any aspect or embodiment of the present invention, the mixture of step (a) is (ib) A step of preparing a solution by combining bellmosdil mesylate with a polar organic solvent while heating as needed, and (ii-b) Adding water as a poor solvent It may be prepared by a method including

[0100] According to any embodiment of the method for preparing form M2 of bellmosdil mesylate, the polar organic solvent in step (ib) 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 (ib) 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 bellmosdil mesylate.

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

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

[0104] In any embodiment of the method for preparing morphology M2, step (d) may be performed. The stirring may be for any suitable time for preparing morphology M2.

[0105] In any embodiment of the method for preparing crystalline vermosdyl 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, and more preferably by centrifugation.

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

[0107] This disclosure includes a crystalline polymorph of belmosdylmesylate designated as morph M3. Crystalline morph M3 of belmosdylmesylate 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 a combination of these data.

[0108] The crystalline form M3 of bellmosdil mesylate may further be characterized by 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 any one, two, three, four, or five 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 bellmosdil 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, crystalline form M3 of bellmosdilmesylate is isolated.

[0111] The crystalline form M3 of bellmosdil mesylate may be characterized by each of the above features individually or in all possible combinations thereof, 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 Figure 8, and combinations thereof.

[0112] This disclosure includes a crystalline polymorph of belmosdyl mesylate designated as morph M4. Crystalline morph M4 of belmosdyl 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 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 a combination of these data.

[0113] The crystalline form M4 of bellmosdil mesylate may further be characterized by 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 any one, two, three, four, or five additional peaks selected from 11.3, 17.4, 20.9, 24.2, and 29.2 degrees 2-theta ± 0.2 degrees 2-theta.

[0114] Alternatively, the crystalline form M4 of bellmosdil mesylate may 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 2-theta ± 0.2 degrees 2-theta.

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

[0116] The crystalline form M4 of bellmosdil mesylate may be characterized by each of the above features individually or in all possible combinations thereof, for example, 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, an XRPD pattern as shown in Figure 11, and combinations thereof.

[0117] This disclosure includes a crystalline polymorph of belmosdylmesylate designated as morph M5. Crystalline morph M5 of belmosdylmesylate may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 12, an X-ray powder diffraction pattern having peaks at 6.2, 15.7, 18.4, 19.2 and 25.1 degrees 2-theta ± 0.2 degrees 2-theta, and a combination of these data.

[0118] The crystalline form M5 of bellmosdil 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 2-theta ± 0.2 degrees 2-theta, and any one, two, three, four, or five additional peaks selected from 17.8, 21.6, 21.9, 24.7, and 25.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0119] Alternatively, the crystalline form M5 of bellmosdil mesylate may 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 2-theta ± 0.2 degrees 2-theta.

[0120] In one embodiment of this disclosure, crystalline form M5 of bellmosdilmesylate is isolated.

[0121] The crystal morphology M5 of bellmosdil mesylate may be characterized by each of the above features individually or in all possible combinations thereof, for example, 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, an XRPD pattern as shown in Figure 12, and combinations thereof.

[0122] This disclosure includes a crystalline polymorph of belmosdylbesylate designated as morph BS1. Crystalline morph BS1 of belmosdylbesylate may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 13; an X-ray powder diffraction pattern having peaks at 6.6, 12.5, 14.9, 17.0 and 20.1 degrees 2-theta ± 0.2 degrees 2-theta; and a solid having characteristic peaks at 158.9, 146.8, 134.3, 121.3 and 117.6 ppm ± 0.2 ppm. 13 Solids with the following absolute differences in chemical shifts from a reference peak of 169.6 ppm ± 1 ppm in their 13C NMR spectra: 10.7, 22.8, 35.3, 48.3, and 52.0 ppm ± 0.1 ppm. 13 ¹³C NMR spectrum, essentially as shown in any of Figures 22, 23, and 24 for a solid. 13 13C NMR spectra, and combinations of these data.

[0123] The crystalline form BS1 of bellmosdilbesylate may further feature an X-ray powder diffraction pattern having peaks at 6.6, 12.5, 14.9, 17.0, and 20.1 degrees 2-theta ± 0.2 degrees 2-theta, and any one, two, three, four, or five additional peaks selected from 11.6, 17.6, 18.2, 21.7, and 25.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0124] Alternatively, the crystalline form BS1 of bellmosdilbesylate may 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 2-theta ± 0.2 degrees 2-theta.

[0125] The crystalline form BS1 of bellmosdilbesylate may be in an anhydrous form, as can be determined by TGA. In certain embodiments, the disclosure includes crystalline form BS1 of bellmosdilbesylate 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, crystalline form BS1 of bellmosdilbesylate 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 The residual organic solvent may be an alcohol, particularly ethanol, methanol, isopropanol, 1-propanol, or n-butanol, and most preferably ethanol. In particular, the crystalline form BS1 of bellmosdilbesylate according to any aspect or embodiment of this 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 bellmosdilbesylate is isolated. In particular, the crystalline form BS1 of bellmosdilbesylate may be isolated according to any aspect or embodiment of the present disclosure.

[0127] In any aspect or embodiment of this disclosure, the crystalline form BS1 of belmosdil mesylate is nonhygroscopic. In particular, the form BS1 of belmosdil mesylate according to any aspect or embodiment is polymorphically stable at room temperature and a maximum relative humidity of 100% for at least 7 days.

[0128] The crystalline form BS1 of bellmosdilbesylate may be characterized by each of the above features individually or in all possible combinations thereof, 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 bellmosdilbesylate may be prepared by crystallizing from a mixture containing bellmosdilbesylate and a polar solvent such as ethanol. In any embodiment or example, the method is as follows: (a) A step of preparing a mixture of vermosdilbesylate in one or more polar solvents, (b) A step of stirring the mixture, raising the temperature as necessary, (c) A step of cooling the mixture as necessary, and (d) If necessary, the step of isolating the crystalline form BS1 of bellmosdil mesylate from the mixture. Includes.

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

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

[0132] In any aspect or embodiment of the method for preparing form BS1, step (ii) comprises the step of combining benzenesulfonic acid with belmosdil. The combining steps may be in any order. Preferably, benzenesulfonic acid may be added to a mixture of belmosdil in a solvent. The addition may be carried out in small amounts or dropwise. The benzenesulfonic acid is added as needed in amounts 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 belmosdil. Preferably, step (ii) comprises the step of adding benzenesulfonic acid to a mixture of belmosdil and a polar solvent.

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

[0134] In any embodiment of the method for preparing form BS1, step (b) is carried out by stirring at a temperature preferably at room temperature, more preferably at 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. Preferably, stirring is carried out at a certain temperature. Stirring may be carried out for any suitable time to form bermosdilbesylate form BS1. 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.

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

[0136] In any embodiment of the method for preparing morphology 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, and more preferably by centrifugation.

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

[0138] This disclosure includes a crystalline polymorph of belmosdil tosylate designated as morph T1. Crystalline morph T1 of belmosdil 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 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; and a solid having characteristic peaks at 152.6, 143.4, 132.3, 125.3 and 119.8 ppm ± 0.2 ppm. 13 Solids with the following absolute differences in chemical shifts from a reference peak of 168.6 ppm ± 1 ppm in their 13C NMR spectra: 16.0, 25.2, 36.3, 43.3, and 48.8 ppm ± 0.1 ppm. 13 ¹³C NMR spectrum, essentially as shown in any of Figures 26, 27, and 28 of the solid. 1313C NMR spectra, and combinations of these data.

[0139] The crystalline form T1 of bellmosdil tosylate may further be characterized by 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, and any one, two, three, four, or five additional peaks selected from 9.9, 14.5, 16.7, 21.5, and 24.6 degrees 2-theta ± 0.2 degrees 2-theta.

[0140] The crystalline morphology T1 of bellmosdil tosylate may alternatively 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 belmosdil tosylate may be anhydrous, as can be determined by TGA. In certain embodiments, the disclosure includes crystalline form T1 of belmosdil tosylate 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 is one or more polar solvents, preferably water and / or alcohol (especially C 1~4 The residual organic solvent may be an alcohol, particularly ethanol, methanol, isopropanol, 1-propanol, or n-butanol, and most preferably methanol. In particular, the crystalline form T1 of bellmosdil tosylate according to any aspect or embodiment of this disclosure may contain methanol at a concentration of 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, crystalline form T1 of belmosdil tosylate is isolated. In particular, crystalline form T1 of belmosdil tosylate may be isolated according to any aspect or embodiment of the present disclosure.

[0143] In any aspect or embodiment of this disclosure, the crystalline form T1 of belmosdil mesylate is nonhygroscopic. In particular, form T1 of belmosdil mesylate according to any aspect or embodiment is polymorphically stable at room temperature and a maximum relative humidity of 100% for at least 7 days.

[0144] The crystalline form T1 of belmosdil tosylate may be characterized by each of the above features individually or in all possible combinations thereof, 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 Figure 14, and combinations thereof.

[0145] The crystalline form T1 of belmosdil tosylate may be prepared by crystallizing from a mixture containing belmosdil tosylate and one or more polar solvents such as alcohols. Preferably, the solvent is methanol. In any embodiment, the method is: (a) A step of preparing a mixture of bermosdil tosylate in one or more polar solvents, preferably methanol. (b) A step of stirring the mixture, raising the temperature as necessary, (c) A step of cooling the mixture as necessary, and (d) If necessary, the step of isolating crystalline form T1 of bellmosdil tosylate from the mixture. Includes.

[0146] In any embodiment of the method, the mixture in step (a) is (i) A step of preparing a mixture of free bermosdil base in a polar solvent, and (ii) The step of combining the mixture with toluenesulfonic acid. It can be prepared by [method].

[0147] Preferably, the method for preparing form T1 of belmosdil tosylate according to any embodiment described herein is carried out in the absence or substantially absence of water, particularly with 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 aspect or embodiment of the method for preparing form T1, the polar solvent is preferably an alcohol (especially C 1~4 The solvent is an alcohol, particularly ethanol, methanol, isopropanol, 1-propanol, or n-butanol, and most preferably methanol is the polar solvent. In step (i), the ratio of solvent to belmosdil may be about 10 to about 40 ml per gram of belmosdil, about 14 to about 35 ml per gram of belmosdil, or about 16 to about 28 ml per gram of belmosdil, or about 18 to about 24 ml per gram of belmosdil, and optionally about 20 ml per gram of belmosdil. The mixture may be a solution or a slurry.

[0149] In step (ii), the step of combining toluenesulfonic acid with belmosdil may be in any order. Preferably, toluenesulfonic acid may be added to the mixture of belmosdil in the solvent. The addition may be carried out in small amounts or dropwise. The toluenesulfonic acid is added as needed in amounts 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 belmosdil. Preferably, step (ii) includes the step of adding toluenesulfonic acid to the mixture of belmosdil and solvent.

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

[0151] In any embodiment of the method for preparing morphology T1, step (b) is carried out by stirring at a temperature of preferably 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 morphology T1, step (c) is performed, preferably cooling to room temperature.

[0153] In any embodiment of the method for preparing morphology T1, 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, and more preferably by centrifugation.

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

[0155] This disclosure includes a crystalline polymorph of belmosdil tosylate designated as morph T2. Crystalline morph T2 of belmosdil 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; and a solid having characteristic peaks at 141.7, 140.2, 131.1, 125.9 and 124.2 ppm ± 0.2 ppm. 13 Solids with the following absolute differences in chemical shifts from a reference peak of 166.3 ppm ± 1 ppm in their 13C NMR spectra: 24.6, 26.1, 35.2, 40.4, and 42.1 ppm ± 0.1 ppm. 13 ¹³C NMR spectrum, essentially as shown in any of Figures 30, 31, and 32 of the solid-state model. 13 13C NMR spectra, and combinations of these data.

[0156] The crystalline form T2 of bellmosdil tosylate may further be characterized by 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, and any one, two, three, four, or five additional peaks selected from 13.7, 14.2, 14.6, 19.1 and 23.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0157] Alternatively, the crystalline form T2 of bellmosdil tosylate 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 2-theta ± 0.2 degrees 2-theta.

[0158] The crystalline form T2 of belmosdil tosylate may be anhydrous, as can be determined by TGA. In certain embodiments, the disclosure includes crystalline form T2 of belmosdil tosylate having a total residual solvent 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 is one or more polar solvents, preferably water or alcohol (especially C 1~4 The residual organic solvent may be an alcohol, particularly ethanol, methanol, isopropanol, 1-propanol, or n-butanol, and most preferably water and / or ethanol. In particular, the crystalline form T2 of bellmosdil tosylate 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 bellmosdil tosylate is isolated. In particular, the crystalline form T2 of bellmosdil tosylate may be isolated according to any aspect or embodiment of the present disclosure.

[0159] In any aspect or embodiment of this disclosure, the crystalline form T2 of belmosdil mesylate is nonhygroscopic. In particular, form T2 of belmosdil mesylate according to any aspect or embodiment is polymorphically stable at room temperature and a maximum relative humidity of 100% for at least 7 days.

[0160] The crystalline form T2 of belmosdil tosylate may be characterized by each of the above features individually or in all possible combinations thereof, for example, an XRPD pattern having peaks at 5.1, 15.7, 16.4, 19.7 and 23.7 degrees 2-theta ± 0.2 degrees 2-theta, an XRPD pattern as shown in Figure 15, and combinations thereof.

[0161] The crystalline form T2 of belmosdil tosylate may be prepared by crystallizing belmosdil tosylate from a mixture containing one or more polar solvents such as water. In any embodiment, the method is (a) A step of preparing a mixture of bermosdil tosylate in one or more polar solvents, (b) A step of stirring the mixture, raising the temperature as necessary, (c) A step of cooling to room temperature as necessary, and (d) If necessary, the step of isolating the crystalline form T2 of bellmosdil mesylate from the mixture. Includes.

[0162] In any embodiment of the method for preparing morphology T2, the mixture of step (a) is (i) a step of preparing a mixture of free bermosdil base (preferably form B1 as described herein) in a polar solvent preferably containing water and / or ethanol, and (ii) A step of combining the mixture with toluenesulfonic acid by raising the temperature as needed, and (iii) Adding a polar solvent as needed. It may be prepared by

[0163] In any aspect or embodiment of the method for preparing form T2, the polar solvent in step (i) preferably comprises water, and more preferably comprises water. In step (i), the ratio of solvent to belmosdil may be about 10 to about 40 ml per gram of belmosdil, about 14 to about 35 ml per gram of belmosdil, or about 16 to about 28 ml per gram of belmosdil, or about 18 to about 24 ml per gram of belmosdil, about 20 to about 30 ml per gram of belmosdil, and optionally 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) comprises adding toluenesulfonic acid to belmosdil in any order. Preferably, the toluenesulfonic acid may be added to the mixture of belmosdil in the solvent. The addition may be carried out in small amounts or dropwise. The toluenesulfonic acid is added as needed in amounts 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 belmosdil. Preferably, step (ii) comprises adding toluenesulfonic acid to the mixture of belmosdil and the solvent.

[0165] In any aspect or embodiment of the method for preparing morphology T2, the polar solvent in step (iii) 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 bermosdil may be about 20 to about 50 ml, about 20 to about 40 ml, about 22 to about 35 ml, or about 25 ml per gram of bermosdil.

[0166] Alternatively, in any embodiment of the method for preparing morphology T2, the mixture of step (a) may be prepared by combining bellmosdil tosylate with one or more polar solvents. Preferably, the polar solvent is water and / or alcohol (especially C1~4 The solvent 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 morphology T2, step (b) is carried out by stirring at a temperature preferably between about 30°C and about 70°C, about 40°C and about 60°C, about 45°C and 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 morphology 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, and more preferably by centrifugation.

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

[0170] The crystalline polymorphs of belmosdil, or belmosdil mesylate, belmosdil tosylate, and / or belmosdil besylate, can be used in the preparation of belmosdil, belmosdil salts, and other crystalline polymorphs of their solid forms.

[0171] This disclosure encompasses methods for preparing belmosudil, belmosudil salts, and other solid forms thereof. The methods include preparing one of the solid forms of belmosudil or its salts by the methods of this disclosure, and converting the salt to one of the other belmosudil salts. The conversion can be carried out by a method including, for example, basing one or a combination of the above salts, such as belmosudil mesylate, belmosudil tosylate, and / or belmosudil besylate, and / or their solid forms, and reacting the resulting belmosudil base with a suitable acid to obtain the corresponding salt. Alternatively, the conversion may be carried out by salt exchange, i.e., by reacting a belmosudil adduct with an acid having a pKa lower than that of the acid of the original belmosudil adduct.

[0172] This disclosure provides the aforementioned crystalline polymorphs of belmosdil or belmosdil mesylate, belmosdil tosylate, and / or belmosdil besylate, for use in the preparation of pharmaceutical compositions comprising belmosdil, its salts, and / or its crystalline polymorphs.

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

[0174] In any aspect or embodiment of this disclosure, any of the solid forms of belmosudil, belmosudil mesylate, belmosudil tosylate, and / or belmosudil besylate described herein may be polymorphically pure or substantially free of any other solid form of the compound of interest (i.e., belmosudil, belmosudil mesylate, belmosudil tosylate, and / or belmosudil besylate, respectively). In any aspect or embodiment of this disclosure, any of the solid forms of belmosudil, belmosudil mesylate, belmosudil tosylate, and / or belmosudil besylate may preferably contain any other solid form of the compound of interest in amounts of 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% as measured by XRPD. Accordingly, any of the disclosed crystalline forms of belmosudil, belmosudil mesylate, belmosudil tosylate, and / or belmosudil besylate described herein may not substantially contain any other solid form of the compound in question, and may contain more than 80% (w / w), more than 90% (w / w), more than 95% (w / w), more than 98% (w / w), more than 99% (w / w), or more than 100% of the solid form of belmosudil, belmosudil mesylate, belmosudil tosylate, and / or belmosudil besylate.

[0175] This disclosure includes a method for preparing the above-described pharmaceutical compositions. The method includes the step of combining one or a combination of crystalline polymorphs of vermosdil or its salts as described herein with at least one pharmaceutically acceptable excipient.

[0176] The pharmaceutical combinations or formulations of this disclosure contain one or a combination of the solid forms of belmosdil or its salts as disclosed herein. In addition to the active ingredient, the pharmaceutical formulations of this disclosure may contain one or more excipients. Excipients are added to the formulation for various purposes. Preferably, the pharmaceutical compositions or formulations according to any aspect or embodiment of this disclosure are in the form of tablets or capsules, more preferably tablets.

[0177] Diluents can increase the volume of solid pharmaceutical compositions and make the pharmaceutical dosage forms containing the composition easier for patients and caregivers to handle. Examples of diluents for solid compositions include microcrystalline cellulose (e.g., Avicel®), fine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrose, dextrin, dextrose, dicalcium phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylate (e.g., Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0178] Solid pharmaceutical compositions that are densified into dosage forms such as tablets may contain excipients whose function includes assisting in the binding of the active ingredient with other excipients after compression. Examples of binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g., carbopol), sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), hydroxypropylmethylcellulose (e.g., Methocel®), liquid glucose, aluminum magnesium silicate, maltodextrin, methylcellulose, polymethacrylate, povidone (e.g., Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.

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

[0180] Lubricants can be added to improve the fluidity of non-densified solid compositions and enhance the accuracy of drug administration. Excipients that can function as lubricants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tricalcium phosphate.

[0181] When dosage forms such as tablets are produced by densifying a powdered composition, the composition is subjected to pressure from the punch and dye. Some excipients and active ingredients tend to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. Lubricants can be added to the composition to reduce adhesion and facilitate the release of the product from the dye. 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 this disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0183] Solid and liquid compositions may also be stained with any pharmaceutically acceptable colorant to improve their appearance and / or to facilitate patient identification of the product and unit dose levels.

[0184] In the liquid pharmaceutical composition of the present invention, belmosdil 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] Liquid pharmaceutical compositions may contain emulsifiers to uniformly disperse insoluble active ingredients or other excipients throughout the composition. Examples of emulsifiers that may be useful in the liquid compositions of the present invention include gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, hornwort, pectin, methylcellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[0186] The liquid pharmaceutical composition of the present invention may contain viscosity enhancers to improve the mouthfeel of the product and / or to coat the inner lining of the gastrointestinal tract. Examples of such agents include acacia, bentonite alginate, carbomer, calcium or sodium carboxymethylcellulose, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin gum, 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 may be added.

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

[0189] According to this disclosure, the liquid composition may also contain buffering agents 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 excipients can be easily determined by a pharmaceutical scientist based on experience and consideration of standard procedures and references in the art.

[0190] The solid compositions of this disclosure include powders, granules, aggregates, and densifying compositions. Dosages include those suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalation, and ophthalmic administration. The most suitable dose 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 method well known in pharmaceutical technology.

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

[0192] The dosage forms of the present disclosure may be capsules containing the powdered or granular solid composition of the present disclosure in either a hard or soft shell. The shell may be made from gelatin and may optionally contain plasticizers such as glycerin and / or sorbitol, opacifiers and / or colorants.

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

[0194] Compositions for tableting or capsule filling may be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended, then further mixed in the presence of a liquid, typically water, to agglomerate the powder into granules. These granules are sieved and / or pulverized and dried, and then sieved and / or pulverized to the desired particle size. The granules may then be tableted, or other excipients, such as lubricants and / or additives, may be added before tableting.

[0195] Tablet compositions can be prepared by conventional methods, such as by dry blending. For example, a blend of activators and excipients may be densified into a slag or sheet, and then crushed to form densified granules. These densified granules may then be compressed into tablets.

[0196] As an alternative to dry granulation, blended compositions can be directly compressed using direct compression technology to form densified dosage forms. Direct compression produces more uniform tablets that do not contain granules. Excipients particularly well suited for direct compression include microcrystalline cellulose, spray-dried lactose, calcium hydrogen phosphate dihydrate, and colloidal silica. The appropriate use of these and other excipients in direct compression is known to those skilled in the art who have experience and expertise in the specific formulation challenges of direct compression.

[0197] The capsule fillings of this disclosure may include any of the aforementioned blends and granules described in relation to tableting, but they are not subjected to the final tableting process.

[0198] Belmosdil pharmaceutical formulations can be administered. Belmosdil may be formulated for administration by injection to mammals, and in embodiments to humans. Belmosdil may be formulated as a viscous liquid solution or suspension, for example, a clear solution for injection. The formulation may contain one or more solvents. Suitable solvents may be selected considering the physical and chemical stability of the solvent at various pH levels, viscosity (to enable injection), fluidity, boiling point, miscibility, and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and castor oil USP. Further substances, such as buffers, solubilizers, and antioxidants, may be added to the formulation. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition.

[0199] The crystalline polymorphs of belmosdil present disclosure, as well as the pharmaceutical compositions and / or formulations of belmosdil, may, in embodiment, be used for the treatment of graft-versus-host diseases, including chronic graft-versus-host disease; systemic sclerosis, including diffuse cutaneous systemic sclerosis; fibrosis, including idiopathic pulmonary fibrosis; psoriasis vulgaris; systemic sclerosis, particularly chronic graft-versus-host disease and / or systemic sclerosis.

[0200] The Disclosure also provides a method for treating graft-versus-host diseases, including chronic graft-versus-host disease; systemic sclerosis, including diffuse cutaneous systemic sclerosis; fibrosis, including idiopathic pulmonary fibrosis; psoriasis vulgaris; systemic sclerosis, particularly chronic graft-versus-host disease and / or systemic sclerosis, by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of belmosdil of the Disclosure, or at least one of the above-mentioned pharmaceutical compositions and / or formulations, to a subject requiring treatment.

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

[0202] Powder X-ray diffraction ("XRPD") method For Examples 1-9 and 12-15: XRPD analysis was performed using an ARL (SCINTAG) powder X-ray diffractometer Model X'TRA equipped with a solid-state detector. Copper radiation of 1.5418 Å was used. Scanning parameters: Range: 2-40 degrees 2-theta, Scanning mode: Continuous scan, Step size: 0.05°, and Speed: 3 deg / min.

[0203] Examples 10 and 11: XRPD analysis was performed using a Bruker Model D8 ADVANCE powder X-ray diffractometer equipped with a solid-state detector. Copper radiation of 1.54060 Å was used. Scanning parameters: Range: 2-40 degrees 2-theta, Scanning mode, Step size: 0.05°.

[0204] The peak position was corrected for the silicon theory peak at 28.45 degrees 2-theta.

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

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

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

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

[0209] (Example 1) Preparation of amorphous vermosdil Procedure A Methanol (90 ml, 90V) was added to vermosdil (1 g, 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 the solution was cooled to room temperature, it was dried in a spray dryer at Tin=140°C (Tout=78°C). The obtained solid was analyzed by X-ray powder diffraction, and the XRPD pattern is shown in Figure 1.

[0210] Procedure B Methanol (3.5 ml, 70V) was added to belmosdil (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 obtained solid was characterized as amorphous belmosdil by X-ray powder diffraction.

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

[0212] Procedure B Ethanol (0.6 ml, 20V) was added to amorphous belmosdil (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 belmosdil crystalline form B1.

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

[0214] Procedure B Amorphous belmosudil (30 mg, 0.066 mmol) was heated to 160°C by TGA over 0.5 hours. The resulting solid was analyzed by X-ray powder diffraction and identified as belmosudil crystal morphology B2.

[0215] Step C Methanol (12 ml, 400V) was added to amorphous belmosdil (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 belmosdil crystal morphology B2.

[0216] (Example 4) Preparation of crystalline form B3 of bellmosdil Tetrahydrofuran (5 ml, 50V) was added to belmosudil (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 obtained wet solid was analyzed by XRPD and characterized as belmosudil crystal morphology B3. The XRPD pattern is shown in Figure 4.

[0217] (Example 5) Preparation of crystalline form M1 of bellmosdyl mesylate Procedure A Ethanol (4 ml, 20V) was added to bermosudil (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 precipitate was observed. Ethanol (3 ml, 15V) was added to the resulting solid precipitate, and the mixture was magnetically stirred at 50°C for 30 minutes. Next, the precipitate was allowed to cool naturally to room temperature. The solid was separated by centrifugation. The obtained solid was washed twice with ethanol (400 μL, 2V) and dried in a vacuum oven at 45°C for 16 hours to obtain a yellow solid. The obtained solid was analyzed by X-ray powder diffraction and characterized as bermosudil mesylate crystal morphology M1. The XRPD pattern is shown in Figure 5.

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

[0219] Step C Isopropyl alcohol (2 ml, 20V) was added to belmosdil (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, a precipitate was observed, and the mixture was magnetically stirred at 50°C for 30 minutes. The precipitate was then allowed to cool naturally to room temperature. The solid was separated by centrifugation. The obtained solid was washed twice with IPA (200 μL, 2V) to obtain a yellow solid. The obtained solid was analyzed by X-ray powder diffraction and identified as belmosdil mesylate crystal morphology M1.

[0220] Step D N-butanol (2 ml, 20V) was added to belmosdil (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, a precipitate was observed, and the mixture was magnetically stirred at 50°C for 30 minutes. The precipitate was then allowed to cool naturally to room temperature. The solid was separated by centrifugation. The obtained solid was washed twice with N-butanol (200 μL, 2V) to obtain a yellow solid. The obtained solid was analyzed by X-ray powder diffraction and identified as belmosdil mesylate crystal morphology M1.

[0221] Step E 1-propanol (2 ml, 20V) was added to belmosdil (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, a precipitate was observed, and the mixture was magnetically stirred at 50°C for 30 minutes. The precipitate was then allowed to cool naturally to room temperature. The solid was separated by centrifugation. The obtained solid was washed twice with 1-propanol (200 μL, 2V) to obtain a yellow solid. The obtained solid was analyzed by X-ray powder diffraction and identified as belmosdil mesylate crystal morphology M1.

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

[0223] (Example 6) Preparation of crystalline form B4 of bellmosdil Procedure A Methanol (0.6 ml, 20V) was added to bellmosdil form B1 (30 mg, 0.066 mmol) to obtain a slurry. Next, the slurry was magnetically stirred at 50°C for 5 hours. Then, the slurry was cooled to room temperature and magnetically stirred for 16 hours. After that, 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, 25V, 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 one week. Subsequently, the solid was isolated at room temperature by centrifugation. The obtained wet solid was characterized as vermosdil crystal morphology B4 by X-ray powder diffraction.

[0225] (Example 7) Preparation of crystalline form M2 of bellmosdyl mesylate Procedure A Water (2 ml, 20V) 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 another slurry. The slurry was heated to 50°C over 45 minutes to obtain a clear solution. The solution was then allowed to cool naturally to room temperature, and a precipitate was observed. The obtained solid was isolated by centrifugation. The isolated solid was washed twice with water (0.2 ml, 2V) 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 mixture (2 ml, 20V, 1:3) 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 another slurry. The slurry was heated to 50°C over 45 minutes to obtain a clear solution. The solution was then allowed to cool naturally to room temperature, and a precipitate was observed. The obtained solid was isolated by centrifugation. The isolated solid was washed twice with water:ethanol (2.2 ml, 22V, 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 vermosdil mesylate crystal form M2.

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

[0228] Procedure D DMSO (2 ml, 40 V) was added to vermoxil 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. Then, 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 vermoxil mesylate crystal form M2.

[0229] Procedure E 2,2,2-Trifluoroethanol (0.3 ml, 10 V) was added to vermoxil 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. Then, 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 vermoxil mesylate crystal form M2.

[0230] (Example 8) Preparation of Vermoxil Mesylate Crystal Form M3 Procedure A Vermoxil mesylate form M2 (prepared according to Procedure C 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 vermoxil mesylate crystal form M3 by X-ray powder diffraction.

[0231] (Example 9) Preparation of crystalline form B5 of bellmosdil Procedure A 2,2,2-trifluoroethanol (TFE) (0.6 ml, 50V) was added to belmosdil (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 lumpy precipitate was observed. Further addition of TFE (0.1 ml, 10V) was obtained to obtain a slurry. Next, the solid was isolated by centrifugation. The mother liquor was then left to crystallize slowly at 4°C for 20 days. The obtained wet solid was filtered through a Buchner filter, and the solid was characterized as belmosdil crystal morphology B5 by X-ray powder diffraction, and the XRPD pattern is shown in Figure 9.

[0232] (Example 10) Preparation of amorphous vermosdyl mesylate Procedure A Methanol (286 ml, 220V) was added to bellmosdil mesylate form M1 (1.3 g, 2.4 mmol) to obtain a slurry. The slurry was magnetically stirred at 62°C for 45 minutes to obtain a clear solution, which was then 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 bellmosdil mesylate, and the XRPD pattern is shown in Figure 10.

[0233] (Example 11) Preparation of form M4 of bellmosdyl mesylate Procedure A 2,2,2-trifluoroethanol (TFE) (0.7 ml, 7V) was added to bellmosdil 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, 8V) pre-cooled to 4°C to obtain two phases. The solution was stirred at 4°C for 4 days. Next, bellmosdil mesylate M3 (approximately 1 wt%) was seeded into the mixture and stirred for 1 day to obtain a solid precipitate. 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, 7V) was added to bellmosdil 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, 8V) pre-cooled to 4°C to obtain two phases. Next, bellmosdil mesylate form M4 (approximately 1 wt%) was seeded into the mixture and stirred for 1 day to obtain a solid precipitate. 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 bellmosdil mesylate crystalline form M4.

[0235] Step C TFE (0.7 ml, 7V) was added to bellmosdil 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, 8V) pre-cooled to 4°C. Next, bellmosdil mesylate form M4 (approximately 1 wt%) was seeded into the mixture and stirred for 18 hours to obtain a solid precipitate. 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 bellmosdil mesylate crystalline form M4.

[0236] Step D TFE (0.7 ml, 7V) was added to bellmosdil 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, 8V) pre-cooled to 4°C to obtain a lumpy slurry. Next, cyclopentyl methyl ether (0.4 ml, 4V) was added to obtain a slurry. Then, NaCl (approximately 1 wt%) was seeded into the mixture and stirred for 1 hour to obtain a precipitate. 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 bellmosdil mesylate crystal form M4.

[0237] (Example 12) Preparation of form M5 of bellmosdyl mesylate Procedure A DMSO (9 ml, 30V) was added to bellmosdil 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, 30V) containing bellmosdil mesylate form M4 seeds (approximately 1 wt%), which had been pre-cooled to approximately 4°C. Additional cyclopentyl methyl ether (18 ml, 60V) and bellmosdil mesylate form M4 seeds (approximately 1 wt%) were added, and some precipitate was observed after 10 minutes. The mixture was stirred at approximately 4°C for 18 hours to obtain a solid 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 BS1 form of bellmosdilbesylate Procedure A Ethanol (10 ml, 20V) was added to bellmosdil form B1 (500 mg, 1.1 mmol) at room temperature to obtain a slurry. Next, benzenesulfonic acid (192.3 mg, 1.1 equivalents) was added, and the slurry was heated to 50°C over 45 minutes while stirring. The slurry was then allowed to cool naturally to room temperature, and the resulting solid was isolated using centrifugation. 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 form T1 of bellmosdil tosylate Procedure A Methanol (2 ml, 20V) was added to bellmosdil 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 equivalents) was added to obtain a clear solution. After stirring at 50°C for 10 minutes, a precipitate was observed. The solution was stirred at 50°C for 45 minutes. Next, the solution was allowed to cool naturally to room temperature, and a solid precipitate was observed. The obtained solid was isolated by centrifugation and washed once with methanol (200 μL, 2V). 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 form T2 of bellmosdil tosylate Procedure A Water (1 ml, 20V) was added to bellmosdil 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 equivalents) was added, and the viscous slurry was stirred at 50°C for 20 minutes. Then, ethanol (250 μl, 5V) 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 obtained solid was isolated by centrifugation. The isolated solid was washed once with water:ethanol (1 ml, 2V, 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 vermosdil mesylate designated as form M1, wherein: (a) XRPD pattern with peaks at 7.1, 17.2, 20.3, 21.5 and 25.5 degrees 2-theta ± 0.2 degrees 2-theta, (c) 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, and further having any one, two, three, four, or five additional peaks selected from 8.4, 15.5, 16.8, 19.5 and 22.1 degrees 2-theta ± 0.2 degrees 2-theta, (d) 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 2 theta ± 0.2 degrees 2 theta, (e) Solids having characteristic peaks at 137.8, 133.8, 122.5, 118.3 and 111.6 ppm ± 0.2 ppm 13 13C NMR spectrum, (f) Solids having the following absolute differences in chemical shift from a reference peak of 167.2 ppm ± 1 ppm: 29.4, 33.4, 44.7, 48.9, and 55.6 ppm ± 0.1 ppm 13 13C NMR spectrum, and (h) combinations of these data A crystal characterized by data selected from one or more of the following.

2. The crystal according to claim 1, wherein the crystal is in an anhydrous form.

3. The crystal according to claim 1 or 2, which contains 20% or less, 10% or less, 5% or less, 2% or less, or 1% or less of any other crystal of belmosdil mesylate, or which does not contain any other crystal of belmosdil mesylate.

4. A crystal according to any one of claims 1 to 3, containing 20% ​​or less, 10% or less, 5% or less, 2% or less, or 1% or less of amorphous bellmosdil mesylate, or not containing amorphous bellmosdil mesylate.

5. A crystalline form of vermosdil mesylate designated as form M2, wherein: (a) XRPD pattern with peaks at 6.3, 12.8, 15.8, 19.3 and 26.5 degrees 2-theta ± 0.2 degrees 2-theta, (c) An XRPD pattern having peaks at 6.3, 12.8, 15.8, 19.3 and 26.5 degrees 2-theta ± 0.2 degrees 2-theta, and further having any one, two, three, four, or five additional peaks selected from 7.8, 20.4, 23.7, 25.1 and 27.4 degrees 2-theta ± 0.2 degrees 2-theta, (d) 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, (e) Solids having characteristic peaks at 156.1, 132.7, 135.5, 119.8 and 110.9 ppm ± 0.2 ppm 13 13C NMR spectrum, (f) Solids having the following absolute differences in chemical shift from a reference peak of 166.9 ppm ± 1 ppm: 10.8, 34.2, 36.4, 47.1 and 56.0 ppm ± 0.1 ppm 13 13C NMR spectrum, and (h) combinations of these data A crystal characterized by data selected from one or more of the following.

6. The crystal according to claim 5, wherein the crystal is a hydrate.

7. The crystal according to claim 5 or 6, containing 1 to 7% by mass of water.

8. The crystal according to claim 7, containing 1.5 to 6.1% by mass of water.

9. The crystal according to any one of claims 5 to 8, which contains 20% or less, 10% or less, 5% or less, 2% or less, or 1% or less of any other crystal of belmosdil mesylate, or which does not contain any other crystal of belmosdil mesylate.

10. A crystal according to any one of claims 5 to 9, containing 20% ​​or less, 10% or less, 5% or less, 2% or less, or 1% or less of amorphous bellmosdil mesylate, or not containing amorphous bellmosdil mesylate.

11. The crystal according to any one of claims 1 to 10, which is polymorphically stable at room temperature and a maximum relative humidity of 100% for at least 7 days.

12. Use of the crystal according to any one of claims 1 to 11 for the preparation of a pharmaceutical composition.

13. A pharmaceutical composition comprising the crystal according to any one of claims 1 to 11, and at least one pharmaceutically acceptable excipient.

14. A method for preparing the pharmaceutical composition according to claim 13, comprising the step of combining the crystal according to any one of claims 1 to 11 with at least one pharmaceutically acceptable excipient.

15. A crystal according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 13 for use in the treatment of graft-versus-host diseases including chronic graft-versus-host disease, systemic sclerosis including diffuse cutaneous systemic sclerosis, fibrosis including idiopathic pulmonary fibrosis, psoriasis vulgaris, systemic sclerosis, particularly chronic graft-versus-host disease and systemic sclerosis.

16. Use of the crystal according to any one of claims 1 to 11 in the preparation of another solid form of belmosudil, or another salt of belmosudil or its solid form.

17. A method for preparing a belmosudil salt or a solid form thereof, comprising the steps of preparing a crystal according to any one of claims 1 to 11 and converting it into another solid form of belmosudil or another salt or a solid form thereof.

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