Salt and crystal form of picolinamide compound, and preparation method therefor

Abstract

The present disclosure relates to a salt and a crystal form of a picolinamide compound, and a preparation method therefor. Specifically, the present disclosure relates to a salt and a crystal form of 4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)pyridine-2-carboxamide, and a preparation method therefor. The crystal form in the present disclosure has high crystallinity, high purity, no hygroscopicity and good thermal stability; moreover, the process has high levels of safety, and is simple to operate and suitable for industrial production.

Description

Salt and crystal form of pyridine amide compound and preparation method thereof

[0001] Reference of Related Applications

[0002] The present disclosure claims priority to the invention patent application with the application number 202411140590.8, the title of which is "Salt and crystal form of pyridine amide compound and preparation method thereof", filed with the China Patent Office on August 16, 2024, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0003] The present disclosure relates to a salt and crystal form of a pyridine amide compound and a preparation method thereof. Specifically, the present disclosure relates to a salt and crystal form of 4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)pyridine-2-carboxamide and a preparation method thereof. BACKGROUND

[0004] According to the market research report of Mordor Intelligence in 2023, the global pain management market is expected to reach 75.4 billion US dollars in 2023, and is expected to reach 90 billion US dollars by 2028. Opioid drugs are a common choice for pain diseases. The dilemma of opioid drugs is not their efficacy, but their safety, tolerance and addiction.

[0005] The Joint Economic Committee of the United States Congress published a report in 2022 that the abuse of opioid drugs caused a loss of nearly 1.5 trillion US dollars to the United States, accounting for about 7% of the gross domestic product of that year. The Lancet magazine once predicted that with the rise of the mixing of methadone and opioid drugs, if no new measures are taken, about 1.22 million Americans will die from overdose of opioid drugs from 2020 to 2029. Therefore, the research and development of non-opioid acute pain drugs has a huge market space and a clear industry pain point.

[0006] NaV1.8 sodium ion channel is a voltage-gated sodium channel that plays a key role in the transmission of pain signals in the peripheral nervous system. This mode of action is completely different from that of opioid drugs. It does not act on the brain, but directly blocks the pain in the peripheral nervous system, has relatively high safety, has no addiction, and has no gastrointestinal side effects and cardiovascular side effects of non-steroidal anti-inflammatory drugs; it can be used in combination with other analgesics to enhance efficacy and reduce side effects.

[0007] It is well known that due to the solid forms having more suitable properties for medical and pharmaceutical uses under certain conditions: such as solubility, bioavailability, physical and / or chemical stability, purity and impurity profile, filtration property, drying property, hygroscopicity or easier handling or micronization or tablet making, etc., it is desirable in the art to develop various solid forms of NaV1.8 blockers. SUMMARY

[0008] A first aspect of the present disclosure provides a crystalline form I of a compound of Formula I,

[0009] A second aspect of the present disclosure provides a salt of a compound of Formula I, which salt is selected from the group consisting of a 1,5-naphthalenedisulfonic acid salt, a sulfate salt and a maleic acid salt, which salt can be in various crystalline forms, such as a crystalline form A of a 1,5-naphthalenedisulfonic acid salt, a crystalline form B of a 1,5-naphthalenedisulfonic acid salt, a sulfate salt crystalline form or a maleic acid salt crystalline form.

[0010] A third aspect of the present disclosure provides a pharmaceutical composition comprising the crystalline form I of a compound of Formula I, a salt of a compound of Formula I (such as a 1,5-naphthalenedisulfonic acid salt, a sulfate salt or a maleic acid salt of a compound of Formula I, in particular a crystalline form A of a 1,5-naphthalenedisulfonic acid salt, a crystalline form B of a 1,5-naphthalenedisulfonic acid salt, a sulfate salt crystalline form or a maleic acid salt crystalline form of a compound of Formula I) or an amorphous form of a compound of Formula I, and one or more pharmaceutically acceptable carriers.

[0011] A fourth aspect of the present disclosure provides the use of the crystalline form I of a compound of Formula I, a salt of a compound of Formula I (such as a 1,5-naphthalenedisulfonic acid salt, a sulfate salt or a maleic acid salt of a compound of Formula I, in particular a crystalline form A of a 1,5-naphthalenedisulfonic acid salt, a crystalline form B of a 1,5-naphthalenedisulfonic acid salt, a sulfate salt crystalline form or a maleic acid salt crystalline form of a compound of Formula I), an amorphous form of a compound of Formula I or a pharmaceutical composition described above in the manufacture of a medicament for the prevention and / or treatment of a NaV1.8 related disease, preferably the NaV1.8 related disease is pain.

[0012] A fifth aspect of the present disclosure provides the crystalline form I of a compound of Formula I, a salt of a compound of Formula I (such as a 1,5-naphthalenedisulfonic acid salt, a sulfate salt or a maleic acid salt of a compound of Formula I, in particular a crystalline form A of a 1,5-naphthalenedisulfonic acid salt, a crystalline form B of a 1,5-naphthalenedisulfonic acid salt, a sulfate salt crystalline form or a maleic acid salt crystalline form of a compound of Formula I), an amorphous form of a compound of Formula I or a pharmaceutical composition described above for use in the prevention and / or treatment of a NaV1.8 related disease, preferably the NaV1.8 related disease is pain.

[0013] The sixth aspect of the present disclosure provides a method for preventing and / or treating a NaV1.8 related disease, comprising administering to an individual a prophylactically and / or therapeutically effective amount of the crystalline form I of the compound of Formula I, the salt of the compound of Formula I (e.g., the 1,5-naphthalene disulfonate salt, the sulfate salt or the maleate salt of the compound of Formula I, in particular the 1,5-naphthalene disulfonate salt Form A, the 1,5-naphthalene disulfonate salt Form B, the sulfate salt Form or the maleate salt Form of the compound of Formula I), the amorphous form of the compound of Formula I or the pharmaceutical composition; preferably, the NaV1.8 related disease is pain.

[0014] The seventh aspect of the present disclosure provides a method for preparing the crystalline form I of the compound of Formula I, the salt of the compound of Formula I (e.g., the 1,5-naphthalene disulfonate salt, the sulfate salt or the maleate salt of the compound of Formula I, in particular the 1,5-naphthalene disulfonate salt Form A, the 1,5-naphthalene disulfonate salt Form B, the sulfate salt Form or the maleate salt Form of the compound of Formula I), the amorphous form of the compound of Formula I, which comprises using solution recrystallization method (e.g., cooling crystallization, anti-solvent crystallization, evaporation crystallization and coupled crystallization of the above-mentioned crystallization methods), grinding method, melt crystallization method, etc.

[0015] The present disclosure has the following advantages: the crystalline form I of the compound of Formula I of the present disclosure has high crystallinity, high purity, uniform particle size distribution, no hygroscopicity, excellent thermal stability and high process safety, simple operation and is suitable for industrial production.

[0016] The crystalline form I of the present disclosure has rod-like shape, large particle size and uniform particle size distribution, and has more excellent powder properties than the crystalline form II and the accompanying polymorphs, and is more suitable for formulation development.

[0017] The amorphous form of the compound of Formula I has good stability and is still in amorphous form after being stored at room temperature for 3 months.

[0018] The 1,5-naphthalene disulfonate salt, the sulfate salt or the maleate salt of the compound of Formula I has solubility ≥1 mg / mL in pure water, and has high solubility. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1: XRPD pattern of the crystalline form I of the compound of Formula I;

[0020] Figure 2: DSC pattern of the crystalline form I of the compound of Formula I;

[0021] Figure 3: TGA pattern of the crystalline form I of the compound of Formula I;

[0022] Figure 4: DVS pattern of the crystalline form I of the compound of Formula I;

[0023] Figure 5: PLM pattern of the crystalline form I of the compound of Formula I (50 times magnification);

[0024] Figure 6: Single crystal cell structure diagram of the crystalline form I of the compound of Formula I;

[0025] Figure 7: XRPD pattern of the amorphous form of the compound of Formula I;

[0026] Figure 8: PLM pattern (50x magnification) of the amorphous form of the compound of Formula I;

[0027] Figure 9: XRPD pattern of the 1,5-naphthalene disulfonate salt Form A of the compound of Formula I;

[0028] Figure 10: PLM pattern (200x magnification) of the 1,5-naphthalene disulfonate salt Form A of the compound of Formula I;

[0029] Figure 11: XRPD pattern of the 1,5-naphthalene disulfonate salt Form B of the compound of Formula I;

[0030] Figure 12: PLM pattern (100x magnification) of the 1,5-naphthalene disulfonate salt Form B of the compound of Formula I;

[0031] Figure 13: XRPD pattern of the sulfate salt Form of the compound of Formula I;

[0032] Figure 14: PLM pattern (50x magnification) of the sulfate salt Form of the compound of Formula I;

[0033] Figure 15: XRPD pattern of the maleate salt Form of the compound of Formula I;

[0034] Figure 16: PLM pattern (100x magnification) of the maleate salt Form of the compound of Formula I;

[0035] Figure 17: Overlay of XRPD patterns of the Form I of the compound of Formula I after stability condition investigation of Form I;

[0036] Figure 18: XRPD pattern of Form II of the compound of Formula I;

[0037] Figure 19: DSC pattern of Form II of the compound of Formula I;

[0038] Figure 20: PLM pattern (50x magnification) of Form II of the compound of Formula I;

[0039] Figure 21: Overlay of XRPD patterns of Form I, Form II, and concomitant polymorphs of Form I and Form II of the compound of Formula I;

[0040] Figure 22: Overlay of XRPD patterns of Form I and concomitant polymorphs of Form I and Form III of the compound of Formula I;

[0041] Figure 23: XRPD patterns of Form I and concomitant polymorphs of Form III of the compound of Formula I;

[0042] Figure 24: PLM patterns (50x magnification) of Form I and concomitant polymorphs of Form III of the compound of Formula I;

[0043] Figure 25: Overlay of XRPD patterns of Form I and Form III of the compound of Formula I before and after 6 months of room temperature storage as a concomitant polymorph;

[0044] Figure 26: Overlay of XRPD patterns of Form I and Form III of the compound of Formula I before and after 48 hours of drying as a concomitant polymorph.

[0045] DETAILED DESCRIPTION

[0046] The following further explains the present disclosure, it being understood that the language used is intended to describe the application for purposes of patentability and is not intended to limit the present disclosure.

[0047] DEFINITIONS

[0048] Unless otherwise indicated, all technical and scientific terms and any acronyms used herein have the same meaning as those that are commonly understood by one of ordinary skill in the art in the field of the disclosure. In case of conflict between the definitions in the present disclosure and that supplied by any document incorporated herein by reference, the definition in the present disclosure controls. When expressing a quantity, concentration, or other value or parameter of interest in the form of a range, a preferred range, or a preferred upper value and a preferred lower value, it is to be understood that any and every sub-range that falls within the indicated range and every upper value and lower value within the indicated range is specifically contemplated. Unless otherwise stated, the numerical values listed herein are intended to include the end points of ranges and all integers and fractions (decimals) within the ranges.

[0049] The term "about" when used before a numerical designator, generally refers to the numerical designator and all numerical values within experimental error (e.g., within 95% confidence interval for a mean) or within ± 20%, ± 10%, ± 5%, or ± 2% of the indicated numerical value.

[0050] The terms "comprising" or "comprise", and grammatical variations thereof are used inclusively and not exclusivity, that is, "comprising" or "comprise" does not exclude the additional, unrecited elements, steps, or ingredients, but allows for the inclusion of additional, unrecited elements, steps, or ingredients. The expression "consisting of" excludes any element, step, or ingredient not specified. The expression "consisting essentially of" indicates a range of elements, steps, or ingredients that is limited to the specified elements, steps, or ingredients, plus an optional additional element, step, or ingredient that does not materially affect the basic and novel characteristics of the claimed subject matter. It is to be understood that the term "comprising", along with other similar terms used herein, are inclusive or open-ended terms that specifically permit the inclusion of the term "consisting of" and "consisting essentially of".

[0051] The terms "optional" or "optionally", as used herein, mean that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0052] Unless otherwise indicated, percentages, parts, and the like herein are by weight.

[0053] As used herein, the term "crystal form" or "crystalline" refers to any solid material that exhibits three-dimensional ordering, as opposed to amorphous solid material, which produces a characteristic XRPD pattern with well-defined peaks.

[0054] As used herein, the term "seed crystal" refers to an addition in a crystallization process that can form a nucleus to speed up or facilitate the growth of crystals of the same enantiomer in the same crystal form or conformation.

[0055] As used herein, the term "X-ray powder diffraction pattern" or "XRPD pattern" refers to the experimentally observed diffraction pattern or parameters, data, or values derived therefrom. An XRPD pattern is typically characterized by peak positions (abscissa) and / or peak intensities (ordinate).

[0056] As used herein, the term "diffraction angle" or "2Θ" refers to the peak position in degrees (°) set based on the X-ray diffraction experiment and is typically the unit of abscissa in the diffraction pattern. If the reflection is diffracted when the incident beam forms an angle θ with a certain lattice plane, the experimental setup requires recording the reflected beam at a 2θ angle. It should be understood that the specific 2θ values mentioned herein for a particular crystal form are intended to represent the 2θ values (in degrees) measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, a Cu-Kα (Kα1 1.5406) monochromatic radiation. The XRPD patterns herein are preferably collected on a PANalytical X'Pert3 Powder X-ray diffractometer, and the transmission patterns are preferably collected on a PANalytical X'Pert3 Powder X-ray diffractometer.

[0057] As used herein, the term "substantially the same" or "substantially as depicted in Figure X" in reference to X-ray diffraction peaks means that representative peak positions and intensity variations are taken into account. For example, one skilled in the art will appreciate that peak positions (2Θ) can show some variation, typically up to 0.1 to 0.2 degrees, and that the instrument used to measure the diffraction can also cause some variation. Additionally, one skilled in the art will appreciate that relative peak intensities can vary from instrument to instrument and as a result of the degree of crystallinity, preferred orientation, surface of the sample prepared, and other factors known to one skilled in the art.

[0058] Similarly, as used herein, "substantially as depicted in Figure X" in reference to DSC and TGA patterns is also intended to encompass variations known to one skilled in the art relating to these analytical techniques. For example, for well-defined peaks in a DSC pattern, there will typically be a variation of up to ±5°C, and even greater (e.g., up to ±10°C) for broad peaks.

[0059] As used herein, the term "room temperature" refers to 20°C ± 5°C.

[0060] As used herein, the term "preventing" includes inhibiting and delaying the onset of a disease, and includes not only preventing the disease from developing prior to treatment, but also preventing the recurrence of the disease after treatment.

[0061] As used herein, the term "treatment" means reversing, alleviating, or ameliorating a disease or condition being treated. A subject is successfully "treated" if, after receiving a therapeutic amount of a salt of a compound of the disclosure or a compound of its crystalline form or a pharmaceutical composition of the disclosure, at least one indicator and symptom of the subject exhibits observable and / or measurable improvement. It is understood that treatment includes not only complete treatment, but also partial treatment that achieves some biological or medically relevant result. In particular, "treatment" indicates that a salt of a compound of the disclosure or a compound of its crystalline form or a pharmaceutical composition of the disclosure can achieve at least one of the following effects: (1) inhibiting the disease (i.e., arresting further progression of the pathology and / or symptomatology), in an animal that is experiencing or displaying the pathology or symptomatology of a disease; (2) ameliorating the disease (i.e., reversing the pathology and / or symptomatology), in an animal that is experiencing or displaying the pathology or symptomatology of a disease.

[0062] Compound of Formula I Form I

[0063] In some embodiments, the XRPD pattern of Form I shows at least two, at least three, at least four, at least five, or at least six diffraction angles 2Q (°).

[0064] The present disclosure provides a compound of Formula I Form I having an XRPD pattern comprising a characteristic peak at a diffraction angle (2Q) at about 12.8 ± 0.2°, 14.6 ± 0.2°, and / or 21.9 ± 0.2°.

[0065] In some embodiments, the XRPD pattern of the compound of Formula I Form I comprises a characteristic peak at a diffraction angle (2Q) at 12.8 ± 0.2°, 13.2 ± 0.2°, 14.6 ± 0.2°, 19.3 ± 0.2°, and / or 21.9 ± 0.2°.

[0066] In some embodiments, the XRPD pattern of the compound of Formula I Form I comprises a characteristic peak at a diffraction angle (2Q) at about 12.8 ± 0.2°, 13.2 ± 0.2°, 14.6 ± 0.2°, 17.9 ± 0.2°, 19.3 ± 0.2°, and / or 21.9 ± 0.2°.

[0067] In some embodiments, the XRPD pattern of the compound of Formula I Form I includes characteristic peaks at diffraction angles (2Θ) at 12.8 ± 0.2°, 13.2 ± 0.2°, 14.6 ± 0.2°, 17.9 ± 0.2°, 19.3 ± 0.2°, 20.6 ± 0.2°, 21.9 ± 0.2°, 25.0 ± 0.2°, 25.6 ± 0.2°, and / or 27.0 ± 0.2°.

[0068] In some embodiments, the XRPD pattern of the compound of Formula I Form I includes characteristic peaks at diffraction angles (2Θ) at 12.8 ± 0.2°, 13.2 ± 0.2°, 14.6 ± 0.2°, 16.0 ± 0.2°, 17.9 ± 0.2°, 18.6 ± 0.2°, 19.3 ± 0.2°, 19.6 ± 0.2°, 20.6 ± 0.2°, 21.4 ± 0.2°, 21.9 ± 0.2°, 23.6 ± 0.2°, 24.3 ± 0.2°, 25.0 ± 0.2°, 25.6 ± 0.2°, 26.0 ± 0.2°, 27.0 ± 0.2°, 27.9 ± 0.2°, 28.5 ± 0.2°, 29.3 ± 0.2°, and / or 36.3 ± 0.2°.

[0069] In some embodiments, the XRPD pattern of the compound of Formula I Form I includes peaks at diffraction angles (2Θ) as set forth in Table 1, wherein the error range for the 2Θ values is ± 0.2°:

[0070] Table 1: XRPD Data for Compound of Formula I Form I

[0071] In some embodiments, the XRPD pattern of the compound of Formula I Form I includes peaks at substantially the same diffraction angles (2Θ) as set forth in Figure 1.

[0072] In some embodiments, the XRPD pattern of the compound of Formula I Form I is substantially as set forth in Figure 1.

[0073] In some embodiments, the XRPD pattern of the compound of Formula I Form I is as set forth in Figure 1.

[0074] In some embodiments, the compound of Formula I Form I is a monohydrate crystalline form of the compound of Formula I.

[0075] In some embodiments, the endothermic peak of the compound of Formula I Form I has an onset temperature (onset value) of about 101.6 °C ± 10 °C, preferably about 101.6 °C ± 5 °C.

[0076] In some embodiments, the DSC of the compound of Formula I in crystalline Form I has no melting peak; it starts to decompose at a temperature higher than 240 °C, combined with single crystal structure analysis, the water molecule in Form I is involved in the API lattice to form a stoichiometrically combined water molecule, and during the heating process of thermal analysis DSC, the lattice collapses into amorphous after the water molecule is removed, so the melting peak of Form I cannot be measured by DSC thermal analysis.

[0077] In some embodiments, the DSC of the compound of Formula I in crystalline Form I is substantially as shown in Figure 2, preferably as shown in Figure 2.

[0078] In some embodiments, the total weight change of the compound of Formula I in crystalline Form I on the TGA thermogravimetric curve at about 101.6 °C ± 10 °C, preferably about 101.6 °C ± 5 °C, is about 3.7% ± 1%, corresponding to the removal of one molecule of crystalline water. Preferably, the TGA of the compound of Formula I in crystalline Form I is substantially as shown in Figure 3, preferably as shown in Figure 3.

[0079] In some embodiments, the dynamic water vapor sorption (DVS) of the compound of Formula I in crystalline Form I is as shown in Figure 4. At RH in the range of 0-90% humidity, Form I is almost non-hygroscopic.

[0080] In some embodiments, the polarized light microscope of the compound of Formula I in crystalline Form I is as shown in Figure 5, in the form of rod-shaped crystals.

[0081] In some embodiments, the single crystal cell structure of the compound of Formula I in crystalline Form I is as shown in Figure 6, the single crystal cell of Form I is monoclinic, the space group is C121, and the single crystal cell parameters of the compound of Formula I in crystalline Form I are: α = 90°, β = 109.743(2)°, γ = 90°, and the number of asymmetric units in a unit cell, Z, is 4, each cell containing one compound of Formula I and one water molecule.

[0082] Amorphous Form of the Compound of Formula I

[0083] The present disclosure provides an amorphous form of the compound of Formula I, which has no diffraction characteristic peaks on the XRPD spectrum, preferably the XRPD spectrum is substantially as shown in Figure 7, in the form of a diffuse hump.

[0084] In some embodiments, the polarized light microscope of the amorphous form of the compound of Formula I is as shown in Figure 8, in the form of a non-birefringent powder.

[0085] Salt of the Compound of Formula I and Crystalline Form Thereof

[0086] The present disclosure provides a salt of the compound of Formula I, wherein the salt is a 1,5-naphthalene disulfonate salt, a sulfate salt, or a maleate salt

[0087] In some embodiments, the salt of the compound of Formula I is a 1,5-naphthalene disulfonic acid salt of the compound of Formula I.

[0088] Formulation A of a 1,5-naphthalene disulfonic acid salt of the compound of Formula I

[0089] In some embodiments, the XRPD pattern of Formulation A of a 1,5-naphthalene disulfonic acid salt of the compound of Formula I shows at least two, at least three, at least four, at least five, or at least six diffraction angles 2 theta (°) of maximum intensity.

[0090] The present disclosure provides Formulation A of a 1,5-naphthalene disulfonic acid salt of the compound of Formula I, the XRPD pattern of Formulation A of the 1,5-naphthalene disulfonic acid salt comprising a characteristic peak at a diffraction angle (2 theta) at about 4.9 ± 0.2°, 16.5 ± 0.2°, and / or 26.2 ± 0.2°.

[0091] In some embodiments, the XRPD pattern of Formulation A of a 1,5-naphthalene disulfonic acid salt of the compound of Formula I comprises a characteristic peak at a diffraction angle (2 theta) at about 4.9 ± 0.2°, 14.9 ± 0.2°, 16.5 ± 0.2°, 19.7 ± 0.2°, 23.1 ± 0.2°, 23.4 ± 0.2°, and / or 26.2 ± 0.2°.

[0092] In some embodiments, the XRPD pattern of Formulation A of a 1,5-naphthalene disulfonic acid salt of the compound of Formula I comprises a characteristic peak at a diffraction angle (2 theta) at about 4.9 ± 0.2°, 14.9 ± 0.2°, 16.5 ± 0.2°, 19.7 ± 0.2°, 21.3 ± 0.2°, 23.1 ± 0.2°, 23.4 ± 0.2°, 24.9 ± 0.2°, 26.2 ± 0.2°, and / or 27.9 ± 0.2°.

[0093] In some embodiments, the XRPD pattern of Formulation A of a 1,5-naphthalene disulfonic acid salt of the compound of Formula I comprises a characteristic peak at a diffraction angle (2 theta) at about 4.9 ± 0.2°, 9.5 ± 0.2°, 10.4 ± 0.2°, 10.6 ± 0.2°, 11.6 ± 0.2°, 13.9 ± 0.2°, 14.9 ± 0.2°, 16.5 ± 0.2°, 18.5 ± 0.2°, 19.1 ± 0.2°, 19.7 ± 0.2°, 20.1 ± 0.2°, 20.5 ± 0.2°, 21.3 ± 0.2°, 22.1 ± 0.2°, 23.1 ± 0.2°, 23.4 ± 0.2°, 24.5 ± 0.2°, 24.9 ± 0.2°, 25.4 ± 0.2°, 26.2 ± 0.2°, and / or 27.9 ± 0.2°.

[0094] In some embodiments, the XRPD pattern of the 1,5-naphthalene disulfonic acid salt Form A of the compound of Formula I includes peaks at diffraction angles (2q) set forth in Table 2, wherein the error range for the 2q values is ±0.2°:

[0095] Table 2: XRPD data for the 1,5-naphthalene disulfonic acid salt Form A of the compound of Formula I

[0096] In some embodiments, the 1,5-naphthalene disulfonic acid salt Form A of the compound of Formula I has an XRPD pattern substantially as set forth in FIG. 9.

[0097] In some embodiments, the 1,5-naphthalene disulfonic acid salt Form A of the compound of Formula I has an XRPD pattern as set forth in FIG. 9.

[0098] In some embodiments, the 1,5-naphthalene disulfonic acid salt Form A of the compound of Formula I has a polarized light microscopy pattern as set forth in FIG. 10, as fine crystals.

[0099] 1,5-Naphthalene disulfonic acid salt Form B of the compound of Formula I

[0100] In some embodiments, the XRPD pattern of the 1,5-naphthalene disulfonic acid salt Form B of the compound of Formula (I) exhibits at least two, at least three, at least four, at least five, or at least six diffraction angles 2q (°) with the maximum intensity.

[0101] The present disclosure provides a 1,5-naphthalene disulfonic acid salt Form B of the compound of Formula I having an XRPD pattern with characteristic peaks at diffraction angles (2q) at about 4.9 ± 0.2°, 9.7 ± 0.2°, 16.7 ± 0.2°, and / or 19.4 ± 0.2°.

[0102] In some embodiments, the XRPD pattern of the 1,5-naphthalene disulfonic acid salt Form B of the compound of Formula I has characteristic peaks at diffraction angles (2q) at about 4.9 ± 0.2°, 9.7 ± 0.2°, 11.5 ± 0.2°, 16.7 ± 0.2°, 19.4 ± 0.2°, and / or 19.8 ± 0.2°.

[0103] In preferred embodiments, the XRPD pattern of the 1,5-naphthalene disulfonic acid salt Form B of the compound of Formula I includes characteristic peaks at diffraction angles (2q) at about 4.9 ± 0.2°, 9.7 ± 0.2°, 11.5 ± 0.2°, 14.9 ± 0.2°, 16.7 ± 0.2°, 19.4 ± 0.2°, 19.8 ± 0.2°, 23.4 ± 0.2°, 26.2 ± 0.2°, and / or 27.9 ± 0.2°.

[0104] In some embodiments, the XRPD pattern of the 1,5-naphthalene disulfonic acid salt Form B of the compound of Formula I includes characteristic peaks at diffraction angles (2 theta) (°) at 4.9 ± 0.2°, 9.7 ± 0.2°, 10.5 ± 0.2°, 10.7 ± 0.2°, 11.5 ± 0.2°, 11.9 ± 0.2°, 12.4 ± 0.2°, 12.7 ± 0.2°, 14.9 ± 0.2°, 15.8 ± 0.2°, 16.7 ± 0.2°, 18.5 ± 0.2°, 19.2 ± 0.2°, 19.4 ± 0.2°, 19.8 ± 0.2°, 21.3 ± 0.2°, 21.5 ± 0.2°, 22.5 ± 0.2°, 23.4 ± 0.2°, 24.5 ± 0.2°, 25.3 ± 0.2°, 25.5 ± 0.2°, 26.2 ± 0.2°, and / or 27.9 ± 0.2°.

[0105] In some embodiments, the XRPD pattern of the 1,5-naphthalene disulfonic acid salt Form B of the compound of Formula I includes peaks at diffraction angles (2 theta) (°) as set forth in Table 3, wherein the error range for the 2 theta values is ± 0.2°:

[0106] Table 3: XRPD data for the 1,5-naphthalene disulfonic acid salt Form B of the compound of Formula I

[0107] In some embodiments, the 1,5-naphthalene disulfonic acid salt Form B of the compound of Formula I has an XRPD pattern substantially as set forth in FIG. 11.

[0108] In some embodiments, the 1,5-naphthalene disulfonic acid salt Form B of the compound of Formula I has an XRPD pattern as set forth in FIG. 11.

[0109] In some embodiments, the 1,5-naphthalene disulfonic acid salt Form B of the compound of Formula I has a polarized light microscopy pattern as set forth in FIG. 12, as short rod-like crystals.

[0110] Sulfate salt Form of the compound of Formula (I)

[0111] In some embodiments, the XRPD pattern of the sulfate salt Form of the compound of Formula I shows at least two, at least three, at least four, at least five, or at least six diffraction angles 2 theta (°) with the maximum intensity.

[0112] The present disclosure provides a sulfate salt Form of the compound of Formula I, the XRPD pattern of which includes characteristic peaks at diffraction angles (2 theta) (°) at about 4.2 ± 0.2°, 12.0 ± 0.2°, 14.5 ± 0.2°, 20.3 ± 0.2°, and / or 20.9 ± 0.2°.

[0113] In some embodiments, the XRPD pattern of the sulfate salt crystalline form of the compound of Formula I includes characteristic peaks at diffraction angles (2Θ) at 4.2±0.2°, 6.9±0.2°, 8.1±0.2°, 12.0±0.2°, 12.7±0.2°, 13.9±0.2°, 14.5±0.2°, 17.6±0.2°, 18.4±0.2°, 18.9±0.2°, 20.3±0.2°, 20.9±0.2°, 24.6±0.2°, and / or 25.6±0.2°.

[0114] In some embodiments, the XRPD pattern of the sulfate salt crystalline form of the compound of Formula I includes characteristic peaks at diffraction angles (2Θ) at 4.2±0.2°, 6.9±0.2°, 8.1±0.2°, 12.0±0.2°, 12.7±0.2°, 13.9±0.2°, 14.5±0.2°, 17.6±0.2°, 18.4±0.2°, 18.9±0.2°, 20.3±0.2°, 20.9±0.2°, 24.6±0.2°, and / or 25.6±0.2°.

[0115] In some embodiments, the XRPD pattern of the sulfate salt crystalline form of the compound of Formula I includes characteristic peaks at diffraction angles (2Θ) at 4.2±0.2°, 6.9±0.2°, 8.1±0.2°, 12.0±0.2°, 12.7±0.2°, 13.9±0.2°, 14.5±0.2°, 17.6±0.2°, 18.4±0.2°, 18.9±0.2°, 20.3±0.2°, 20.9±0.2°, 24.6±0.2°, and / or 25.6±0.2°.

[0116] In some embodiments, the XRPD pattern of the sulfate salt crystalline form of the compound of Formula I includes peaks at diffraction angles (2Θ) set forth in Table 4, wherein the error range for the 2Θ values is ±0.2°:

[0117] Table 4: XRPD data for the sulfate salt crystalline form of the compound of Formula I

[0118] In some embodiments, the sulfate salt crystalline form of the compound of Formula I has an XRPD pattern substantially as set forth in FIG. 13.

[0119] In some embodiments, the sulfate salt crystalline form of the compound of Formula I has an XRPD pattern as set forth in FIG. 13.

[0120] In some embodiments, the sulfate salt crystalline form of the compound of Formula I has a polarized light microscopy pattern as set forth in FIG. 14, as a plate-like crystal.

[0121] Maleate salt crystalline form of the compound of Formula (I)

[0122] In some embodiments, the maleate salt crystalline form of the compound of Formula I has an XRPD pattern showing at least two, at least three, at least four, at least five, or at least six diffraction angles 2-theta (°) of maximum intensity.

[0123] The present disclosure provides a maleate salt crystalline form of the compound of Formula I having an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at diffraction angles (2-theta) of 3.8 ± 0.2°, 13.1 ± 0.2°, 16.4 ± 0.2°, 18.5 ± 0.2°, 19.9 ± 0.2°, and / or 26.3 ± 0.2°.

[0124] In some embodiments, the maleate salt crystalline form of the compound of Formula I has an XRPD pattern comprising peaks at diffraction angles (2-theta) set forth in Table 5, wherein the error range for the 2-theta values is ± 0.2°:

[0125] Table 5: XRPD data for the maleate salt crystalline form of the compound of Formula I

[0126] In some embodiments, the maleate salt crystalline form of the compound of Formula I has an XRPD pattern substantially as set forth in FIG. 15.

[0127] In some embodiments, the maleate salt crystalline form of the compound of Formula I has an XRPD pattern as set forth in FIG. 15.

[0128] In some embodiments, the maleate salt crystalline form of the compound of Formula I has a polarized light microscopy pattern as set forth in FIG. 16, as fine crystals.

[0129] Methods of preparing crystalline forms

[0130] For the compound of Formula I and its salts of the present disclosure, the formation of various crystalline forms depends to some extent on the selection of a particular solvent or combination of solvents, and the method of combining solvents can also affect the formation of crystalline forms. Solvents that can be used to prepare various crystalline forms of the present disclosure include, but are not limited to, for example, nitriles (e.g., acetonitrile), ketones (e.g., acetone), alcohols (e.g., ethanol, methanol, isopropanol), tetrahydrofuran, purified water, or esters (e.g., ethyl acetate), and any mixed solvents thereof.

[0131] The present disclosure provides methods of preparing one or more of the above-mentioned crystalline forms of Compound I or its salts.

[0132] In some embodiments, the present disclosure provides a method for preparing the crystalline form I of the compound of Formula I, which comprises mixing the compound of Formula I with a solvent, and then isolating the resulting solid; wherein the solvent is a combination of a first solvent selected from the group consisting of nitriles (e.g., acetonitrile), ketones (e.g., acetone), alcohols (e.g., ethanol, methanol, isopropanol), and tetrahydrofuran, and a second solvent selected from the group consisting of purified water and esters (e.g., ethyl acetate); or the solvent is an alcohol (e.g., isopropanol) or an ester (e.g., ethyl acetate).

[0133] In some embodiments, the first solvent is selected from the group consisting of nitriles (e.g., acetonitrile), ketones (e.g., acetone), and tetrahydrofuran; and the second solvent is purified water.

[0134] In some embodiments, the volume ratio of the first solvent to the second solvent is 1:10-10:1, such as 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1.

[0135] In some embodiments, the present disclosure provides a method for preparing the crystalline form I of the compound of Formula I, which comprises mixing the compound of Formula I with a first solvent, and then adding a second solvent for crystallization, and isolating the resulting solid to obtain the crystalline form I of the compound of Formula I.

[0136] In some embodiments, in the method for preparing the crystalline form I, the compound of Formula I is mixed with the first solvent to form a clear solution at 40-60°C, and then the second solvent is added for crystallization at room temperature to 60°C (e.g., room temperature, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C), and the resulting solid is isolated to obtain the crystalline form I of the compound of Formula I.

[0137] In some embodiments, the present disclosure provides a method for preparing the crystalline form I of the compound of Formula I, which comprises mixing the compound of Formula I with a mixed solution of a first solvent and a second solvent, and then slowly evaporating in a small hole, and isolating the resulting solid to obtain the crystalline form I of the compound of Formula I.

[0138] In some embodiments, in the method for preparing the crystalline form I, the compound of Formula I is mixed with a mixed solution of a first solvent and a second solvent to form a supersaturated solution, and then filtered through a membrane (e.g., a 0.22 μm filter membrane), and then slowly evaporated in a small hole at room temperature, and the resulting solid is isolated to obtain the crystalline form I of the compound of Formula I.

[0139] In some embodiments, in the method for preparing the crystalline form I, the compound of Formula I is mixed with a mixed solution of acetonitrile and water to form a supersaturated solution, and then filtered through a membrane (e.g., a 0.22 μm filter membrane), and then slowly evaporated in a small hole at room temperature, and the resulting solid is isolated to obtain the crystalline form I of the compound of Formula I.

[0140] In some embodiments, this disclosure provides a method for preparing crystal form I of compound I, which includes mixing compound I of formula with isopropanol or ethyl acetate, then slowly evaporating through a small pore, and separating the resulting solid as crystal form I of compound I.

[0141] In some embodiments, this disclosure provides a method for preparing crystal form I of compound I, which includes mixing compound I of formula with isopropanol or ethyl acetate to form a supersaturated solution, then filtering it through a membrane (e.g., a 0.22 μm membrane), then punching small holes and slowly evaporating it at room temperature, and the resulting solid is compound I of formula I crystal form I.

[0142] In some embodiments, this disclosure provides a method for preparing an amorphous form of a compound of formula I, comprising mixing a crystalline form I of a compound of formula I with a solvent, evaporating the solvent to obtain a solid, wherein the solvent is selected from nitrile (e.g., acetonitrile), ketone (e.g., acetone), alcohol (e.g., ethanol, methanol, isopropanol), purified water, or ester (e.g., ethyl acetate) and any mixture thereof.

[0143] In some embodiments, this disclosure provides a method for preparing crystal form A of the 1,5-naphthalenedisulfonate of compound I, comprising reacting compound I with 1,5-naphthalenedisulfonic acid in a solvent, and then stirring to separate the resulting solid, wherein the solvent is selected from a mixture of alcohols (e.g., methanol, ethanol, isopropanol) and water.

[0144] In some embodiments, this disclosure provides a method for preparing crystal form B of the 1,5-naphthalenedisulfonate of compound I, comprising reacting the compound of formula I with 1,5-naphthalenedisulfonic acid in a solvent, and then stirring to separate the resulting solid, wherein the solvent is selected from ketones (e.g., acetone), esters (e.g., ethyl acetate), and any mixture thereof.

[0145] In some embodiments, this disclosure provides a method for preparing the sulfate crystal form of a compound of formula I, comprising reacting the compound of formula I with sulfuric acid in a solvent and then separating the resulting solid, wherein the solvent is selected from nitrile compounds (e.g., acetonitrile).

[0146] In some embodiments, this disclosure provides a method for preparing the maleate crystal form of a compound of formula I, comprising reacting the compound of formula I with maleic acid in a solvent, and then stirring to separate the resulting solid, wherein the solvent is selected from ketones (e.g., acetone), esters (e.g., ethyl acetate), nitriles (e.g., acetonitrile), and any mixture thereof. Detailed Implementation

[0147] The present disclosure will be further illustrated by the following embodiments. The embodiments of the present disclosure are only used to illustrate the technical solutions of the present disclosure and are not intended to limit the scope of the present disclosure. Those skilled in the art can make some non-essential improvements and adjustments, which still fall within the protection scope of the present disclosure.

[0148] The crystal forms or amorphous forms prepared in the examples were characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), polarized light microscopy (PLM), dynamic vapor sorption (DVS) and X-ray single crystal diffractometer.

[0149] (1) X-ray powder diffraction (XRPD)

[0150] The XRPD patterns of the crystal forms or amorphous forms were collected by X’Pert3 Powder diffractometer, which used Cu palladium radiation, and was detected at room temperature using Absolute scan. The detection range was 3.5° to 40°, the step was 0.013°, the dwell time was 50 s, and the scanning was 1 time.

[0151] (2) Differential scanning calorimetry (DSC)

[0152] The DSC patterns of the crystal forms were collected by TA DSC 2500 differential scanning calorimeter, and the test temperature range was 35°C to 250°C, and the heating rate was 10°C / min.

[0153] (3) Thermogravimetric analysis (TGA)

[0154] The TGA patterns of the crystal forms were collected by METTLER TOLEDO thermogravimetric analyzer, and the test temperature range was 35°C to 500°C, and the heating rate was 10°C / min.

[0155] (4) Dynamic vapor sorption (DVS)

[0156] The DVS patterns of the crystal forms were tested by DVS Intrinsic (SMS), and the test temperature was 25°C, and the detection was carried out under DMDT mode.

[0157] (5) Single crystal The single crystal was tested and analyzed by X-ray single crystal diffractometer, and the detection instrument model was Bruker D8QUEST (copper target). The in-depth exploration of the theory of single crystal X-ray diffraction method and the definition of evaluation of crystal data and parameters can be found in Stout & Jensen, X-Ray Structure Determination; A Practical Guide, Mac Millian Co., New York, N.Y. (1968) Chapter 3.

[0158] Preparation Example 1: Preparation of the compound of formula I

[0159] Step one: synthesis of methyl 4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5- (trifluoromethyl)tetrahydrothiophene-2-carboxamido)picolinate

[0160] Into a dry round-bottom flask was added 3-(3,4-difluoro-2-methoxyphenyl)-5- methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxylic acid (837 mg, 2.35 mmol), DMF (30 mL), NMI (1.17 g, 11.4 mmol) and methyl 4-aminopicolinate (550 mg, 3.64 mmol), TCFH (2.08 mg, 7.2 mmol) was added under ice bath, and the reaction was stirred at room temperature for 1 h. The reaction was quenched by adding water (20 mL), extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with water for three times, saturated brine for once, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by Pre-HPLC to give the target compound (910 mg, 1.86 mmol, 78.99% yield), MS: m / z = 491.1, [M+H]+.

[0161] Step two: synthesis of 4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5- (trifluoromethyl)tetrahydrothiophene-2-carboxamido)picolinamide

[0162] Into an autoclave was added the product of step one (910 mg, 1.86 mmol) and 2M ammonia in methanol (15 mL). The system was heated to 60°C and stirred overnight. The system was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated by Pre-HPLC to give the target compound (711 mg, 1.5 mmol, 80.6% yield), MS: m / z = 476.3, [M+H]+, 1H NMR (400 MHz, DMSO) δ 10.81 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.15 (d, J = 1.7 Hz, 1H), 8.03 (s, 1H), 7.67 (dd, J = 5.5, 2.0 Hz, 1H), 7.60 (s, 1H), 7.28 - 7.09 (m, 2H), 4.61 (d, J = 10.6 Hz, 1H), 4.39 - 7.18 (m, 1H), 3.97 (d, J = 1.5 Hz, 3H), 2.47 - 2.13 (m, 2H), 1.74 (s, 3H).

[0163] The product of step two was separated by the following chiral separation method: column AD-H, column temperature 30°C, mobile phase (n-hexane-anhydrous ethanol-isopropanol-diethylamine = 80:16:4:0.05), flow rate 1 mL / min, and the component with retention time of about 5.3 min was dried to give the compound of formula I.

[0164] Preparation of single crystal of compound of formula I in crystalline form I

[0165] To 11.55 mg of compound of formula I, 2 mL of acetonitrile and 2 mL of purified water were added, and the mixture was ultrasonically dissolved at 45°C. After the solution was clear, the sample was filtered through a 0.25 μm needle filter into a 5 mL glass bottle. The mouth of the glass bottle was sealed with a sealing film, and 7-8 small holes were made in the capillary tube. The single crystal of compound of formula I in crystalline form I was obtained after culturing for 7-10 days. The cell structure of the single crystal obtained by X-ray diffraction analysis is shown in Figure 6.

[0166] The XRPD pattern of the single crystal of compound of formula I in crystalline form I obtained is substantially shown in Figure 1.

[0167] Example 1

[0168] Preparation of compound of formula I in crystalline form I

[0169] To 5 g of compound of formula I obtained in Preparation 1, 25 mL of acetone was added, and the mixture was stirred and warmed to 50°C until the solution was clear. The solution was cooled to 20°C, and purified water was added dropwise to the solution at a constant temperature. After the dropwise addition was completed, the solution was cooled to 20°C, and the crystals were aged for 30 min. The crystals were filtered, and dried at 55°C under a vacuum of -0.07 MPa for 16 h to obtain 4.85 g of compound of formula I in crystalline form I.

[0170] The XRPD pattern of compound of formula I in crystalline form I obtained is shown in Figure 1, the DSC pattern is shown in Figure 2, the TGA pattern is shown in Figure 3, and the DVS pattern is shown in Figure 4. The PLM pattern is shown in Figure 5. It can be seen that the compound of formula I in crystalline form I is rod-shaped, has a large particle size, and has a uniform particle size distribution.

[0171] Example 2

[0172] Preparation of compound of formula I in crystalline form I

[0173] To 5 g of compound of formula I obtained in Preparation 1, 25 mL of acetonitrile was added, and the mixture was stirred and warmed to 50°C until the solution was clear. The solution was cooled to 40°C, and purified water was added dropwise to the solution at a constant temperature. 25 mg of the crystals prepared in Example 1 was added as a crystal seed to induce crystallization, and the crystals were aged for 30 min. Then, purified water was further added dropwise to the solution. After the dropwise addition was completed, the solution was cooled to 30°C, and the crystals were aged for 30 min. The crystals were filtered, and dried at 50°C under a vacuum of -0.07 MPa for 16 h to obtain 4.6 g of compound of formula I in crystalline form I.

[0174] The XRPD pattern of compound of formula I in crystalline form I obtained is substantially shown in Figure 1, the DSC pattern is substantially shown in Figure 2, the TGA pattern is substantially shown in Figure 3, and the DVS pattern is substantially shown in Figure 4. The PLM pattern is substantially shown in Figure 5.

[0175] Example 3

[0176] Preparation of amorphous form of compound of formula I

[0177] To 0.572 g of the compound of formula I prepared in Example 1, 20 ml of acetonitrile and 5 ml of purified water were added, and the mixture was dissolved under ultrasonic wave. The solution was rotary evaporated at 35 °C until the sample became gelatinous, and then the rotary evaporation was stopped. After being freeze-dried for 15 h, the amorphous form of the compound of formula I was obtained (the yield was 87%).

[0178] The XRPD pattern of the amorphous form of the compound of formula I obtained is shown in Figure 7, and the PLM pattern is shown in Figure 8.

[0179] Example 4

[0180] Preparation of 1,5-naphthalenedisulfonate salt crystal form A of compound of formula I

[0181] To 263 mg of the compound of formula I obtained in Preparation Example 1, 5 ml of ethanol was added to dissolve the sample, and then a 1,5-naphthalenedisulfonic acid solution (1,5-naphthalenedisulfonic acid (193 mg, 1.2 eq) was dissolved in 5 mL of purified water) was added. After being stirred at 20 °C for 20 h, the sample was separated by filtration and dried to obtain the 1,5-naphthalenedisulfonate salt crystal form A of the compound of formula I.

[0182] The XRPD pattern of the 1,5-naphthalenedisulfonate salt crystal form A of the compound of formula I obtained is shown in Figure 9, and the PLM pattern is shown in Figure 10.

[0183] Example 5

[0184] Preparation of 1,5-naphthalenedisulfonate salt crystal form B of compound of formula I

[0185] To 263 mg of the compound of formula I obtained in Preparation Example 1, 193 mg of 1,5-naphthalenedisulfonic acid and 10 ml of ethyl acetate were added. After being stirred at room temperature for 20 h, the sample was separated by filtration and dried to obtain the 1,5-naphthalenedisulfonate salt crystal form B of the compound of formula I.

[0186] The XRPD pattern of the 1,5-naphthalenedisulfonate salt crystal form B of the compound of formula I obtained is shown in Figure 11, and the PLM pattern is shown in Figure 12.

[0187] Example 6

[0188] Preparation of sulfate salt crystal form of compound of formula I

[0189] To 263 mg of the compound of formula I obtained in Preparation Example 1, 20 mL of acetonitrile was added, and the system was dissolved at 45 °C. Then 550 μL of 1 mol / L aqueous sulfuric acid solution (1 eq) was added, and the system was dissolved at 45 °C. After being cooled to room temperature, the compound of formula I in sulfate salt crystal form was obtained by volatilization.

[0190] The XRPD pattern of the sulfate salt crystal form of the compound of formula I obtained is shown in Figure 13, and the PLM pattern is shown in Figure 14.

[0191] Example 7

[0192] Preparation of the maleate salt crystal form of the compound of formula I

[0193] To 263 mg of the compound of formula I prepared in Preparation Example 1, 15 mL of acetone was added, the system was dissolved at room temperature, then maleic acid (76.2 mg, 1.2 eq) was added, and the solution was stirred at room temperature. The solution was warmed and evaporated to crystallize to obtain the maleate salt crystal form of the compound of formula I.

[0194] The XRPD spectrum of the obtained maleate salt crystal form of the compound of formula I is shown in Figure 15, and the PLM spectrum is shown in Figure 16.

[0195] Example 8

[0196] Preparation of the crystal form I of the compound of formula I

[0197] The compound of formula I obtained in Preparation Example 1 was prepared into a saturated solution with isopropanol at room temperature, then filtered through a 0.22 μm filter membrane, and a small hole was sealed and slowly evaporated at room temperature to obtain the crystal form I of the compound of formula I.

[0198] Example 9

[0199] Preparation of the crystal form I of the compound of formula I

[0200] The compound of formula I obtained in Preparation Example 1 was prepared into a saturated solution with ethyl acetate at room temperature, then filtered through a 0.22 μm filter membrane, and a small hole was sealed and slowly evaporated at room temperature to obtain the crystal form I of the compound of formula I.

[0201] Example 10

[0202] Preparation of the crystal form I of the compound of formula I

[0203] The compound of formula I obtained in Preparation Example 1 was prepared into a saturated solution with tetrahydrofuran at 40°C, and purified water was slowly added dropwise at a constant temperature of 40°C to crystallize to obtain the crystal form I of the compound of formula I.

[0204] Comparative Preparation Example 1:

[0205] By the method of solution crystallization, such as cooling crystallization, evaporation crystallization, and cooling-evaporation coupling crystallization, the compound of formula I was reacted with the following acids in solvents such as ethanol / water = 1:1, acetone, ethyl acetate, acetonitrile, and the results showed that the compound of formula I could not obtain a crystal salt with most of the commonly used inorganic acids or organic acids.

[0206] Comparative Preparation Example 2: Investigation of crystallization conditions

[0207] The compound of formula I crystal form I or amorphous and solvent were mixed, and then the crystallization conditions in the following table were followed to obtain the product after centrifugation.

[0208] The amorphous or co-polymorphic crystal Form I and Form II or co-polymorphic crystal Form I and Form III of the compound of Formula I were slurried in the solvents listed in the table below, and the slurry was cycled through temperature changes (temperature 25 °C for 2 h, then temperature increased to 45 °C for 2 h, and the cycle was repeated for one week). The product was obtained by centrifugation of the solid. The XRPD results are shown below:

[0209] The results show that pure Form I can be obtained under the crystallization solvents and conditions in Examples 1-2 and Examples 8-10; pure Form II can be obtained by controlling the crystallization conditions when the crystallization solvent is 1,4-dioxane. However, under other solvent systems and conditions, co-polymorphic Form I and Form II and co-polymorphic Form I and Form III can be obtained.

[0210] Co-polymorphism refers to the phenomenon that two or more crystal forms are crystallized at the same time, which has a great impact on the quality of the product. The occurrence of co-polymorphism is unpredictable, and the reasons are various, such as similar crystal energies, interactions between crystallization thermodynamics and kinetics, and competition between different crystal nucleation rates and growth rates. It is well known that different crystal forms of drugs have different bioavailability. Once co-polymorphism occurs, the efficacy stability of the drug product will be severely compromised, affecting the efficacy of the product. At the same time, different crystal forms of drugs have different habits, and the occurrence of co-polymorphism will lead to uneven particle size distribution of the product, which will seriously affect the subsequent processing of the drug product, such as filtration, drying, storage, and transportation. Therefore, it is necessary to strictly control the crystallization solvent and conditions to obtain a crystal form with high crystallinity, high purity, uniform particle size distribution, and no hygroscopicity.

[0211] <Formula I compound Form II>

[0212] The XRPD data of the compound of Formula I Form II (crystallized from 1,4-dioxane) are shown in Table 6, wherein the error range of the 2θ value is ±0.2°, and the XRPD spectrum is shown in Figure 18; the DSC spectrum is shown in Figure 19; and the PLM spectrum is shown in Figure 20, which presents irregular block crystals with obvious aggregation and poor morphology.

[0213] Table 6: XRPD data of the compound of Formula I Form II

[0214] <Co-polymorphism of Form I and Form II (co-polymorphic Form I and Form II)>

[0215] The XRPD spectra of Form I, Form II, and the co-polymorphic Form I and Form II are shown in Figure 21.

[0216] From the PLM morphology, the particle size of Form I is large and uniform, which has more excellent powder properties than Form II and the concomitant polymorphs of Form I and Form II, and is more suitable for subsequent formulation development of drug materials.

[0217] <Concomitant polymorphs of Form I and Form III (concomitant polymorphs of Form I and Form III)>

[0218] The XRPD patterns of Form I and the concomitant polymorphs of Form I and Form III are shown in FIG. 22. The XRPD data of Form I and the concomitant polymorphs of Form I and Form III are shown in Table 7, wherein the error range of 2θ value is ±0.2°, and the XRPD patterns thereof are shown in FIG. 23.

[0219] Table 7: XRPD data of Form I and the concomitant polymorphs of Form I and Form III of the compound of Formula I

[0220] Polarized light microscopy (PLM)

[0221] The polarized light microscopy patterns of Form I and the concomitant polymorphs of Form I and Form III are shown in FIG. 24, which exhibit fine rod-shaped crystals and aggregated fine needle-shaped morphology.

[0222] Stability experiment

[0223] The concomitant polymorphs of Form I and Form III were placed at room temperature for 6 months, and the superimposed XRPD patterns before and after the room temperature placement are shown in FIG. 25, indicating that the concomitant polymorphs are stable.

[0224] The concomitant polymorphs of Form I and Form III were placed at 45°C / 0.08 MPa, vacuum dried for 48 hours, and the superimposed XRPD patterns before and after the drying are shown in FIG. 26, indicating that the crystallinity does not change before and after the drying, and the concomitant polymorphs are stable.

[0225] In summary, since Form I is easy to form concomitant polymorphs with anhydrous Form II and Form III, and the concomitant polymorphs still exist stably for 6 months under long-term storage conditions, the generation of Form I and the concomitant polymorphs of Form II / Form III should be avoided.

[0226] Stability experiment of Experimental Example 1

[0227] The stability experiment of the crystal form of the compound of Formula I prepared in the present disclosure was carried out under high temperature (60°C±2°C), high humidity (45°C±2°C / 75%RH±5%RH), light (4500lx±500lx and ≥0.80×102μW / cm2), and light with packaging (4500lx±500lx and ≥0.80×102μW / cm2) conditions.

[0228] The results of the stability experiment of the compound of formula I in the form of crystal form I are shown in Table 8 and Figure 17 below.

[0229] Table 8: Stability experiment of the compound of formula I in the form of crystal form I

[0230] The results show that the chemical stability and crystal form stability of the crystal form I are both good under the conditions of light, light with packaging, high temperature, high humidity and light and shadow, and the purity of 29 days is basically unchanged compared with that of 0 day.

[0231] Solubility test

[0232] The solubility of the solid form of the compound of formula I prepared by the present disclosure in different solutions was tested, and the test results are as follows: the solubility of the compound of formula I in the form of crystal form I in FeSSIF (fasted state simulated intestinal fluid), FaSSIF (fasted state simulated intestinal fluid) and FaSSGF (fasted state simulated gastric fluid) is 58 μg / mL, 14 μg / mL and 3 μg / mL respectively; the solubility of the compound of formula I in the form of amorphous, 1,5-naphthalene disulfonate crystal form B, maleate crystal form and sulfate crystal form in purified water is ≥1 mg / mL.

[0233] The solubility of the compound of formula I in the form of amorphous, crystal form I, crystal form II and accompanying polymorphic crystal I and crystal III in FaSSIF (fasted state simulated intestinal fluid) is shown in Table 9.

[0234] Table 9

[0235] Although it is generally believed that the amorphous form has higher solubility than the crystal form due to its disorder, the results in Table 9 show that the solubility of the crystal form II in the biological solvent medium of the simulated fasted state intestinal fluid is slightly better than that of the amorphous form; and the solubility of the crystal form I in the biological solvent medium of the simulated fasted state intestinal fluid is significantly better than that of the amorphous form.

Claims

1. Form I of a compound of formula I, characterized in that The XRPD pattern of the compound of Formula I Form I includes characteristic peaks at diffraction angles (2θ) at about 12.8±0.2°, 14.6±0.2° and / or 21.9±0.2°.

2. The crystalline Form I of the compound of Formula I according to claim 1, characterized in that, The XRPD pattern of the compound of Formula I Form I includes characteristic peaks at diffraction angles (2θ) at about 12.8±0.2°, 13.2±0.2°, 14.6±0.2°, 19.3±0.2° and / or 21.9±0.2°. Preferably, the XRPD pattern of the compound of Formula I Form I includes characteristic peaks at diffraction angles (2θ) at about 12.8±0.2°, 13.2±0.2°, 14.6±0.2°, 17.9±0.2°, 19.3±0.2° and / or 21.9±0.2°.

3. The crystalline Form I of the compound of Formula I according to claim 1 or 2, characterized in that, The XRPD pattern of the compound of Formula I Form I includes characteristic peaks at diffraction angles (2θ) at about 12.8±0.2°, 13.2±0.2°, 14.6±0.2°, 17.9±0.2°, 19.3±0.2°, 20.6±0.2°, 21.9±0.2°, 25.0±0.2°, 25.6±0.2° and / or 27.0±0.2°.

4. The crystalline Form I of the compound of Formula I according to any one of claims 1-3, characterized in that, The XRPD pattern of the compound of Formula I Form I includes peaks at diffraction angles (2θ) as shown in Table 1: Table 1 5. The crystalline Form I of the compound of Formula I according to any one of claims 1-4, characterized in that: The XRPD pattern of the compound of Formula I Form I is substantially as shown in Figure 1; preferably, the XRPD pattern of the compound of Formula I Form I is as shown in Figure 1.

6. The crystalline Form I of the compound of Formula I according to any one of claims 1-5, characterized in that, The compound of Formula I Form I is a monohydrate crystalline form of the compound of Formula I.

7. The crystalline Form I of the compound of Formula I according to any one of claims 1-6, characterized in that, The unit cell of the compound of Formula I Form I is monoclinic, space group C121; Preferably, the unit cell parameters of the single crystal of the crystalline form I of the compound of formula I are: α = 90°, β = 109.743(2)°, γ = 90°.

8. A salt of a compound of formula I, wherein the salt is selected from the group consisting of 1,5-naphthalene disulfonate salt, sulfate salt and maleate salt; Preferably, the salt is 1,5-naphthalene disulfonate salt.

9. A salt of a compound of formula I according to claim 8, which is crystalline Form A of the 1,5-naphthalenedisulfonic acid salt of a compound of formula I, characterized by, The XRPD pattern of the 1,5-naphthalene disulfonate salt Form A includes characteristic peaks at diffraction angles (2θ) at about 4.9±0.2°, 16.5±0.2° and / or 26.2±0.2°. Preferably, the XRPD pattern of the 1,5-naphthalene disulfonate salt Form A includes characteristic peaks at diffraction angles (2θ) at about 4.9±0.2°, 14.9±0.2°, 16.5±0.2°, 19.7±0.2°, 23.1±0.2°, 23.4±0.2° and / or 26.2±0.2°.

10. The salt of the compound of formula I according to claim 9, characterized in that The XRPD pattern of the 1,5-naphthalene disulfonate salt Form A includes characteristic peaks at diffraction angles (2θ) at about 4.9±0.2°, 14.9±0.2°, 16.5±0.2°, 19.7±0.2°, 21.3±0.2°, 23.1±0.2°, 23.4±0.2°, 24.9±0.2°, 26.2±0.2° and / or 27.9±0.2°.

11. Salt of a compound of formula I according to claim 9 or 10, characterized in that 1,5-naphthalene disulfonate salt Form A has an XRPD pattern comprising characteristic peaks at diffraction angles (2Θ) at about 4.9±0.2°, 9.5±0.2°, 10.4±0.2°, 10.6±0.2°, 11.6±0.2°, 13.9±0.2°, 14.9±0.2°, 16.5±0.2°, 18.5±0.2°, 19.1±0.2°, 19.7±0.2°, 20.1±0.2°, 20.5±0.2°, 21.3±0.2°, 22.1±0.2°, 23.1±0.2°, 23.4±0.2°, 24.5±0.2°, 24.9±0.2°, 25.4±0.2°, 26.2±0.2°, and / or 27.9±0.2°.

12. The salt of a compound of formula I according to any one of claims 9 to 11, characterized in that 1,5-naphthalene disulfonate salt Form A has an XRPD pattern comprising peaks at diffraction angles (2Θ) as shown in Table 2: Table 2 13. The salt of a compound of formula I according to any one of claims 9 to 12, characterized in that The XRPD pattern of 1,5-naphthalene disulfonate salt Form A is substantially as shown in Figure 9; preferably, the XRPD pattern of 1,5-naphthalene disulfonate salt Form A is as shown in Figure 9.

14. A salt of a compound of formula I according to claim 8, which is crystalline Form B of the 1,5-naphthalenedisulfonic acid salt of a compound of formula I, characterized by, The XRPD pattern of 1,5-naphthalene disulfonate salt Form B comprises characteristic peaks at diffraction angles (2Θ) at about 4.9±0.2°, 9.7±0.2°, 16.7±0.2°, and / or 19.4±0.2°; Preferably, the XRPD pattern of 1,5-naphthalene disulfonate salt Form B comprises characteristic peaks at diffraction angles (2Θ) at about 4.9±0.2°, 9.7±0.2°, 11.5±0.2°, 16.7±0.2°, 19.4±0.2°, and / or 19.8±0.2°.

15. The salt of the compound of formula I according to claim 14, characterized in that The XRPD pattern of 1,5-naphthalene disulfonate salt Form B comprises characteristic peaks at diffraction angles (2Θ) at about 4.9±0.2°, 9.7±0.2°, 11.5±0.2°, 14.9±0.2°, 16.7±0.2°, 19.4±0.2°, 19.8±0.2°, 23.4±0.2°, 26.2±0.2°, and / or 27.9±0.2°.

16. The salt of a compound of formula I according to claim 14 or 15, characterized in that The XRPD pattern of 1,5-naphthalene disulfonate salt Form B comprises characteristic peaks at diffraction angles (2Θ) at about 4.9±0.2°, 9.7±0.2°, 10.5±0.2°, 10.7±0.2°, 11.5±0.2°, 11.9±0.2°, 12.4±0.2°, 12.7±0.2°, 14.9±0.2°, 15.8±0.2°, 16.7±0.2°, 18.5±0.2°, 19.2±0.2°, 19.4±0.2°, 19.8±0.2°, 21.3±0.2°, 21.5±0.2°, 22.5±0.2°, 23.4±0.2°, 24.5±0.2°, 25.3±0.2°, 25.5±0.2°, 26.2±0.2°, and / or 27.9±0.2°.

17. The salt of a compound of formula I according to any one of claims 14 to 16, characterized in that The XRPD pattern of 1,5-naphthalene disulfonate salt Form B comprises peaks at diffraction angles (2Θ) as shown in Table 3: The XRPD pattern of 1,5-naphthalene disulfonate salt Form B comprises peaks at diffraction angles (2Θ) as shown in Table 3: Table 3 18. The salt of the compound of formula I according to any one of claims 14 to 17, characterized in that, 1,5-naphthalenedisulfonate salt Form B has an XRPD pattern substantially as shown in Figure 11; preferably the XRPD pattern of 1,5-naphthalenedisulfonate salt Form B is as shown in Figure 11.

19. A salt of a compound of formula I according to claim 8, which is a sulfate salt crystalline form of a compound of formula I, characterized by, The XRPD pattern of the sulfate salt form comprises characteristic peaks at diffraction angles (2Θ) at about 4.2±0.2°, 12.0±0.2°, 14.5±0.2°, 20.3±0.2° and / or 20.9±0.2°; Preferably, the XRPD pattern of the sulfate salt form comprises characteristic peaks at diffraction angles (2Θ) at about 4.2±0.2°, 12.0±0.2°, 14.5±0.2°, 17.6±0.2°, 18.4±0.2°, 20.3±0.2° and / or 20.9±0.2°.

20. The salt of the compound of formula I according to claim 19, characterized in that The XRPD pattern of the sulfate salt form comprises characteristic peaks at diffraction angles (2Θ) at about 4.2±0.2°, 6.9±0.2°, 8.1±0.2°, 12.0±0.2°, 12.7±0.2°, 13.9±0.2°, 14.5±0.2°, 17.6±0.2°, 18.4±0.2°, 18.9±0.2°, 20.3±0.2°, 20.9±0.2°, 24.6±0.2° and / or 25.6±0.2°.

21. The salt of a compound of formula I according to claim 19 or 20, characterized in that The XRPD pattern of the sulfate salt form comprises characteristic peaks at diffraction angles (2Θ) at about 4.2±0.2°, 6.9±0.2°, 8.1±0.2°, 8.5±0.2°, 12.0±0.2°, 12.7±0.2°, 13.9±0.2°, 14.5±0.2°, 15.3±0.2°, 16.1±0.2°, 17.6±0.2°, 18.4±0.2°, 18.9±0.2°, 20.3±0.2°, 20.9±0.2°, 22.5±0.2°, 24.6±0.2° and / or 25.6±0.2°.

22. The salt of the compound of formula I according to any one of claims 19 to 21, characterized in that The XRPD pattern of the sulfate salt form comprises peaks at diffraction angles (2Θ) as shown in Table 4: Table 4 23. The salt of the compound of formula I according to any one of claims 19 to 22, characterized in that, The XRPD pattern of the sulfate salt form is substantially as shown in Figure 13; preferably the XRPD pattern of the sulfate salt form is as shown in Figure 13.

24. A salt of a compound of Formula I according to claim 8, which is a maleate salt crystalline form of a compound of Formula I, characterized by, The XRPD pattern of the maleate salt form comprises characteristic peaks at diffraction angles (2Θ) at about 3.8±0.2°, 13.1±0.2°, 16.4±0.2°, 18.5±0.2°, 19.9±0.2° and / or 26.3±0.2°.

25. The salt of the compound of formula I according to claim 24, characterized in that The XRPD pattern of the maleate salt form comprises peaks at diffraction angles (2Θ) as shown in Table 5: Table 5 Preferably, the XRPD pattern of the maleate salt form is substantially as shown in Figure 15; More preferably, the XRPD pattern of the maleate salt form is as shown in Figure 15.

26. An amorphous form of the compound of formula I, characterized in that The XRPD pattern of the amorphous form of the compound of Formula I is free of diffraction characteristic peaks; Preferably, the XRPD pattern of the amorphous form of the compound of Formula I is as shown in Figure 7.

27. A pharmaceutical composition comprising the crystalline form I of the compound of Formula I according to any one of claims 1-7, the salt of the compound of Formula I (e.g., the 1,5-naphthalenedisulfonate salt, the sulfate salt, or the maleate salt of the compound of Formula I, particularly the 1,5-naphthalenedisulfonate salt Form A, the 1,5-naphthalenedisulfonate salt Form B, the sulfate salt Form, or the maleate salt Form of the compound of Formula I) according to any one of claims 8-25, or the amorphous form of the compound of Formula I according to claim 26, and one or more pharmaceutically acceptable carriers.

28. Use of the crystalline form I of the compound of Formula I according to any one of claims 1-7, the salt of the compound of Formula I (e.g., the 1,5-naphthalenedisulfonate salt, the sulfate salt, or the maleate salt of the compound of Formula I, particularly the 1,5-naphthalenedisulfonate salt Form A, the 1,5-naphthalenedisulfonate salt Form B, the sulfate salt Form, or the maleate salt Form of the compound of Formula I) according to any one of claims 8-25, the amorphous form of the compound of Formula I according to claim 26, or the pharmaceutical composition according to claim 27 in the manufacture of a medicament for the prevention and / or treatment of a NaV1.8 related disease, preferably the NaV1.8 related disease is pain.

29. A method for preparing the crystalline form I of the compound of Formula I according to any one of claims 1-7, comprising mixing the compound of Formula I with a solvent, and then isolating the obtained solid; wherein, the solvent is a combination of a first solvent selected from the group consisting of nitriles (e.g., acetonitrile), ketones (e.g., acetone), alcohols (e.g., ethanol, methanol, isopropanol), and tetrahydrofuran, and a second solvent selected from the group consisting of purified water and esters (e.g., ethyl acetate); or, the solvent is an alcohol (e.g., isopropanol) or an ester (e.g., ethyl acetate); preferably, the method for preparing comprises: Method A1: mixing the compound of Formula I with a first solvent, then adding a second solvent for crystallization, and isolating the obtained solid as the crystalline form I of the compound of Formula I; Method A2: mixing the compound of Formula I with a mixed solution of a first solvent and a second solvent, then slowly volatilizing through a small hole at room temperature, and isolating the obtained solid as the crystalline form I of the compound of Formula I; or, Method A3: mixing the compound of Formula I with isopropanol or ethyl acetate, then slowly volatilizing through a small hole at room temperature, and isolating the obtained solid as the crystalline form I of the compound of Formula I; more preferably, the method for preparing comprises: Method A1: mixing the compound of Formula I with a first solvent at 40-60 °C to form a clear solution, then adding a second solvent for crystallization at room temperature to 60 °C (e.g., room temperature, 30 °C, 35 °C, 40 °C, 45 °C, 50 °C, 55 °C, 60 °C), and isolating the obtained solid as the crystalline form I of the compound of Formula I; Method A2: mixing the compound of Formula I with a mixed solution of a first solvent and a second solvent to form a supersaturated solution, then filtering through a membrane, and slowly volatilizing through a small hole at room temperature, and isolating the obtained solid as the crystalline form I of the compound of Formula I; or, Method A3: mixing the compound of Formula I with isopropanol or ethyl acetate to form a supersaturated solution, then filtering through a membrane, and slowly volatilizing through a small hole at room temperature, and isolating the obtained solid as the crystalline form I of the compound of Formula I. ​ ​ 30. A process for preparing crystalline Form I of the compound of Formula I according to claim 29, wherein, the first solvent is selected from the group consisting of nitriles (e.g. acetonitrile), ketones (e.g. acetone) and tetrahydrofuran; and the second solvent is purified water.

31. A process for preparing crystalline Form II of the compound of Formula I according to claim 29, wherein, the first solvent is selected from the group consisting of nitriles (e.g. acetonitrile), ketones (e.g. acetone) and tetrahydrofuran; and the second solvent is purified water.

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