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

Abstract

To provide 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.SOLUTION: 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. Form C is an MSA salt of Compound (I), and Form D is a sulfate salt thereof. Characterization data for the Forms are disclosed.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 860,439, filed June 12, 2019, the disclosure of which is incorporated herein by reference in its entirety.

[0002] The present 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, designated herein as "Form C" and "Form D," respectively. Form C is the MSA salt of the compound, and Form D is the sulfate salt. [Background technology]

[0003] The compound 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide has the formula (I): [ka] and is referred to herein as "Compound (I)." Compound (I) is disclosed in commonly assigned U.S. Pat. No. 9,505,748 B2. U.S. Pat. No. 9,505,748 B2 also discloses a method of treatment using Compound (I).

[0004] Compound (I) is a Tyk2 inhibitor 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.

[0005] In the synthesis of chemical compounds intended for pharmaceutical use, it is necessary to isolate and purify the compound upon completion of the synthesis process and prior to further processing to provide the compound as a pharmaceutical formulation. The isolation and purification steps may be combined or may be separate, sequential steps, providing the compound as a purified solid with minimal loss in yield during isolation from other components of the reaction mixture and / or during purification to remove impurities from an isolated compound sample.

[0006] It is desirable to provide a solid form that can be reproducibly produced from the isolation and / or purification steps.

[0007] Additionally, the purified compound is preferably isolated in a solid form that is physically and chemically stable under a range of storage conditions, such as different conditions of temperature and humidity.

[0008] Additionally, it is desirable to provide a solid form of the compound that has sufficient solubility in the solvent / solution to allow for the preparation of other solid forms.

[0009] Additionally, applicants have surprisingly discovered a crystalline form of Compound (I) that provides a solid form of Compound (I) that is physically and chemically stable over a range of storage conditions and has sufficient solubility in solvents / solutions to enable the preparation of other solid forms.

[0010] Additionally, applicants have surprisingly discovered a crystalline form of Compound (I) that provides Compound (I) in a solid form that mitigates pH effects more than other salts tested. The present invention also relates to other important aspects. Summary of the Invention

[0011] The present invention provides crystalline Form C and Form D of Compound (I). It should be understood that the designations used herein to characterize a particular form, such as "Form C or Form D," should not be considered limiting with respect to any other substance having similar or identical physical and chemical properties, but rather are merely identifiers that should be interpreted in accordance with the property information also presented herein. [Brief explanation of the drawings]

[0012] [Figure 1] FIG. 1 shows the observed powder X-ray diffraction pattern (CuKα, T=25° C.) of crystalline Form C of Compound (I). [Figure 2] FIG. 2 shows a differential scanning calorimetry (DSC) thermogram of crystalline Form C of Compound (I). [Figure 3] FIG. 3 shows a thermogravimetric analysis (TGA) thermogram of Form C of Compound (I). [Figure 4] FIG. 4 shows the 13C solid-state nuclear magnetic resonance (ssNMR) spectrum (280 K) of Form C of Compound (I). [Figure 5] FIG. 5 shows the observed powder X-ray diffraction pattern (CuKα, T=25° C.) of crystalline form D of Compound (I). [Figure 6] FIG. 6 shows a differential scanning calorimetry (DSC) thermogram of crystalline form D of Compound (I). [Figure 7] FIG. 7 shows a thermogravimetric analysis (TGA) thermogram of Form D of Compound (I).

[0013] Detailed Description of the Invention The features and advantages of the present invention will be more readily understood by those skilled in the art upon reading the following detailed description. It should be understood that, for clarity, certain features of the present invention described above and below in the context of separate embodiments may also be combined to form a single embodiment. Conversely, various features of the present invention that are, for brevity, described in the context of a single embodiment, may also be combined to form subcombinations thereof.

[0014] Designations used herein to characterize particular forms, such as "Form C," are merely identifiers that should be interpreted in accordance with the properties information set forth herein, and are not intended to be limiting to the exclusion of any other materials having similar or identical physical and chemical properties.

[0015] The definitions set forth herein take precedence over definitions set forth in any patent, patent application, and / or patent application publication incorporated herein by reference.

[0016] All numerical values ​​preceded by the term "about" expressing amounts of ingredients, weight percent, temperatures, and the like, should be understood as approximations only, where small variations above and below the stated value can be used to achieve substantially the same results as the stated number. Thus, unless otherwise indicated, numerical parameters preceded by the term "about" are approximations that may vary depending upon the nature of the objective sought to be achieved. 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.

[0017] All measurements are subject to experimental error and are within the scope of the present invention.

[0018] As used herein, "polymorph" refers to crystalline forms that have the same chemical structure but different spatial arrangements of the molecules and / or ions that form the crystal.

[0019] As used herein, "amorphous" refers to a solid form of molecules and / or ions that is not crystalline. Amorphous solids do not exhibit a characteristic X-ray diffraction pattern with sharp maxima.

[0020] As used herein, "substantially pure," when used in reference to a crystalline form, refers to a compound having a purity of 90% by weight or greater of Compound (I), such as 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99% by weight or greater, and also equivalent to about 100% by weight, based on the weight of the compound. The remaining material includes other forms of the compound, and / or reaction impurities, and / or process impurities resulting from its manufacture. For example, a crystalline form of Compound (I) can be considered substantially pure having a purity of 90% by weight or greater, as measured by methods currently known and generally accepted in the art, wherein the remaining less than 10% by weight of the material includes amorphous and / or other forms of Compound (I), and / or reaction impurities and / or process impurities.

[0021] As used herein, a powder X-ray diffraction (PXRD) pattern comprising a number of peaks selected from a particular group of peaks is intended to include a PXRD pattern having additional peaks not included in the particular group of peaks. For example, a PXRD pattern comprising four or 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 having (a) four or more, preferably five or more 2θ values ​​selected from A, B, C, D, E, F, G, and H; and (b) zero or more peaks that are not any of the peaks of A, B, C, D, E, F, G, and H.

[0022] The presence of reaction and / or process impurities may be determined by analytical techniques known in the art, such as, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectroscopy, and / or infrared spectroscopy.

[0023] As used herein, the unit cell parameter "molecules per unit cell" refers to the number of molecules of Compound (I) in a unit cell.

[0024] Form C of Compound (I) In certain embodiments, Compound (I) is provided as a crystalline material comprising Form C. Crystalline Form C of Compound (I) is an MSA salt. Table 1. 13C CPMAS chemical shift values ​​for Form C at 280 K [Table 1]

[0025] In certain embodiments, crystalline Form C of Compound (I) is characterized by a powder X-ray diffraction pattern comprising four or more 2θ values ​​at frequencies (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.

[0026] In certain embodiments, crystalline Form C of Compound (I) is characterized by 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 Form C is measured at a temperature of about 25° C.

[0027] In certain embodiments, crystalline Form C of Compound (I) is characterized by a powder X-ray diffraction pattern comprising six or more 2θ values ​​at frequencies (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.

[0028] In certain embodiments, crystalline Form C of Compound (I) is characterized by a powder X-ray diffraction pattern comprising 2θ values ​​at 7.8±0.2 and 9.5±0.2 degrees (CuKα), and three or more 2θ values ​​at 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.

[0029] In certain embodiments, crystalline Form C of Compound (I) comprises four or more chemical shift values ​​at ppm (all ±0.2) 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. 13 It is characterized by a C ssNMR spectrum; where the spectrum of Form C is measured at a temperature of about 280K.

[0030] In certain embodiments, crystalline Form C of Compound (I) comprises five or more chemical shift values ​​at ppm (all ±0.2) 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. 13 It is characterized by a C ssNMR spectrum, where the spectrum of Form C is measured at a temperature of about 280K.

[0031] In certain embodiments, crystalline Form C of Compound (I) comprises six or more chemical shift values ​​at ppm (all ±0.2) 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. 13 It is characterized by a C ssNMR spectrum, where the spectrum of Form C is measured at a temperature of about 280K.

[0032] In certain embodiments, crystalline form C of Compound (I) is characterized by (i) a powder X-ray diffraction pattern comprising 2θ values ​​at 7.8±0.2 and 9.5±0.2 degrees (CuKα), measured at a temperature of about 25°C; and (ii) a variable endotherm at about 220°C.

[0033] In certain embodiments, crystalline Form C of Compound (I) is characterized by an observed powder X-ray diffraction pattern substantially as shown in FIG.

[0034] In certain embodiments, crystalline form C of Compound (I) is characterized by a variable endotherm at about 220°C.

[0035] In certain embodiments, crystalline Form C of Compound (I) is characterized by a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG.

[0036] In certain embodiments, crystalline Form C of Compound (I) is characterized by (i) a powder X-ray diffraction pattern comprising 2θ values ​​at 7.8±0.2 and 9.5±0.2 degrees (CuKα); and (ii) a differential scanning calorimetry (DSC) thermogram substantially in accordance with that shown in FIG. 2.

[0037] In certain embodiments, 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 a sample of Form C, when heated to a temperature of about 150° C.

[0038] In certain embodiments, crystalline Form C of Compound (I) exhibits a thermogravimetric analysis (TGA) thermogram substantially as shown in FIG.

[0039] In still further embodiments, crystalline Form C of Compound (I) is substantially pure.

[0040] 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%, preferably at least about 95%, and more preferably at least about 99%, by weight, based on the weight of Form C of Compound (I), which is the crystalline form.

[0041] An 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% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight 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 crystalline form C.

[0042] Form D of Compound (I) In certain embodiments, Compound (I) is provided as a crystalline material comprising Form D. Crystalline Form D of Compound (I) is a sulfate salt.

[0043] In certain embodiments, crystalline form D of Compound (I) has the following structure: a=8.49±0.05Å b=12.39±0.05Å c=12.52±0.05Å α=63.0±0.5° β=80.5±0.5° γ=81.4±0.5° Space group: P-1 Molecules per unit cell (Z): 2 Unit cell volume = 1153 ± 10 Å 3 Calculated density 1.508g / cm 3 wherein the unit cell parameters of Form D of Compound (I) are measured at a temperature of about 25°C.

[0044] In certain embodiments, crystalline Form D of Compound (I) is characterized by 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 Form D is measured at a temperature of about 25° C.

[0045] In certain embodiments, crystalline Form D of Compound (I) is characterized by a powder X-ray diffraction pattern comprising five or more 2θ values ​​at frequencies (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.

[0046] In certain embodiments, crystalline Form D of Compound (I) is characterized by a powder X-ray diffraction pattern comprising 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.

[0047] In certain embodiments, crystalline Form D of Compound (I) is characterized by a powder X-ray diffraction pattern comprising 2θ values ​​at degrees (CuKα) of 8.5±0.2 and 18.3±0.2; and three or more 2θ values ​​at 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.

[0048] In certain embodiments, crystalline form D of compound (I) is characterized by (i) a powder X-ray diffraction pattern comprising 2θ values ​​at 8.5±0.2 and 18.3±0.2 degrees (CuKα), measured at a temperature of about 25° C.; and (ii) a variable endotherm with a peak maximum at about 233° C.

[0049] In certain embodiments, crystalline Form D of Compound (I) is characterized by an observed powder X-ray diffraction pattern substantially as shown in FIG.

[0050] In certain embodiments, crystalline form D of Compound (I) is characterized by a variable endotherm with a peak maximum at about 233°C.

[0051] In certain embodiments, crystalline Form D of Compound (I) is characterized by a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG.

[0052] In certain embodiments, crystalline form D of compound (I) is characterized by (i) a powder X-ray diffraction pattern comprising 2θ values ​​at 8.5±0.2 and 18.3±0.2 degrees (CuKα), measured at a temperature of about 25° C.; and (ii) a differential scanning calorimetry (DSC) thermogram substantially in accordance with that shown in FIG. 5.

[0053] In certain embodiments, crystalline Form D of Compound (I) exhibits a thermogravimetric analysis (TGA) thermogram substantially as shown in FIG.

[0054] In still further embodiments, crystalline form D of Compound (I) is substantially pure.

[0055] 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%, preferably at least about 95%, and more preferably at least about 99%, by weight, based on the weight of Form D of Compound (I), which is the crystalline form.

[0056] An 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% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight 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 crystalline form D.

[0057] Crystalline forms can be prepared by a variety of methods, such as, for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from the melt, solid-state phase transformation from another phase, crystallization from supercritical fluids, and jet spray. Techniques for crystallizing or recrystallizing crystalline forms from solvent mixtures include, for example, evaporation of the solvent, lowering the temperature of the solvent mixture, seeding a supersaturated solvent mixture of the molecule and / or salt with crystals, freeze-drying the solvent mixture, and adding an anti-solvent to the solvent mixture. High-throughput crystallization techniques can be used to prepare crystalline forms, including polymorphs.

[0058] Drug crystals, including polymorphs, methods of preparation, and properties of drug crystals are described in Solid-State Chemistry of Drugs, SR Byrn, RR Pfeiffer, and JG Stowell, 2nd Edition, SSCI, West Lafayette, Indiana (1999).

[0059] For the crystallization technique using solvent, the choice of solvent generally depends on one or more factors such as the solubility of compound, crystallization technique, and the vapor pressure of solvent.A combination of solvents can be used, for example, a compound can be dissolved in a first solution to obtain a solution, and then an anti-solvent can be added to reduce the solubility of the compound in the solution, resulting in the formation of crystals.Anti-solvent is a solvent in which the solubility of the compound is low.

[0060] In one method of preparing crystals, a compound is suspended and stirred in a suitable solvent to obtain a slurry, which can be heated to promote dissolution. As used herein, the term "slurry" refers to a saturated solution of a compound, which may also contain an additional amount of compound to produce a heterogeneous mixture of the compound and solvent at a given temperature.

[0061] Seed crystals can be added to any crystallization mixture to promote crystallization. Seeding can be used to control the growth of a particular polymorph or to control the particle size distribution of the crystalline product. Therefore, as described, for example, in "Programmed Cooling of Batch Crystallizers," J. W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369-377, the calculation of the amount of seeds needed depends on the size of the available seeds and the desired size of the average product particle. Generally, small-sized seeds are required to effectively control the growth of crystals within a batch. Small-sized seeds can be produced by sieving, grinding, or atomizing larger crystals or by microcrystallizing a solution. Care must be taken when grinding or atomizing crystals to avoid any change in the crystallinity of the desired crystalline form (i.e., to amorphous or another polymorph).

[0062] The cooled crystallization mixture can be filtered under vacuum, and the isolated solid can be washed with an appropriate solvent, such as a cooled recrystallization solvent, and dried under a nitrogen purge to obtain the desired crystalline form. The isolated solid can be analyzed by appropriate spectroscopic or analytical techniques, such as solid-state nuclear magnetic resonance, differential scanning calorimetry, or powder X-ray diffraction, to ensure the formation of the desired crystalline form of the product. The resulting crystalline form is generally produced in an isolated yield of about 70% by weight or greater, preferably 90% by weight or greater, based on the weight of the compound initially used in the crystallization procedure. If necessary, the product can be co-milled or crushed by passing it through a mesh screen.

[0063] The crystalline form may be prepared directly from the reaction medium of the final step in preparing Compound (I). This may be achieved, for example, by using a solvent or mixture of solvents that will crystallize Compound (I) in the final manufacturing step. Alternatively, the crystalline form may be obtained by distillation or solvent addition techniques. Suitable solvents for this purpose include, for example, the nonpolar and polar solvents mentioned above, for example, protic polar solvents such as alcohols, and aprotic polar solvents such as ketones.

[0064] The presence of multiple polymorphs 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, the presence of extra peaks in a comparison of an experimentally measured PXRD pattern with a simulated PXRD pattern can indicate multiple polymorphs in a sample. Simulated PXRD can be calculated from single crystal X-ray data. See Smith, DK, "A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns," Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963).

[0065] Forms C and D of Compound (I) can be characterized using a variety of techniques known to those skilled in the art. The forms can be characterized and distinguished using single crystal X-ray diffraction based on unit cell measurements of a single crystal at a fixed analysis temperature. A detailed description of the unit cell is provided in Stout & Jensen, X-Ray Structure Determination: A Practical Guide, Macmillan Co., New York (1968), Chapter 3, incorporated herein by reference. Alternatively, another method for characterizing the crystal structure is by powder X-ray diffraction analysis, in which the diffraction profile is compared to a simulated profile representing the pure powder material, with both measurements of the form of interest performed at the same analysis temperature and characterized as a series of 2θ degree values ​​(usually four or more).

[0066] Other methods of characterizing forms may be used, such as solid-state nuclear magnetic resonance, differential scanning calorimetry, thermal analysis, and vibrational spectroscopy. These parameters may also be used in combination to characterize the form of interest.

[0067] usefulness Crystalline Forms C and D of Compound (I) can be used to isolate Compound (I) from other components upon completion of the synthetic procedure and / or to purify Compound (I) by one or a series of crystallization procedures. The isolation and purification steps can be combined or performed as separate processing steps.

[0068] Example The present invention is further described in the following examples, which are preferred embodiments of the invention. Unless otherwise specified, all temperatures are in degrees Celsius (°C). It should be understood that these examples are illustrative rather than limiting, and that there may be other embodiments that are within the spirit and scope of the invention, as defined in the claims appended hereto.

[0069] For ease of reference, the following abbreviations may be used herein: [Table 2] [Table 3]

[0070] Example 1: Preparation of crystalline form C of compound (I) A solution was prepared by mixing 360 mg of Compound I in 23 mL of THF and 1 mL of water at room temperature (25 °C) until completely dissolved, and then adding 55 μL of methanesulfonic acid. 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 at 60 °C overnight. The slurry was filtered, and the wet cake was dried in a vacuum oven at temperatures ranging from 50 to 60 °C to obtain Form C of Compound I.

[0071] Example 2: Preparation of crystalline form C of compound (I) A solution was prepared by mixing 550 mg of Compound I in 35 mL of THF and 2 mL of water at room temperature (25 °C) until completely dissolved, and then adding 84 μL of methanesulfonic acid. 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 at 60 °C overnight. The slurry was filtered, and the wet cake was dried in a vacuum oven at temperatures ranging from 50 to 60 °C to obtain Form C of Compound I.

[0072] Example 3: Preparation of crystalline form D of compound (I) A solution was prepared by mixing 50 mg of Compound I and 0.5 ml of 0.25 M H2SO4 in 2 ml of acetone and heating to 55° C. The mixture was stirred at 55° C. overnight, then the heat was removed and the mixture was allowed to stand overnight at room temperature without stirring, resulting in the formation of Form D crystals.

[0073] Example 4: Preparation of crystalline form D of compound (I) A solution of 550 mg of Compound I was prepared by mixing 35 mL of THF and 2 mL of water at room temperature (25 °C) until completely dissolved, and then 72 μL of 96% H2SO4 was added. 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 at 60 °C overnight. The slurry was filtered, and the wet cake was dried in a vacuum oven at temperatures ranging from 50 to 60 °C to obtain Form D of Compound I.

[0074] Form C PXRD X-ray powder diffraction (PXRD) data were acquired using a Bruker C2 GADDS detector with a Vantec-500 detector. The radiation was Cu Kα (40 kV, 40 mA). The sample-detector distance was ~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 using a sample exposure time of at least 1000 seconds and 2000 nm. < 2θ < The resulting 2D diffraction arcs were integrated to generate conventional 1D PXRD patterns ranging from 2 to 30 degrees 2θ with a 0.05 degree 2θ step size.

[0075] DSC Differential scanning calorimetry (DSC) experiments were performed on a TA Instruments® Model Q1000. Samples (approximately 2-6 mg) were weighed into aluminum pans, recorded to the hundredth of a milligram, and transferred to the DSC. The instrument was purged with nitrogen gas at 50 mL / min. Data were collected between room temperature and 300°C at a heating rate of 10°C / min. Plots were made with the endothermic peak pointing downward.

[0076] TGA Thermogravimetric analysis (TGA) experiments were performed on a TA Instruments® Model Q500. Samples (approximately 10-30 mg) were placed in pre-tared platinum pans. The sample weight was accurately measured and recorded by the instrument to the nearest thousandth of a milligram. The furnace was purged with nitrogen gas at 100 mL / min. Data were collected between room temperature and 300 °C at a heating rate of 10 °C / min.

[0077] Solid state nuclear magnetic resonance (ssNMR) Carbon-13 cross-polarization magic-angle spinning (CPMAS) solid-state NMR was performed on a Bruker AV III instrument operating at a proton frequency of 500 MHz. Solid samples were spun at 13 kHz on a 4 mm ZrO2 spindle. The contact time was 4 ms, increasing from 50 to 100% in the proton channel (AE Bennett et al., J. Chem. Phys., 1995, 103, 6951), (G. Metz, X. Wu and SO Smith, J. Magn. Reson. A., 1994, 110, 219-227). The relaxation delay was 5x that of the API. 1 The H T1 was maintained at 9.1 seconds. Proton decoupling was applied using a TPPM sequence with a 4.2 microsecond pulse (59.5 kHz nominal bandwidth). The spectral sweep width was 300 ppm centered at 100 ppm. 4380 data points were acquired (giving 20 Hz digital resolution) and padded from zero to 8192 before apodization with 20 Hz line broadening. 1024 free induction decays were simultaneously applied. 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.

[0078] Form D Single crystal data Single crystal X-ray data were collected using a Bruker X8-Proteum diffractometer equipped with an APEX II CCD detector and a MICROSTAR microfocus rotating anode X-ray generator of monochromated Cu Kα radiation. The single crystal was at room temperature (approximately 25°C) during data collection.

[0079] The final unit cell parameters were obtained from least-squares refinement using set angles of 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, GM (2015). Acta Cryst. C71, 3-8). The refinement of the structure was performed by Σw(|F o |-|F c |) 2 where w is an appropriate weighting factor based on the error of the observed intensity, and F o is the measured reflection-based structure factor, and F c is the calculated reflection-based structure factor. The agreement between the refined crystal structure model and the experimental X-ray diffraction data is given by the residual factors R=Σ||F o |-|F c || / Σ|F o | and wR = [Σw(|F o |-|F c |) 2 / Σw|F o |] 1 / 2 The differential Fourier maps were examined at every stage of refinement. All non-hydrogen atoms were refined by anisotropic thermal displacement parameters. Hydrogen atoms were refined independently.

[0080] PXRD X-ray powder diffraction (PXRD) data were acquired using a Bruker C2 GADDS equipped with a Vantec-500 detector. The radiation was Cu Kα (40 kV, 40 mA). The sample-detector distance was ~20 cm. The incident optics included a Goebel mirror and a 0.3 mm collimator. The powder sample was placed in a closed glass capillary with a diameter of 1 mm or less; the capillary was rotated during data collection. Data were collected over 20 min with a sample exposure time of at least 1000 seconds. < 2θ < The resulting two-dimensional diffraction arcs were integrated to generate conventional one-dimensional PXRD patterns ranging from 2 to 30° 2θ with a 0.05° 2θ step size.

[0081] DSC Differential scanning calorimetry (DSC) experiments were performed on a TA Instruments® Model Q1000. Samples (approximately 2-6 mg) were weighed into aluminum pans, recorded to the nearest hundredth of a milligram, and transferred to the DSC. The instrument was purged with nitrogen gas at 50 mL / min. Data were collected between room temperature and 300°C at a heating rate of 10°C / min. Plots were made with the endothermic peak pointing downward.

[0082] TGA Thermogravimetric analysis (TGA) experiments were performed on a TA Instruments® Model Q500. Samples (approximately 10-30 mg) were placed in pre-weighed platinum pans. The sample weight was accurately measured and recorded by the instrument to the nearest thousandth of a milligram. The furnace was purged with nitrogen gas at 100 mL / min. Data were collected between room temperature and 300 °C at a heating rate of 10 °C / min.

Claims

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

2. 10. The crystalline form of claim 1, characterized by a powder X-ray diffraction pattern comprising five or more 2θ values ​​at frequencies (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.

3. 12. The crystalline form of claim 1, characterized by a powder X-ray diffraction pattern comprising 2θ values ​​at degrees (CuKα) of 7.8±0.2 and 9.5±0.2; and three or more 2θ values ​​at 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 Form C is measured at a temperature of about 25°C.

4. (i) a powder X-ray diffraction pattern comprising 2θ values ​​at 7.8±0.2 and 9.5±0.2 degrees (CuKα), measured at a temperature of about 25° C.; and (ii) five or more chemical shift values ​​in ppm (all ±0.2) 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. １３ 10. The crystalline form of claim 1 characterized by a C ssNMR spectrum, wherein the spectrum for Form C is measured at a temperature of about 280°K.

5. 2. The crystalline form of claim 1, consisting essentially of Form C.

6. 2. The crystalline form of claim 1, wherein said Form C is a substantially pure form.

7. 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ３ )pyridazine-3-carboxamide, wherein the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ３ 2.) A composition wherein at least 95% by weight of the pyridazine-3-carboxamide is crystalline form C.

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

9. below: i) a powder X-ray diffraction pattern comprising four or more 2-theta values ​​at frequencies (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.; or ii) an observed powder X-ray diffraction pattern substantially as shown in Figure 5; or iii) unit cell parameters substantially equal to the following values: a=8.49±0.05Å b=12.39±0.05Å c=12.52±0.05Å α＝６３．０±０．５° β＝８０．５±０．５° γ=81.4±0.5° Space group: P-1 Molecules per unit cell (Z): 2 9. The crystalline form of claim 8, characterized by at least one of the following unit cell parameters of Form D of Compound (I) measured at a temperature of about 25°C.

10. 10. The crystalline form of claim 8, characterized by a powder X-ray diffraction pattern comprising five or more 2-theta values ​​at frequencies (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. 10. The crystalline form of claim 8, characterized by a powder X-ray diffraction pattern comprising 2θ values ​​at degrees (CuKα) selected from 8.5±0.2 and 18.3±0.2; and three or more 2θ values ​​at 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. 9. The crystalline form of claim 8, consisting essentially of Form D.

13. 9. The crystalline form of claim 8, wherein Form D is a substantially pure form.

14. 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ３ )pyridazine-3-carboxamide, wherein the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ３ 2.) A composition wherein at least 95% by weight of the pyridazine-3-carboxamide is crystalline form D.

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