Crystalline salt form of 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-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 of related applications This application claims the benefit of U.S. Provisional Application No. 62 / 860439 (filed June 12, 2019), which is incorporated herein by reference in its entirety.

[0002] The present invention generally relates to crystalline salt forms of 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, which are collectively referred to 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-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is given by formula (I): [ka] It has the structure and is referred to herein as “Compound (I)”. Compound (I) is disclosed in U.S. Patent No. 9,505,748 B2, which has been transferred to the Transferee. U.S. Patent No. 9,505,748 B2 also discloses a therapeutic method using Compound (I).

[0004] Compound (I) is a Tyk2 inhibitor currently undergoing clinical trials for the treatment of autoimmune and autoinflammatory diseases such as psoriasis, psoriatic arthritis, lupus, lupus nephritis, Sjögren'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 before further processing to provide the compound as a pharmaceutical formulation. The isolation and purification steps may be combined or separate, sequential steps, and the compound should be provided as a purified solid with minimal loss of yield during isolation from other components of the reaction mixture and / or during purification to remove impurities from the isolated compound sample.

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

[0007] Furthermore, it is preferable to isolate the purified compound in a physically and chemically stable solid form under a range of storage conditions, including different temperatures and humidity levels.

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

[0009] Furthermore, the applicants have surprisingly discovered a crystalline form of compound (I) that provides a solid form of compound (I) that is physically and chemically stable under a range of storage conditions, has sufficient solubility in solvents / solutions, and allows for the preparation of other solid forms.

[0010] Furthermore, the applicants have surprisingly discovered a crystalline form of compound (I) that provides compound (I) in a solid form that mitigates the pH effect more than the other salts tested. The present invention also relates to other important aspects. [Overview of the Initiative]

[0011] The present invention provides crystalline forms C and D of compound (I). Names used herein to characterize specific forms, such as "form C or form D," should not be considered limiting to any other substance having similar or identical physical and chemical properties. Rather, these notations should be understood as mere identifiers, to be interpreted according to the characteristic information presented herein. [Brief explanation of the drawing]

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

[0013] Detailed description of the present 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. For clarity, it should be understood that some of the features of the present invention described above and below in the context of other embodiments may also be combined to form a single embodiment. Conversely, for brevity, various features of the present invention described in the context of a single embodiment may also be combined to form their subcombinations.

[0014] Names used in this specification to characterize particular forms, such as "Form C", are merely identifiers that should be interpreted in accordance with the characteristic information described in this specification and do not limit so as to exclude any other substance having similar or identical physical and chemical properties.

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

[0016] All numerical values representing amounts, weight percentages, temperatures, etc. of components preceded by the term "about" should be understood only as approximations that can achieve substantially the same results as the recited numerical values by using a slight variation above and below the recited numerical value. Therefore, unless otherwise specifically stated, numerical parameters preceded by the term "about" are approximations that can vary depending on the nature of the desired purpose. At least, without intending to limit the application of the doctrine of equivalents to the claims, each numerical parameter should be interpreted by considering at least the reported significant digits and 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 a crystalline form having the same chemical structure but different spatial arrangements of molecules and / or ions that form crystals.

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

[0020] As used herein, “substantially pure” means, when applied to a crystalline form, a compound having a purity of 90% by weight or more of compound (I), such as 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99% by weight or more of the compound, and also equivalent to about 100% by weight. The remaining substance includes other forms of the compound, and / or reaction impurities, and / or process impurities resulting from its manufacture. For example, the crystalline form of compound (I) can be considered substantially pure, having a purity of 90% by weight or more, as measured by methods known and generally accepted in the art at present, where the remaining less than 10% by weight of the substance includes amorphous and / or other forms of compound (I), and / or reaction impurities, and / or process impurities.

[0021] In this specification, a powder X-ray diffraction (PXRD) pattern containing several 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 containing 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) four or more, preferably five or more, 2θ values ​​selected from A, B, C, D, E, F, G, and H; and (b) a PXRD pattern having zero or more peaks that are not any of the peaks A, B, C, D, E, F, G, and H.

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

[0023] In this specification, the unit cell parameter "molecule per unit cell" refers to the number of molecules of compound (I) within the unit cell.

[0024] Form C of compound (I) In one embodiment, compound (I) is provided as a crystalline substance containing form C. The crystalline form C of compound (I) is an MSA salt. Table 1. 13C CPMAS chemical shift values ​​of morphology C at 280K [Table 1]

[0025] In one embodiment, the crystalline morphology C of compound (I) is characterized by a powder X-ray diffraction pattern containing 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, where the PXRD pattern of morphology C is measured at a temperature of approximately 25°C.

[0026] In one embodiment, the crystalline morphology C of compound (I) is characterized by a powder X-ray diffraction pattern containing 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, where the PXRD pattern of morphology C is measured at a temperature of approximately 25°C.

[0027] In one embodiment, the crystalline morphology C of compound (I) is characterized by a powder X-ray diffraction pattern containing 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, where the PXRD pattern of morphology C is measured at a temperature of approximately 25°C.

[0028] In one embodiment, the crystalline morphology C of compound (I) is characterized by a powder X-ray diffraction pattern including 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, where the PXRD pattern of morphology C is measured at a temperature of approximately 25°C.

[0029] In one embodiment, the crystalline form C of compound (I) includes 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 the ssNMR spectrum; here, the spectrum of morphology C is measured at a temperature of approximately 280 K.

[0030] In one embodiment, the crystalline form C of compound (I) includes 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 the ssNMR spectrum, where the spectrum of morphology C is measured at a temperature of approximately 280 K.

[0031] In one embodiment, the crystalline form C of compound (I) includes 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 the ssNMR spectrum, where the spectrum of morphology C is measured at a temperature of approximately 280 K.

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

[0033] In one embodiment, the crystalline form C of compound (I) is characterized by an observed powder X-ray diffraction pattern, substantially as shown in Figure 1.

[0034] In one embodiment, the crystalline form C of compound (I) is characterized by variable endothermic properties at approximately 220°C.

[0035] In one embodiment, the crystalline form C of compound (I) is characterized substantially by a differential scanning calorimetry (DSC) thermogram as shown in Figure 2.

[0036] In one embodiment, the crystalline form C of compound (I) is characterized by (i) a powder X-ray diffraction pattern including 2θ values ​​at 7.8±0.2 and 9.5±0.2 degrees (CuKα); and (ii) a differential scanning calorimetry (DSC) thermogram substantially consistent with that shown in Figure 2.

[0037] 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 sample of form C when heated to a temperature of about 150°C.

[0038] In one embodiment, the crystalline form C of compound (I) exhibits a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 3.

[0039] In yet another embodiment, the crystalline form C of compound (I) is substantially pure.

[0040] In another embodiment, the crystalline form of compound (I) consists substantially of form C. The crystalline form of this embodiment may consist of at least about 90% by weight, preferably at least about 95% by weight, 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] One embodiment provides a composition comprising 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-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-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is in crystalline form C.

[0042] Form D of compound (I) In one embodiment, compound (I) is provided as a crystalline substance containing form D. The crystalline form D of compound (I) is a sulfate.

[0043] In one embodiment, the crystalline form D of compound (I) is as follows: a = 8.49 ± 0.05 Å b = 12.39 ± 0.05 Å c = 12.52 ± 0.05 Å 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 Characterized by unit cell parameters that are nearly equal, where the unit cell parameters of morphology D of compound (I) are measured at a temperature of approximately 25°C.

[0044] In one embodiment, the crystalline morphology D of compound (I) is characterized by a powder X-ray diffraction pattern containing four 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, where the PXRD pattern of morphology D is measured at a temperature of approximately 25°C.

[0045] In one embodiment, the crystalline morphology D of compound (I) is characterized by a powder X-ray diffraction pattern containing 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, where the PXRD pattern of morphology D is measured at a temperature of approximately 25°C.

[0046] In one embodiment, the crystalline morphology D of compound (I) is characterized by a powder X-ray diffraction pattern containing six 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, where the PXRD pattern of morphology D is measured at a temperature of approximately 25°C.

[0047] In one embodiment, the crystalline morphology D of compound (I) is characterized by a powder X-ray diffraction pattern including 2θ values ​​at 8.5±0.2 and 18.3±0.2 degrees (CuKα); 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; where the PXRD pattern of morphology D is measured at a temperature of approximately 25°C.

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

[0049] In one embodiment, the crystalline form D of compound (I) is characterized by the observed powder X-ray diffraction pattern, substantially as shown in Figure 4.

[0050] In one embodiment, the crystalline form D of compound (I) is characterized by variable endothermia, with a peak maximum value at approximately 233°C.

[0051] In one embodiment, the crystalline form D of compound (I) is characterized by a differential scanning calorimetry (DSC) thermogram, substantially as shown in Figure 5.

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

[0053] In one embodiment, the crystalline form D of compound (I) is substantially shown in the thermogravimetric analysis (TGA) thermogram in Figure 6.

[0054] In yet another embodiment, the crystalline form D of compound (I) is substantially pure.

[0055] In another embodiment, the crystalline form of compound (I) consists substantially of form D. The crystalline form of this embodiment may consist of at least about 90% by weight, preferably at least about 95% by weight, 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] One embodiment provides a composition comprising 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-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-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is in crystalline form D.

[0057] Crystal morphologies can be prepared by various methods, such as crystallization or recrystallization from a suitable solvent, sublimation, growth from a molten material, solid-state transformation from another phase, crystallization from a supercritical fluid, and jet spraying. Techniques for crystallizing or recrystallizing crystalline morphologies from solvent mixtures include, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, crystal seeding of molecules and / or salts in a supersaturated solvent mixture, freeze-drying of the solvent mixture, and addition of an antisolvent (countersolvent) to the solvent mixture. High-throughput crystallization techniques can be used to prepare crystalline materials containing polymorphs.

[0058] The crystals of drugs, including polymorphs, their preparation methods, and the 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] In crystallization techniques that use solvents, the choice of solvent generally depends on one or more factors, such as the solubility of the compound, the crystallization technique, and the vapor pressure of the solvent. A combination of solvents may be used; for example, a compound may be dissolved in a first solution to obtain a solution, and then an antisolvent may be added to reduce the solubility of the compound in the solution, thereby achieving crystal formation. The antisolvent is a solvent in which the compound has low solubility.

[0060] In one method for preparing crystals, a compound may be suspended and stirred in a suitable solvent to obtain a slurry, which may then be heated to promote dissolution. As used herein, the term "slurry" means a saturated solution of the compound, which may also contain further amounts of the compound to produce a heterogeneous mixture of the compound and the 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 specific polymorphs or to control the particle size distribution of the crystalline product. Therefore, as described, for example, in "Programmed Cooling of Batch Crystallizers," JW Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369-377, the calculation of the required amount of seed depends on the size of the available seed and the desired average particle size of the product. In general, small-sized seeds are needed to effectively control crystal growth in a batch. Small-sized seeds can be produced by sieving, grinding, or micronizing large crystals, or by microcrystallization of a solution. When grinding or micronizing crystals, care must be taken to avoid any change in the crystalline nature of the desired crystalline form (i.e., a change to amorphous or other polymorphs).

[0062] The cooled crystalline mixture can be filtered under vacuum, the isolated solid can be washed with a suitable solvent, such as a cooling recrystallization solvent, and dried under 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 isolation yield of about 70% by weight or more, preferably 90% by weight or more, based on the weight of the compound initially used in the crystallization procedure. If necessary, the product may be co-ground or crushed by passing it through a mesh screen.

[0063] The crystalline form may be prepared directly from the reaction medium in the final step of preparing compound (I). This can be achieved, for example, by using a solvent or mixture of solvents capable of crystallizing 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 aforementioned nonpolar and polar solvents, such as protic polar solvents like alcohols and aprotic polar solvents like 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 between experimentally measured and simulated PXRD patterns may suggest the presence of multiple polymorphs in the 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] Morphologies C and D of compound (I) can be characterized using various techniques of operation well known to those skilled in the art. The morphologies can be characterized and distinguished using single-crystal X-ray diffraction based on unit cell measurements of single crystals at a fixed analytical 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, which is 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 by both measurements of the morphology in question, performed at the same analytical temperature and characterized as a series of 2θ frequency values ​​(usually four or more).

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

[0067] usefulness Using the crystalline forms C and D of compound (I), compound (I) can be isolated from other components upon completion of the synthesis procedure; and / or purified by one or a series of crystallization steps. The isolation and purification steps may be combined or carried out as separate processing steps.

[0068] Examples 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). These examples are illustrative and not limiting, and it should be understood that other embodiments may exist that are in the spirit and scope of the invention as defined in the claims appended herein.

[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 of 360 mg of compound I was prepared by mixing it in 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 speed bag. 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 moist cake was dried in a vacuum oven at a temperature in the range of 50-60°C to obtain compound I in form C.

[0071] Example 2: Preparation of crystalline form C of compound (I) A solution of 550 mg of compound I was prepared by mixing it in 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 speed bag. 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 moist cake was dried in a vacuum oven at a temperature in the range of 50–60°C to obtain compound I in form C.

[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 overnight at 55°C, then the heating was stopped and the mixture was left at room temperature overnight without stirring, resulting in the formation of crystals of form D.

[0073] Example 4: Preparation of crystalline form D 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 72 μL of 96% H2SO4. The resulting slurry was dried overnight using a speed bag. 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 moist cake was dried in a vacuum oven at a temperature in the range of 50–60°C to obtain compound I in form D.

[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 (40KV, 40mA). The sample detector distance was ~20cm. The incident optics included a Goebel mirror and a 0.3mm collimator. The powder sample was placed in a sealed glass capillary with a diameter of 1mm or less; the capillary was rotated during data acquisition. Data was obtained with a sample exposure time of at least 1000 seconds. < 2θ < The data was collected at 35°. The resulting two-dimensional diffraction arcs were integrated to create a conventional one-dimensional PXRD pattern in the 2θ range from ~2 to ~30 degrees, with a 2θ step size of 0.05 degrees.

[0075] DSC Differential scanning calorimetry (DSC) experiments were performed using a TA Instruments® Model Q1000. Samples (approximately 2–6 mg) were weighed into an aluminum pot, accurately 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 created with the endothermic peak facing downwards.

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

[0077] Solid state nuclear magnetic resonance (ssNMR) Carbon-13 cross-polarization magic-angle rotation (CPMAS) solid-state NMR was performed using a Bruker AV III instrument operating at a proton frequency of 500 MHz. The solid sample was rotated at 13 kHz on a 4 mm ZrO2 rotation axis. The contact time was 4 milliseconds, and the proton level increased from 50 to 100% (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 of the API. 1 The H₀ T1 interval was maintained at 9.1 seconds. Proton decoupling was applied using a TPPM sequence with 4.2 microsecond pulses (59.5 kHz nominal bandwidth). The spectral sweep width was 300 ppm, centered at 100 ppm. 4380 data points were acquired (achieving a digital resolution of 20 Hz) and filled from zero to 8192 before apodization by 20 Hz line broadening. 1024 free induction decays were simultaneously added. The spectrum was indirectly referenced using 3-methylglutaric acid to TMS (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 in each experiment. The temperature was set to 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 with monochromatic Cu Kα radiation. During data collection, the single crystal was at room temperature (about 25 °C).

[0079] The final unit cell parameters were obtained from least-squares refinement using the setting 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 methods using SHELXL-97 software (Sheldrick, G. M. (2015). Acta Cryst. C71, 3-8). The refinement of the structure was with respect to the minimization of the function defined by Σw(|F o |-|F c |) 2 where w is an appropriate weighting factor based on the error of the observed intensities, F o is the structure factor based on the measured reflections, and F c is the structure factor based on the calculated reflections. The agreement between the refined crystal structure model and the experimental X-ray diffraction data was evaluated using 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 Difference Fourier maps were examined at all stages of refinement. All non-hydrogen atoms were refined with anisotropic thermal displacement parameters. Hydrogen atoms were refined independently.

[0080] PXRD X-ray powder diffraction (PXRD) data were acquired using a Bruker C2 GADDS with a Vantec-500 detector. The radiation was Cu Kα (40KV, 40mA). The sample detector distance was ~20cm. The incident optics included a Goebel mirror and a 0.3mm collimator. The powder sample was placed in a sealed glass capillary with a diameter of 1mm or less; the capillary was rotated during data acquisition. Data were acquired with a sample exposure time of at least 1000 seconds. < 2θ < We collected data for 35°. The resulting two-dimensional diffraction arcs were integrated to create a conventional one-dimensional PXRD pattern with a 2θ step size of 0.05° in the 2θ range from ~2 to ~30°.

[0081] DSC Differential scanning calorimetry (DSC) experiments were performed using a TA Instruments® Model Q1000. Samples (approximately 2–6 mg) were weighed into an aluminum pot, accurately 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 created with the endothermic peak facing downwards.

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

Claims

1. The crystal of form C is 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d ３ ) A crystal of pyridazine-3-carboxamide, wherein form C is 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d ３ ) is the methanesulfonic acid (MSA) salt of pyridazine-3-carboxamide, The above-mentioned form C is as follows: (i) A powder X-ray diffraction (PXRD) 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 is measured at a temperature of approximately 25°C; (ii) Observed powder X-ray diffraction pattern shown in Figure 1 below Table 1 (iii) Including four 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 A C ssNMR spectrum, wherein the spectrum is measured at a temperature of approximately 280 K; (iv) Differential scanning calorimetry (DSC) thermogram with an endothermic peak at 220°C: (v) Differential scanning calorimetry (DSC) thermogram shown in Figure 2 below Table 2 (vi) Thermogravimetric analysis (TGA) thermogram shown in Figure 3 below Table 3 A crystal characterized by one or more of the following:

2. The crystal according to claim 1, characterized by a powder X-ray diffraction pattern including 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 the form C is measured at a temperature of about 25°C.

3. The crystal according to claim 1, 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 the form C is measured at a temperature of about 25°C.

4. The crystal of form C is 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d ３ ) A crystal of pyridazine-3-carboxamide, wherein form C is 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d ３ ) a methanesulfonic acid (MSA) salt of pyridazine-3-carboxamide, wherein the crystal of form C includes (i) a powder X-ray diffraction pattern measuring at a temperature of about 25°C, with 2θ values ​​at 7.8 ± 0.2 and 9.5 ± 0.2 degrees (CuKα); 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 A crystal characterized by a C ssNMR spectrum, wherein the spectrum of the aforementioned form C is measured at a temperature of approximately 280 K.

5. 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d ３ A composition comprising pyridazine-3-carboxamide, wherein the 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d ３ A composition wherein at least 90% by weight of pyridazine-3-carboxamide is form C according to any one of claims 1 to 4.

6. 6-(Cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ３ )pyridazine-3-carboxamide, wherein at least 95% by weight of the 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ３ )pyridazine-3-carboxamide is in Form C as described in claim 3.

7. 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d ３ A composition comprising pyridazine-3-carboxamide, wherein the 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d ３ A composition wherein at least 95% by weight of pyridazine-3-carboxamide is form C as described in claim 4.

8. The crystal of form D is 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d ３ ) A crystal of pyridazine-3-carboxamide, wherein form D is 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d ３ ) It is the sulfate salt of pyridazine-3-carboxamide, The above-mentioned form D is as follows: (i) A powder X-ray diffraction (PXRD) pattern comprising four 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 is measured at a temperature of approximately 25°C; (ii) Unit cell parameters 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 The unit cell parameter is measured at a temperature of approximately 25°C; (iii) Differential scanning calorimetry (DSC) thermogram with an endothermic peak at 233°C; (iv) Differential scanning calorimetry (DSC) thermogram shown in Figure 6 below Table 4 (v) Thermogravimetric analysis (TGA) thermogram shown in Figure 7 below Table 5 A crystal characterized by one or more of the following:

9. below: i) A powder X-ray diffraction pattern including four 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 the form D is measured at a temperature of approximately 25°C; ii) Unit cell parameters 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 A crystal according to claim 8, characterized by at least one of the following, wherein the unit cell parameter of morphology D is measured at a temperature of about 25°C.

10. A crystal according to claim 8, 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 the form D is measured at a temperature of about 25°C.

11. A crystal according to claim 8, characterized by a powder X-ray diffraction pattern comprising 2θ values ​​at 8.5±0.2 and 18.3±0.2 degrees (CuKα); 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 the form D is measured at a temperature of about 25°C.

12. 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d ３ A composition comprising pyridazine-3-carboxamide, wherein the 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d ３ A composition wherein at least 90% by weight of pyridazine-3-carboxamide is form D according to any one of claims 8 to 11.

13. 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d ３ A composition comprising pyridazine-3-carboxamide, wherein the 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d ３ A composition wherein at least 95% by weight of pyridazine-3-carboxamide is the form D described in claim 9.

14. 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d ３ A composition comprising pyridazine-3-carboxamide, wherein the 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d ３ A composition wherein at least 95% by weight of pyridazine-3-carboxamide is the form D described in claim 11.

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