Crystalline salt forms of compound

Abstract

Disclosed are crystalline salt forms C and D of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino)-N-(methyl-d3) pyridazine-3-carboxamide, as well as methods for preparing the same. Form C is an MSA salt and Form D is a sulfate of Compound (I). Feature data in the form is disclosed.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202080052992.6 (filing date: June 9, 2020, invention title: Crystalline salt forms of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide).

[0002] This invention relates to cross-reference of related applications

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 860439, filed on June 12, 2019, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0004] This invention generally relates to crystalline salt forms of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, hereinafter referred to as "Form C" and "Form D", respectively. Form C is the MSA salt, and Form D is the sulfate salt of the said compound. Background Art

[0005] The 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide compound has the structure of formula (I):

[0006]

[0007] And is referred to as "Compound (I)". U.S. Patent No. 9,505,748 B2 assigned to the assignee of this invention discloses Compound (I). U.S. Patent No. 9,505,748 B2 also discloses a treatment method using Compound (I).

[0008] Compound (I) is a Tyk2 inhibitor, which is currently in clinical trials for the treatment of autoimmune and autoinflammatory diseases, such as psoriasis, psoriatic arthritis, lupus, lupus nephritis, Sjogren's syndrome, inflammatory bowel disease, Crohn's disease, and ankylosing spondylitis.

[0009] In the synthesis of chemical compounds intended for pharmaceutical use, it is necessary to separate and purify the compound at the end of the synthesis process and before further processing to provide the compound in a pharmaceutical formulation. The separation and purification steps, which can be provided as combined or separate sequential steps, provide the compound in a purified solid form with minimal loss of yield during separation from the other components of the reaction mixture and / or during purification to remove impurities from the separated compound sample.

[0010] It is desirable to provide a solid form that can be reproducibly produced by the separation and / or purification steps.

[0011] Furthermore, it is desirable to isolate the purified compound in a solid form that is physically and chemically stable under a range of storage conditions, such as at different temperature and humidity conditions.

[0012] Furthermore, it is desirable to provide a compound in solid form that has sufficient solubility in a solvent / solution to permit the preparation of other solid forms.

[0013] Furthermore, the applicant has found a crystalline form of compound (I) that surprisingly provides a compound (I) in solid form that is physically and chemically stable under a range of storage conditions and has sufficient solubility in a solvent / solution to permit the preparation of other solid forms.

[0014] Furthermore, the applicant has found a crystalline form of compound (I) that surprisingly provides a compound (I) in solid form that better alleviates the pH effect than other salts tested.

[0015] The present invention also relates to other important aspects. Summary of the Invention

[0016] The present invention provides crystalline Form C and Form D of compound (I). The names used herein to characterize a particular form (e.g., "Form C or Form D", etc.) should not be considered limiting to any other substance having similar or identical physical and chemical characteristics, but should be understood that this name is merely an identifier that should be interpreted in accordance with the characterization information also presented herein. Brief Description of the Drawings

[0017] Figure 1 The observed powder x-ray diffraction pattern (CuKα, at T = 25 °C) of crystalline Form C of compound (I) is shown.

[0018] Figure 2 The differential scanning calorimetry (DSC) thermogram of crystalline Form C of compound (I) is shown.

[0019] Figure 3The thermogravimetric analysis (TGA) thermogram of Form C of compound (I) is shown.

[0020] Figure 4 The 13 C solid-state nuclear magnetic resonance (ssNMR) spectrum (at 280 K) of Form C of compound (I) is shown.

[0021] Figure 5 The observed powder X-ray diffraction pattern (CuKα, at T = 25 °C) of crystalline Form D of compound (I) is shown.

[0022] Figure 6 The differential scanning calorimetry (DSC) thermogram of crystalline Form D of compound (I) is shown.

[0023] Figure 7 The thermogravimetric analysis (TGA) thermogram of Form D of compound (I) is shown. Detailed Description

[0024] After reading the following detailed description, those of ordinary skill in the art can more easily understand the features and advantages of the present invention. It should be understood that, for reasons of clarity, certain features of the present invention described in the context of separate embodiments may also be combined to form a single embodiment. Conversely, for reasons of brevity, the various features of the present invention described in the context of a single embodiment may also be combined to form sub-combinations thereof.

[0025] The names used herein to characterize specific forms (e.g., "Form C", etc.) are merely identifiers to be interpreted based on the characterization information provided herein and should not be construed so as to exclude any other substances having similar or identical physical and chemical characteristics.

[0026] The definitions set forth herein are controlling over any definitions set forth in any patent, patent application, and / or patent application publication incorporated herein by reference.

[0027] All numbers expressing quantities of ingredients, weight percentages, temperatures, etc., preceded by the word "about" are to be understood as approximations only. Thus, minor variations above and below the stated numbers can be used to achieve substantially the same results as the stated numbers. Accordingly, unless indicated to the contrary, the numerical parameters set forth before the word "about" are approximations that can vary depending on the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0028] All measurements are subject to experimental error and are within the spirit of the present invention.

[0029] As used herein, "polymorph" refers to a crystalline form having the same chemical structure but a different spatial arrangement of the molecules and / or ions that form the crystal.

[0030] As used herein, "amorphous" refers to a non-crystalline molecular and / or ionic solid form. An amorphous solid does not exhibit a defined X-ray diffraction pattern with sharp maxima.

[0031] As used herein, "substantially pure", when used in reference to a crystalline form, means a compound having the following purity: greater than 90% by weight, based on the weight of the compound, including greater than 90% by weight, 91% by weight, 92% by weight, 93% by weight, 94% by weight, 95% by weight, 96% by weight, 97% by weight, 98% by weight, and 99% by weight, and also including a compound (I) equal to approximately 100% by weight. The remaining material includes one or more other forms of the compound and / or reaction impurities and / or processing impurities resulting from its preparation. For example, a crystalline form of compound (I) can be considered substantially pure because it has a purity greater than 90% by weight, as measured by means known and generally accepted in the art at the time, where the remaining less than 10% by weight of the material contains an amorphous form of compound (I) and / or one or more other forms and / or reaction impurities and / or processing impurities.

[0032] As used herein, a powder X-ray diffraction (PXRD) pattern that contains a plurality of peaks selected from a specified group of peaks is intended to include a PXRD pattern that has additional peaks not included in the specified group of peaks. For example, a PXRD pattern that contains four or more, more preferably five or more 2θ values selected from A, B, C, D, E, F, G, and H is intended to include a PXRD pattern that has: (a) four or more, more preferably five or more 2θ values selected from the following: A, B, C, D, E, F, G, and H; and (b) zero or more peaks that are not one of peaks A, B, C, D, E, F, G, and H.

[0033] The presence of reaction impurities and / or processing impurities can be determined by analytical techniques known in the art, such as chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry, and / or infrared spectroscopy.

[0034] As used herein, the unit cell parameter "molecules / unit cell" refers to the number of molecules of compound (I) in the unit cell.

[0035] Form C of compound (I)

[0036] In one embodiment, compound (I) is provided as a crystalline material that contains Form C. The crystalline Form C of compound (I) is an MSA salt.

[0037] Table 1. Of Form C at 280K 13C CPMAS chemical shift

[0038] ppm (±0.2) 177.8 163.2 159.8 151.2 146.3 136.0 132.9 127.0 124.7 123.8 121.1 97.5 63.5 40.3 36.7 24.2

[0039] In one embodiment, crystalline Form C of compound (I) is characterized by a powder X-ray diffraction pattern that includes four or more 2θ values in degrees (CuKα) selected from: 7.1 ± 0.2; 7.8 ± 0.2; 9.5 ± 0.2; 10.6 ± 0.2; 11.4 ± 0.2; 12.8 ± 0.2; 15.6 ± 0.2; 17.5 ± 0.2; and 24.1 ± 0.2, wherein the PXRD pattern of Form C is measured at a temperature of about 25 °C;

[0040] In one embodiment, crystalline Form C of compound (I) is characterized by a powder X-ray diffraction pattern that includes five or more 2θ values in degrees (CuKα) selected from: 7.1 ± 0.2; 7.8 ± 0.2; 9.5 ± 0.2; 10.6 ± 0.2; 11.4 ± 0.2; 12.8 ± 0.2; 15.6 ± 0.2; 17.5 ± 0.2; and 24.1 ± 0.2, wherein the PXRD pattern of Form C is measured at a temperature of about 25 °C;

[0041] In one embodiment, crystalline Form C of compound (I) is characterized by a powder X-ray diffraction pattern that includes six or more 2θ values in degrees (CuKα) selected from: 7.1 ± 0.2; 7.8 ± 0.2; 9.5 ± 0.2; 10.6 ± 0.2; 11.4 ± 0.2; 12.8 ± 0.2; 15.6 ± 0.2; 17.5 ± 0.2; and 24.1 ± 0.2, wherein the PXRD pattern of Form C is measured at a temperature of about 25 °C;

[0042] In one embodiment, crystalline Form C of compound (I) is characterized by a powder X-ray diffraction pattern that includes 2θ values in degrees (CuKα) of 7.8 ± 0.2 and 9.5 ± 0.2; and two or more 2θ values in degrees (CuKα) selected from: 7.1 ± 0.2; 10.6 ± 0.2; 11.4 ± 0.2; 12.8 ± 0.2; 15.6 ± 0.2; 17.5 ± 0.2; and 24.1 ± 0.2; wherein the PXRD pattern of Form C is measured at a temperature of about 25 °C.

[0043] In one embodiment, crystalline Form C of compound (I) is characterized by 13A C ssNMR spectrum comprising four or more chemical shift values (all ±0.2) in ppm selected from: 177.8; 163.2; 159.8; 151.2; 146.3; 136.0; 132.9; 127.0; 124.7; 123.8; 121.1; 97.5; 63.5; 40.3; 36.7; and 24.2; wherein the spectrum of Form C is measured at a temperature of about 280K.

[0044] In one embodiment, crystalline Form C of compound (I) is characterized by 13 A C ssNMR spectrum comprising five or more chemical shift values (all ±0.2) in ppm selected from: 177.8; 163.2; 159.8; 151.2; 146.3; 136.0; 132.9; 127.0; 124.7; 123.8; 121.1; 97.5; 63.5; 40.3; 36.7; and 24.2; wherein the spectrum of Form C is measured at a temperature of about 280K.

[0045] In one embodiment, crystalline Form C of compound (I) is characterized by 13 A C ssNMR spectrum comprising six or more chemical shift values (all ±0.2) in ppm selected from: 177.8; 163.2; 159.8; 151.2; 146.3; 136.0; 132.9; 127.0; 124.7; 123.8; 121.1; 97.5; 63.5; 40.3; 36.7; and 24.2; wherein the spectrum of Form C is measured at a temperature of about 280K.

[0046] In one embodiment, crystalline Form C of compound (I) is characterized by (i) a powder X-ray diffraction pattern measured at a temperature of about 25°C, which comprises 2θ values in degrees (CuKα) of 7.8 ± 0.2 and 9.5 ± 0.2; and (ii) a variable endotherm at about 220°C.

[0047] In one embodiment, crystalline Form C of compound (I) is characterized by substantially as Figure 1 The observed powder X-ray diffraction pattern shown.

[0048] In one embodiment, crystalline Form C of compound (I) is characterized by a variable endotherm at about 220°C.

[0049] In one embodiment, crystalline Form C of compound (I) is characterized by substantially as Figure 2 The differential scanning calorimetry (DSC) thermogram shown.

[0050] In one embodiment, crystalline Form C of compound (I) is characterized by (i) a powder X-ray diffraction pattern measured at a temperature of about 25 °C, which comprises 2θ values in degrees (CuKα) of 7.8 ± 0.2 and 9.5 ± 0.2; and (ii) a differential scanning calorimetry (DSC) thermogram substantially according to Figure 2 as shown.

[0051] In one embodiment, crystalline Form C of compound (I) is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of 0.2% or less based on the weight of the Form C sample after heating to a temperature of about 150 °C.

[0052] In one embodiment, crystalline Form C of compound (I) exhibits a thermogravimetric analysis (TGA) thermogram substantially as Figure 3 shown.

[0053] In yet a still further embodiment, crystalline Form C of compound (I) is substantially pure.

[0054] In another embodiment, the crystalline form of compound (I) consists essentially of Form C. The crystalline form of this embodiment may comprise at least about 90 wt.%, preferably at least about 95 wt.%, and more preferably at least about 99 wt.% of Form C of compound (I) based on the weight of the crystalline form.

[0055] One embodiment provides a composition comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95 wt.%, preferably at least 97 wt.%, and more preferably at least 99 wt.% of said 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is in crystalline Form C.

[0056] Form D of compound (I)

[0057] In one embodiment, compound (I) is provided as a crystalline material comprising Form D. Crystalline Form D of compound (I) is a sulfate.

[0058] In one embodiment, crystalline Form D of compound (I) is characterized by unit cell parameters approximately equal to the following:

[0059]

[0060] α = 63.0 ± 0.5°

[0061] β = 80.5 ± 0.5°

[0062] γ = 81.4 ± 0.5°

[0063] Space group: P-1

[0064] Molecules / cell (Z): 2

[0065]

[0066] Calculated density 1.508 g / cm 3

[0067] wherein the unit cell parameters of Form D of the compound (I) are measured at a temperature of about 25 °C.

[0068] In one embodiment, crystalline Form D of compound (I) is characterized by a powder X-ray diffraction pattern that includes four or more 2θ values in degrees (CuKα) selected from: 8.5 ± 0.2; 14.4 ± 0.2; 14.8 ± 0.2; 17.0 ± 0.2; 18.3 ± 0.2; 21.9 ± 0.2; and 27.9 ± 0.2, wherein the PXRD pattern of Form D is measured at a temperature of about 25 °C;

[0069] In one embodiment, crystalline Form D of compound (I) is characterized by a powder X-ray diffraction pattern that includes five or more 2θ values in degrees (CuKα) selected from: 8.5 ± 0.2; 14.4 ± 0.2; 14.8 ± 0.2; 17.0 ± 0.2; 18.3 ± 0.2; 21.9 ± 0.2; and 27.9 ± 0.2, wherein the PXRD pattern of Form D is measured at a temperature of about 25 °C;

[0070] In one embodiment, crystalline Form D of compound (I) is characterized by a powder X-ray diffraction pattern that includes six or more 2θ values in degrees (CuKα) selected from: 8.5 ± 0.2; 14.4 ± 0.2; 14.8 ± 0.2; 17.0 ± 0.2; 18.3 ± 0.2; 21.9 ± 0.2; and 27.9 ± 0.2, wherein the PXRD pattern of Form D is measured at a temperature of about 25 °C;

[0071] In one embodiment, crystalline Form D of compound (I) is characterized by a powder X-ray diffraction pattern that includes 2θ values in degrees (CuKα) of 8.5 ± 0.2 and 18.3 ± 0.2; and two or more 2θ values in degrees (CuKα) selected from: 14.4 ± 0.2; 14.8 ± 0.2; 17.0 ± 0.2; 21.9 ± 0.2; and 27.9 ± 0.2; wherein the PXRD pattern of Form D is measured at a temperature of about 25 °C.

[0072] In one embodiment, crystalline Form D of compound (I) is characterized by (i) a powder X-ray diffraction pattern measured at a temperature of about 25 °C, which comprises 2θ values in degrees (CuKα) of 8.5 ± 0.2 and 18.3 ± 0.2; and (ii) a variable endotherm, wherein the maximum peak is at about 233 °C.

[0073] In one embodiment, crystalline Form D of compound (I) is characterized by substantially as Figure 4 the observed powder X-ray diffraction pattern shown.

[0074] In one embodiment, crystalline Form D of compound (I) is characterized by a variable endotherm, wherein the maximum peak is at about 233 °C.

[0075] In one embodiment, crystalline Form D of compound (I) is characterized by substantially as Figure 5 the differential scanning calorimetry (DSC) thermogram shown.

[0076] In one embodiment, crystalline Form D of compound (I) is characterized by (i) a powder X-ray diffraction pattern measured at a temperature of about 25 °C, which comprises 5θ values in degrees (CuKα) of 8.5 ± 0.2 and 18.3 ± 0.2; and (ii) a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 2 the one shown.

[0077] In one embodiment, crystalline Form D of compound (I) exhibits a thermogravimetric analysis (TGA) thermogram substantially as Figure 6 the one shown.

[0078] In yet a still further embodiment, crystalline Form D of compound (I) is substantially pure.

[0079] In another embodiment, the crystalline form of compound (I) consists essentially of Form D. The crystalline form of this embodiment may comprise at least about 90 wt.%, preferably at least about 95 wt.%, and more preferably at least about 99 wt.% of Form D of compound (I) based on the weight of the crystalline form.

[0080] One embodiment provides a composition comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95 wt.%, preferably at least 97 wt.%, and more preferably at least 99 wt.% of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is in crystalline Form D.

[0081] Crystalline forms can be prepared by various methods, including, for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from the melt, solid-state transformation from another phase, crystallization from a supercritical fluid, and spray spraying. Techniques for crystallizing or recrystallizing a crystalline form from a solvent mixture include, for example, evaporating the solvent, lowering the temperature of the solvent mixture, seeding the supersaturated solvent mixture with the molecule and / or salt, freeze-drying the solvent mixture, and adding an antisolvent (antisolvent) to the solvent mixture. High-throughput crystallization techniques can be used to prepare crystalline forms including polymorphs.

[0082] The crystals of drugs (including polymorphs), methods for preparing drug crystals, and characterization are discussed in Solid-State Chemistry of Drugs, S.R. Byrn, R.R. Pfeiffer and J.G. Stowell, 2nd Edition, SSCI, West Lafayette, Indiana (1999).

[0083] For crystallization techniques using solvents, the choice of one or more solvents generally depends on one or more factors such as the solubility of the compound, the crystallization technique, and the vapor pressure of the solvent. Combinations of solvents can be used. For example, the compound can be dissolved in a first solvent to provide a solution, and then an antisolvent is added to reduce the solubility of the compound in the solution and provide crystal formation. An antisolvent is a solvent in which the compound has low solubility.

[0084] In one method of preparing crystals, the compound is suspended and / or stirred in a suitable solvent to provide a slurry, which can be heated to facilitate dissolution. As used herein, the term "slurry" means a saturated solution of the compound, which may also contain additional amounts of the compound to provide a non-uniform mixture of the compound and the solvent at a given temperature.

[0085] Seeds can be added to any crystallization mixture to promote crystallization. Seeds can be used to control the growth of a specific polymorph or to control the particle size distribution of the crystallization product. Thus, the calculation of the amount of seeds required depends on the available seeds and the desired size of the average product particles, as described, for example, in "Programmed Cooling of Batch Crystallizers," J.W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369-377. Generally, small-sized seeds are required to effectively control the growth of crystals in a batch. Small-sized seeds can be produced by sieving, grinding, or micronizing large crystals, or by microcrystallization of a solution. It should be noted that the grinding or micronizing of crystals does not result in any change in the form of crystallinity (i.e., becoming amorphous or another polymorph) compared to the desired crystal form.

[0086] The cooled crystallization mixture can be filtered under vacuum, and the separated solid can be washed with a suitable solvent (such as a cold recrystallization solvent) and dried under a nitrogen purge to provide the desired crystalline form. The separated solid can be analyzed by suitable spectroscopic or analytical techniques (such as solid-state nuclear magnetic resonance, differential scanning calorimetry, powder x-ray diffraction, etc.) to ensure the formation of the preferred crystalline form of the product. The resulting crystalline form is typically produced in an amount greater than about 70% by weight, preferably greater than 90% by weight, based on the weight of the compound initially used in the crystallization procedure. If desired, the product can be co-ground or passed through a sieve to deblock the product.

[0087] The crystalline form can be prepared directly from the reaction medium of the final process for preparing compound (I). This can be achieved, for example, by using a solvent or a solvent mixture in the final process step from which compound (I) can crystallize. Alternatively, the crystalline form can be obtained by distillation or solvent addition techniques. Suitable solvents for this purpose include, for example, the aforementioned non-polar solvents and polar solvents, including protic polar solvents (such as alcohols) and aprotic polar solvents (such as ketones).

[0088] The presence of more than one polymorph in a sample can be determined by techniques such as powder X-ray diffraction (PXRD) or solid-state nuclear magnetic resonance (ssNMR) spectroscopy. For example, when comparing an experimentally measured PXRD pattern to a simulated PXRD pattern, the presence of additional peaks may indicate more than one polymorph in the sample. Simulated PXRD can be calculated from single-crystal X-ray data. See Smith, D.K., “A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns,” Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963).

[0089] Forms C and D of compound (I) can be characterized using a variety of techniques, the operation of which is well known to those of ordinary skill in the art. Single-crystal X-ray diffraction can be used to characterize and distinguish the forms, which is based on the measurement of the unit cell of a single crystal at a fixed analysis temperature. A detailed description of the unit cell is provided in Stout and Jensen, X-Ray Structure Determination: A Practical Guide, Macmillan Co., New York (1968), Chapter 3, which is incorporated herein by reference. Alternatively, another means of characterizing the crystal structure is by powder X-ray diffraction analysis (wherein the diffraction spectrum is compared to a simulated spectrum representative of the pure powder material, both run at the same analysis temperature) and measurement of the subject form (characterized as a series of 2θ values in degrees (usually four or more)).

[0090] Other means of characterizing the forms can be used, such as solid-state nuclear magnetic resonance, differential scanning calorimetry, thermal analysis, and vibrational spectroscopy. These parameters can also be used in combination to characterize the subject forms.

[0091] Utility

[0092] Crystalline forms C and D of compound (I) can be used to separate compound (I) from other components upon completion of the synthesis process; and / or to purify compound (I) by one or a series of crystallization steps. The separation and purification steps can be combined or practiced as separate method steps.

[0093] Examples

[0094] The present invention will now be further described by means of one or more working examples, which are preferred embodiments of the present invention. Unless otherwise indicated, all temperatures are in degrees Celsius (°C). These examples are illustrative and not restrictive, and it should be understood that other embodiments may exist that fall within the spirit and scope of the present invention as defined by the appended claims.

[0095] For ease of reference, the following abbreviations may be used herein.

[0096] Abbreviation

[0097]

[0098]

[0099] Example 1: Preparation of Crystalline Form C of Compound (I)

[0100] A solution was prepared by mixing 360 mg of Compound I into 23 mL of THF and 1 mL of water at room temperature (25 °C) until completely dissolved, and 55 μL of methanesulfonic acid was added thereto. The resulting slurry was dried overnight using a Speedvac. 90 mg of the dried solid was suspended in 1 ml of BuOAc at 60 °C, and the resulting slurry was aged overnight at 60 °C. The slurry was filtered and the wet cake was dried in a vacuum oven at a temperature in the range of 50 °C - 60 °C to provide Compound I in Form C.

[0101] Example 2: Preparation of Crystalline Form C of Compound (I)

[0102] A solution was prepared by mixing 550 mg of Compound I into 35 mL of THF and 2 mL of water at room temperature (25 °C) until completely dissolved, and 84 μL of methanesulfonic acid was added thereto. The resulting slurry was dried overnight using a Speedvac. The dried solid was suspended in 5 ml of BuOAc at 60 °C, and the resulting slurry was aged overnight at 60 °C. The slurry was filtered and the wet cake was dried in a vacuum oven at a temperature in the range of 50 °C - 60 °C to provide Compound I in Form C.

[0103] Example 3: Preparation of Crystalline Form D of Compound (I)

[0104] A solution was prepared by mixing 50 mg of Compound I and 0.5 ml of 0.25 M H2SO4 into 2 ml of acetone and heating to 55 °C. The mixture was stirred overnight at 55 °C, after which the heating was turned off and the mixture was allowed to stand overnight at room temperature without stirring, yielding crystals of Form D.

[0105] Example 4: Preparation of Crystalline Form D of Compound (I)

[0106] A solution was prepared by mixing 550 mg of Compound I into 35 mL of THF and 2 mL of water at room temperature (25 °C) until completely dissolved, and adding 72 μL of 96% H2SO4 thereto. The resulting slurry was dried overnight using a Speedvac. The dried solid was suspended in 5 ml of BuOAc at 60 °C, and the resulting slurry was aged overnight at 60 °C. The slurry was filtered and the wet cake was dried in a vacuum oven at a temperature in the range of 50 °C - 60 °C to afford Compound I in Form D.

[0107] Form C

[0108] PXRD

[0109] X-ray powder diffraction (PXRD) data was obtained using a Bruker C2 GADDS with a Vantec-500 detector. The radiation was Cu Kα (40 kV, 40 mA). The sample-detector distance was approximately 20 cm. The incident optics included a Goebel mirror and a 0.3 mm collimator. The powder sample was placed in a sealed glass capillary with a diameter of 1 mm or less; the capillary was rotated during data collection. Data was collected for 2 ≤ 2θ ≤ 35°, with a sample exposure time of at least 1000 seconds. The resulting two-dimensional diffraction arcs were integrated to establish a conventional one-dimensional PXRD pattern in the range of approximately 2 to approximately 30 degrees 2θ, with a step size of 0.05 degrees 2θ.

[0110] DSC

[0111] Differential scanning calorimetry (DSC) experiments were performed in a TA Instruments TM Model Q1000. Samples (approximately 2 - 6 mg) were weighed in aluminum pans and accurately recorded to the nearest hundredth of a milligram, and transferred to the DSC. The instrument was purged with nitrogen at 50 mL / min. Data was collected at a heating rate of 10 °C / min between room temperature and 300 °C. Plots were made with endothermic peaks pointing downwards.

[0112] TGA

[0113] Thermogravimetric analysis (TGA) experiments were performed in a TA Instruments TM Model Q500. Samples (approximately 10 - 30 mg) were placed in pre-tared platinum pans. The weight of the samples was accurately measured and recorded by the instrument to the nearest thousandth of a milligram. The furnace was purged with nitrogen at 100 mL / min. Data was collected at a heating rate of 10 °C / min between room temperature and 300 °C.

[0114] Solid state nuclear magnetic resonance (ssNMR)

[0115] Carbon-13 cross-polarization magic angle spinning (CPMAS) solid-state NMR experiments were performed on a Bruker AVIII instrument operating at a proton frequency of 500 MHz. The solid sample was spun at 13 kHz in a 4 mm ZrO2 rotor. The contact time was 4 ms, and ramping from 50% to 100% was performed on the proton channel (A.E. Bennett et al., J. Chem. Phys., 1995, 103, 6951), (G. Metz, X. Wu and S.O. Smith, J. Magn. Reson. A., 1994, 110, 219-227). The relaxation delay was maintained at 5x 1 HT1 of the API, which was 9.1 s. Proton decoupling was applied using a TPPM sequence with a 4.2 μs pulse (59.5 kHz nominal bandwidth). The spectral sweep width was 300 ppm, centered at 100 ppm. 4380 data points were acquired (giving a digital resolution of 20 Hz) and zero-filled to 8192, followed by apodization with 20 Hz line broadening. 1024 free induction decays were co-added. The spectra were indirectly referenced to TMS using 3-methylglutaric acid (D. Barich, E. Gorman, M. Zell and E. Munson, Solid State Nuc. Mag. Res., 2006, 30, 125-129). Approximately 70 mg of sample was used for each experiment. The temperature was set at 280 K.

[0116] Form D

[0117] Single crystal data

[0118] Single-crystal X-ray data were collected on a Bruker X8-Proteum diffractometer equipped with an APEX II CCD detector and a MICROSTAR microfocus rotating anode X-ray generator with monochromated Cu Kα radiation. The single crystal was at room temperature (ca. 25 °C) during data collection.

[0119] The final cell parameters were obtained by least-squares refinement using setting angles for 6414 reflections in the range 3.99° < θ < 60.10°. The structure was solved by direct methods using SHELXS-97 software and refined by full-matrix least-squares using SHELXL-97 software (Sheldrick, G.M. (2015). Acta Cryst. C71, 3-8.). Structure refinement involved minimizing the function defined by ∑w(|F o |-|F c |) 2 where w is a suitable weighting factor based on the errors of the observed intensities, F ois based on the measured structure factor of the reflection, and F c is based on the calculated structure factor of the reflection. By using the residual factor R = ∑||F o |-|F c || / ∑|F o | and wR = [∑w(|F o |-|F c |) 2 / ∑w|F o |] 1 / 2 the agreement between the refined crystal structure model and the experimental X-ray diffraction data is evaluated. Difference Fourier maps are inspected at all stages of the refinement. All non-hydrogen atoms are refined using anisotropic thermal displacement parameters. Hydrogen atoms are refined independently.

[0120] PXRD

[0121] X-ray powder diffraction (PXRD) data were obtained using a Bruker C2 GADDS with a Vantec-500 detector. The radiation was Cu Kα (40 kV, 40 mA). The sample-detector distance was approximately 20 cm. The incident optics included a Goebel mirror and a 0.3 mm collimator. The powder sample was placed in a sealed glass capillary with a diameter of 1 mm or less; the capillary was rotated during data collection. Data were collected for 2 ≤ 2θ ≤ 35°, with a sample exposure time of at least 1000 s. The resulting two-dimensional diffraction arcs were integrated to create a conventional one-dimensional PXRD pattern in the range of approximately 2 to approximately 30 degrees 2θ, with a step size of 0.05 degrees 2θ.

[0122] DSC

[0123] Differential scanning calorimetry (DSC) experiments were performed in a TA Instruments TM Model Q1000. Samples (approximately 2 - 6 mg) were weighed in aluminum pans and accurately recorded to the nearest milligram, and transferred to the DSC. The instrument was purged with nitrogen at 50 mL / min. Data were collected at a heating rate of 10 °C / min between room temperature and 300 °C. Plots were made with endothermic peaks pointing downwards.

[0124] TGA

[0125] Thermogravimetric analysis (TGA) experiments were performed in a TA Instruments TM Model Q500. Samples (approximately 10 - 30 mg) were placed in pre-tared platinum pans. The weight of the samples was accurately measured and recorded by the instrument to the nearest microgram. The furnace was purged with nitrogen at 100 mL / min. Data were collected at a heating rate of 10 °C / min between room temperature and 300 °C.

Claims

1. The crystalline form C of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

2. The crystalline form according to claim 1, characterized in that A powder X-ray diffraction pattern comprising five or more 2θ values in degrees (CuKα) selected from: 7.1 ± 0.2; 7.8 ± 0.2; 9.5 ± 0.2; 10.6 ± 0.2; 11.4 ± 0.2; 12.8 ± 0.2; 15.6 ± 0.2; 17.5 ± 0.2; and 24.1 ± 0.2, wherein the PXRD pattern of said form C is measured at a temperature of about 25 °C.

3. The crystalline form according to claim 1, wherein A powder X-ray diffraction pattern comprising 2θ values in degrees (CuKα) of 7.8 ± 0.2 and 9.5 ± 0.2; and two or more 2θ values in degrees (CuKα) selected from: 7.1 ± 0.2; 10.6 ± 0.2; 11.4 ± 0.2; 12.8 ± 0.2; 15.6 ± 0.2; 17.5 ± 0.2; and 24.1 ± 0, wherein the PXRD pattern of said form C is measured at a temperature of about 25 °C.

4. The crystalline form according to claim 1, characterized in that (i) Powder X-ray diffraction pattern measured at a temperature of about 25 °C, which contains 2θ values in degrees (CuKα) of 7.8 ± 0.2 and 9.5 ± 0.2; and (ii) 13 13C ssNMR spectrum, which contains five or more chemical shift values in ppm (all ± 0.2) selected from the following: 177.8; 163.2; 159.8; 151.2; 146.3; 136.0; 132.9; 127.0; 124.7; 123.8; 121.1; 97.5; 63.5; 40.3; 36.7 and 24.2; wherein the spectrum of Form C is measured at a temperature of about 280 °K.

5. The crystalline form according to claim 1, which consists essentially of form C.

6. The crystalline form according to claim 1, wherein said form C is in a substantially pure form.

7. A composition comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95 wt.% of said 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is in crystalline form C.

8. The crystalline form D of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

9. The crystalline form according to claim 8, characterized in that the following at least one of: i) A powder X-ray diffraction pattern comprising four or more 2θ values in degrees (CuKα) selected from: 8.5 ± 0.2; 14.4 ± 0.2; 14.8 ± 0.2; 17.0 ± 0.2; 18.3 ± 0.2; 21.9 ± 0.2; and 27.9 ± 0.2, wherein the PXRD pattern of said form D is measured at a temperature of about 25 °C; or (ii) The observed powder X-ray diffraction pattern substantially as shown in Figure 5; or (iii) The unit cell parameters substantially equal to: α＝63.0±0.5° β＝80.5±0.5° γ = 81.4 ± 0.5 ° Space group: P-1 Molecules / cell (Z): 2 wherein the unit cell parameters of form D of said compound (I) are measured at a temperature of about 25 °C.

10. The crystalline form according to claim 8, wherein Powder X-ray diffraction pattern comprising five or more 2θ values in degrees (CuKα) selected from: 8.5 ± 0.2; 14.4 ± 0.2; 14.8 ± 0.2; 17.0 ± 0.2; 18.3 ± 0.2; 21.9 ± 0.2; and 27.9 ± 0.2, wherein the PXRD pattern of Form D is measured at a temperature of about 25 °C.

11. The crystalline form according to claim 8, wherein Powder X-ray diffraction pattern comprising 2θ values in degrees (CuKα) of 8.5 ± 0.2 and 18.3 ± 0.2; and two or more 2θ values in degrees (CuKα) selected from: 14.4 ± 0.2; 14.8 ± 0.2; 17.0 ± 0.2; 21.9 ± 0.2; and 27.9 ± 0.2, wherein the PXRD pattern of Form D is measured at a temperature of about 25 °C.

12. The crystalline form according to claim 8, which consists essentially of Form D.

13. The crystalline form according to claim 8, wherein Form D is in a substantially pure form.

14. A composition comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95 wt.% of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is in crystalline Form D.

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