Crystalline forms, salt forms of (2-pyrimidylpiperazinyl)(4-methyl-6-phenylpyridazinyl)methanone and methods of their preparation and uses

Abstract

This disclosure relates to the crystalline form and / or salt form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone or its pharmaceutically acceptable solvates, methods of preparation, pharmaceutical compositions, and uses thereof. The crystalline forms and / or salt forms of this disclosure exhibit excellent stability, solubility, and / or pharmacokinetic properties. The preparation methods disclosed are simple to operate, have good reproducibility, and achieve good crystallization yields, making them suitable for industrial-scale production.

Description

Technical Field

[0001] This disclosure relates to the pharmaceutical field, and more particularly to the field of drug crystal forms, specifically to the crystalline form, salt form, preparation method, pharmaceutical composition and use of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone. Background Technology

[0002] Alzheimer's disease (AD), also known as senile dementia, is a neurodegenerative disease characterized by progressive cognitive impairment and memory loss. Clinically, it manifests as short-term memory impairment, followed by persistent cognitive decline, loss of judgment and reasoning abilities, aphasia, and motor disorders. Its pathological features include numerous senile plaques (SPs) and neurofibrillary tangles (NFTs). Currently, there are two main types of medications available: cholinesterase inhibitors (AChEIs) and N-methyl-D-aspartic acid (NMDA) receptor antagonists. Examples of AChEIs include tacrine, donepezil, rivastigmine, and huperzine A.

[0003] (2-Pyrimidinoperazinyl)(4-Methyl-6-phenylpyridazine) methyl ketone (AD-16) is a compound with good anti-Alzheimer's disease properties, and its specific structure is shown below:

[0004]

[0005] Currently, no studies have been found on the crystal form or salt form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) ketone. It is well known that the crystal form and salt form of a drug affect formulation quality, pharmacokinetic properties, and manufacturing processes. Different crystal forms or salt forms of the same drug may exhibit significant differences in appearance, solubility, melting point, dissolution rate, and bioequivalence, thus affecting drug stability, bioavailability, and efficacy. Therefore, research on the crystal form and salt form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) ketone is urgently needed. Summary of the Invention

[0006] In view of this, this disclosure provides crystalline form, salt form, preparation method, pharmaceutical composition and use of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone, with the aim of providing crystalline form and / or salt form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone with good stability, good solubility, low hygroscopicity and / or good pharmacokinetic properties.

[0007] In a first aspect, this disclosure provides crystalline forms of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone or pharmaceutically acceptable solvates thereof and / or salt forms of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone.

[0008] In some embodiments, (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone has crystal form A, and the X-ray powder diffraction pattern of crystal form A has characteristic peaks at 2θ angles of 7.798°±0.2°, 15.103°±0.2°, 18.215°±0.2° and 18.436°±0.2°.

[0009] The A-crystal form provided in this disclosure has low hygroscopicity and good stability in high temperature and high humidity environments. Furthermore, the A-crystal form of this disclosure is in a free state, has good safety, and has pharmacokinetic characteristics suitable for drug development.

[0010] In some embodiments, (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is a tetrahydrofuran solvate, which has a B crystal form. The X-ray powder diffraction pattern of the B crystal form has characteristic peaks at 2θ angles of 12.640°±0.2°, 16.584°±0.2°, and 18.101°±0.2°.

[0011] The B-type crystal provided in this disclosure has low hygroscopicity and good stability in high temperature and high humidity environments.

[0012] In some embodiments, (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is in the form of hydrobromide.

[0013] In some embodiments, the hydrobromide form has a crystalline form, and optionally, in the crystalline form, the molar ratio of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone to hydrobromic acid is 1:1.

[0014] In some embodiments, the X-ray powder diffraction pattern of the hydrobromide crystalline form has characteristic peaks at 2θ angles of 9.334°±0.2°, 10.112°±0.2°, 22.083°±0.2°, 22.677°±0.2°, 24.299°±0.2°, 25.905°±0.2°, and 27.674°±0.2°.

[0015] The hydrobromide crystalline form disclosed herein exhibits good solubility and low hygroscopicity, and maintains high chemical purity without significant changes under high temperature and high humidity conditions. Oral administration of the hydrobromide crystalline form results in higher peak plasma concentrations and a faster time to peak concentration.

[0016] In some embodiments, (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is in the form of a hydrochloride salt. In some embodiments, the hydrochloride salt form has a crystalline form, optionally in which the molar ratio of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone to hydrochloric acid is 1:1.

[0017] In some embodiments, the X-ray powder diffraction pattern of the hydrochloride crystalline form has characteristic peaks at 2θ angles of 8.793°±0.2°, 10.133°±0.2°, 10.321°±0.2°, 10.483°±0.2°, 10.834°±0.2°, 17.249°±0.2°, 22.204°±0.2°, 22.474°±0.2°, 24.178°±0.2°, and 24.590°±0.2°.

[0018] The hydrochloride crystalline form disclosed herein exhibits good solubility and stability, maintains good chemical purity under high temperature and high humidity conditions, and shows no significant change in crystal form. After administration, the hydrochloride crystalline form results in a higher peak plasma concentration, a higher exposure value (AUC), and a faster time to peak concentration. This is beneficial for reducing clinical dosage and increasing medication safety.

[0019] In some embodiments, (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is in the form of p-toluenesulfonate. In some embodiments, the p-toluenesulfonate form has a crystalline p-toluenesulfonate form, optionally in which the molar ratio of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone to p-toluenesulfonic acid is 1:1.

[0020] In some embodiments, the X-ray powder diffraction pattern of the crystalline form of p-toluenesulfonate has characteristic peaks at 2θ angles of 4.173°±0.2°, 4.357°±0.2°, 7.090°±0.2°, 8.737°±0.2°, 10.399°±0.2°, and 19.037°±0.2°.

[0021] The crystalline form of p-toluenesulfonate provided in this disclosure has good solubility.

[0022] In some embodiments, (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is in the form of a 1,5-naphthalenedisulfonate. In some embodiments, the 1,5-naphthalenedisulfonate form has a crystalline form, optionally in which the molar ratio of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone to 1,5-naphthalenedisulfonate is 1:0.5.

[0023] In some embodiments, the X-ray powder diffraction pattern of the crystalline form of 1,5-naphthalenedisulfonate has characteristic peaks at 2θ angles of 8.923°±0.2°, 12.830°±0.2°, 14.328°±0.2°, and 17.824°±0.2°.

[0024] The 1,5-naphthalenedisulfonate crystal form disclosed herein exhibits good solubility and stability, good chemical purity under high temperature and high humidity conditions, and no significant change in crystal form.

[0025] In some embodiments, (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is in the form of β-naphthalenesulfonate. In some embodiments, the β-naphthalenesulfonate form has a crystalline form, optionally in which the molar ratio of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone to β-naphthalenesulfonic acid is 1:1.

[0026] In some embodiments, the X-ray powder diffraction pattern of the β-naphthalenesulfonate crystalline form has characteristic peaks at 2θ angles of 3.999°±0.2°, 7.977°±0.2°, 18.160°±0.2°, 18.540°±0.2°, 20.199°±0.2°, 20.479°±0.2°, and 24.844°±0.2°.

[0027] The β-naphthalenesulfonate crystal form disclosed herein has good solubility.

[0028] In some embodiments, (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is in the form of hydroiodide, sulfate, methanesulfonate, benzenesulfonate, nitrate, and / or camphorsulfonate.

[0029] The sulfate and benzenesulfonate forms disclosed herein have good solubility.

[0030] In a second aspect, this disclosure provides a method for preparing crystalline form and / or salt form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone or a pharmaceutically acceptable solvate thereof, as described in the first aspect of this disclosure.

[0031] Thirdly, this disclosure provides a pharmaceutical composition comprising, as in the crystalline form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone or a pharmaceutically acceptable solvate thereof as in the first aspect of this disclosure, and / or a salt form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone, as prepared by the method of the second aspect of this disclosure, and a pharmaceutically acceptable carrier.

[0032] Fourthly, this disclosure provides the use of crystalline forms and / or salt forms of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) ketone or pharmaceutically acceptable solvates thereof as in the first aspect of this disclosure, crystalline forms and / or salt forms of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) ketone prepared by the method of the second aspect of this disclosure, and / or the use of pharmaceutical compositions as in the third aspect of this disclosure in the preparation of medicaments for the prevention, treatment and / or relief of diseases, symptoms and / or disorders;

[0033] Optional, diseases, symptoms, or disorders include neurodegenerative diseases, psychosis, epilepsy, seizures, stroke, and pain;

[0034] Alternatively, neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, and cognitive impairment, and pain includes chronic inflammatory pain.

[0035] The above description is merely an overview of the technical solution disclosed herein. In order to better understand the technical means of this disclosure and to implement it in accordance with the contents of the specification, and to make the above and other objects, features and advantages of this disclosure more apparent and understandable, specific embodiments of this disclosure are described below. Attached Figure Description

[0036] The following is a brief description of the accompanying drawings, which are used to illustrate the exemplary embodiments disclosed herein and are not intended to limit these implementations.

[0037] Figure 1The X-ray powder diffraction pattern of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone of Example 1 is shown in crystal form A.

[0038] Figure 2 The differential scanning calorimeter of crystal form A of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone of Example 1 is shown.

[0039] Figure 3 The thermogravimetric analysis (TGA) spectrum of the A crystal form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone from Example 1 is shown.

[0040] Figure 4 The B-type X-ray powder diffraction pattern of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone of Example 3 is shown.

[0041] Figure 5 Differential scanning calorimetry (DSC) spectra of the B crystal form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone of Example 3 are shown.

[0042] Figure 6 The thermogravimetric analysis (TGA) spectrum of the B crystal form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone from Example 3 is shown.

[0043] Figure 7 The B-type crystal of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone of Example 3 is shown. 1 H-NMR spectrum.

[0044] Figure 8 The X-ray powder diffraction pattern of the hydrobromide crystalline form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) ketone of Example 4.1.2 is shown.

[0045] Figure 9 Thermogravimetric analysis (TGA) spectrum of the hydrobromide crystal form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) ketone from Example 4.1.2 is shown.

[0046] Figure 10 Differential scanning calorimetry (DSC) spectra of the hydrobromide crystalline form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone of Example 4.1.2 are shown.

[0047] Figure 11 The crystalline form of the hydrobromide of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone of Example 4.1.2 is shown. 1 H-NMR spectrum.

[0048] Figure 12The X-ray powder diffraction pattern of the p-toluenesulfonate crystalline form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone of Example 4.1.5 is shown.

[0049] Figure 13 Thermogravimetric analysis (TGA) spectrum of the p-toluenesulfonate crystal form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone of Example 4.1.5 is shown.

[0050] Figure 14 Differential scanning calorimetry (DSC) spectra of the p-toluenesulfonate crystal form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone of Example 4.1.5 are shown.

[0051] Figure 15 The crystalline form of p-toluenesulfonate of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone of Example 4.1.5 is shown. 1 H-NMR spectrum.

[0052] Figure 16 The X-ray powder diffraction pattern of the 1,5-naphthalene disulfonate crystal form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) ketone of Example 4.2.7 is shown.

[0053] Figure 17 Thermogravimetric analysis (TGA) spectrum of the 1,5-naphthalenedisulfonic acid v salt of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) ketone from Example 4.2.7 is shown.

[0054] Figure 18 Differential scanning calorimetry (DSC) spectra of the 1,5-naphthalene disulfonate crystal form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone of Example 4.2.7 are shown.

[0055] Figure 19 The crystalline form of the 1,5-naphthalene disulfonate of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone of Example 4.2.7 is shown. 1 H-NMR spectrum.

[0056] Figure 20 The X-ray powder diffraction pattern of the hydrochloride crystalline form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone of Example 4.4.1 is shown.

[0057] Figure 21 Thermogravimetric analysis (TGA) spectrum of the hydrochloride crystalline form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone from Example 4.4.1 is shown.

[0058] Figure 22Differential scanning calorimetry (DSC) spectra of the crystalline form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone hydrochloride of Example 4.4.1 are shown.

[0059] Figure 23 The crystalline form of the hydrochloride salt of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone of Example 4.4.1 is shown. 1 H-NMR spectrum.

[0060] Figure 24 The X-ray powder diffraction pattern of the β-naphthalene sulfonate crystal form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone of Example 4.5.7 is shown.

[0061] Figure 25 Thermogravimetric analysis (TGA) spectrum of the β-naphthalene sulfonate crystal form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone from Example 4.5.7 is shown.

[0062] Figure 26 Differential scanning calorimetry (DSC) spectra of the β-naphthalene sulfonate crystal form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone of Example 4.5.7 are shown.

[0063] Figure 27 The crystalline form of the β-naphthalene sulfonate of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone of Example 4.5.7 is shown. 1 H-NMR spectrum.

[0064] Figure 28 The X-ray powder diffraction patterns of crystal form A under different stability conditions in test example 2.1 are shown in comparison.

[0065] Figure 29 The X-ray powder diffraction patterns of crystal form B under different stability conditions in test example 2.1 are shown in comparison.

[0066] Figure 30 The X-ray powder diffraction pattern of the (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone salt crystal form under open conditions of 40°C / 75% humidity in Test Example 2.2 is shown as a function of time. Figure 30 A shows the change of X-ray powder diffraction pattern of the crystalline form of hydrobromide over time; Figure 30 B shows the change of X-ray powder diffraction pattern of the hydrochloride crystal form over time; Figure 30 C shows the change of X-ray powder diffraction pattern of 1,5-naphthalene disulfonate crystals over time.

[0067] Figure 31The DVS isotherm diagram of crystal form A in test example 3.1 is shown.

[0068] Figure 32 The DVS isotherm diagram of crystal form B in test example 3.1 is shown.

[0069] Figure 33 The X-ray powder diffraction patterns of crystal form A in test example 3.1 before and after the DVS test are shown.

[0070] Figure 34 The X-ray powder diffraction patterns of crystal form B in test example 3.1 before and after DVS testing are shown.

[0071] Figure 35 The DVS isotherm spectrum of the hydrobromide crystalline form in Test Example 3.2.1 is shown.

[0072] Figure 36 The DVS isotherm spectrum of the hydrochloride crystal form in test example 3.2.2 is shown.

[0073] Figure 37 The X-ray powder diffraction patterns of the hydrochloride crystal form before and after the DVS test in Test Example 3.2.2 are shown.

[0074] Figure 38 The DVS isotherm spectrum of the crystalline form of p-toluenesulfonate in test example 3.2.3 is shown.

[0075] Figure 39 The X-ray powder diffraction patterns of the crystalline form of p-toluenesulfonate in Test Example 3.2.3 before and after the DVS test are shown.

[0076] Figure 40 The DVS isotherm spectrum of the crystalline form of 1,5-naphthalenedisulfonate in test example 3.2.4 is shown.

[0077] Figure 41 The X-ray powder diffraction patterns of the crystalline form of 1,5-naphthalene disulfonate in Test Example 3.2.4 before and after DVS testing are shown.

[0078] Figure 42 The changes in plasma drug concentration over time after administration of crystal form A, hydrobromide crystal form, and hydrochloride crystal form in Test Example 4 are shown. Figure 42 A shows the changes over 24 hours. Figure 42 B shows the changes over 8 hours. Detailed Implementation

[0079] Unless otherwise stated, all figures used in this specification and claims to represent content, concentration, proportion, weight, particle size, percentage, technical effect, etc., should in any instance be understood to be modified by the terms “about” or “approximately”. Therefore, unless indicated to the contrary, the numerical parameters listed in the following specification and appended claims are approximate values. Unless otherwise stated, the terminology used herein has its common meaning as understood by one of ordinary skill in the art. It may vary for those skilled in the art depending on the desired properties and effects sought through this disclosure, and each numerical parameter should be interpreted according to the number of significant figures and conventional rounding methods or as understood by those skilled in the art.

[0080] Although the numerical ranges and parameters described in this disclosure are approximate, the values ​​presented in the specific embodiments are provided as precisely as possible. However, any numerical value will inherently contain some errors, which are necessarily caused by the standard deviation found in its corresponding test measurements. Each numerical range given in this specification will include every narrower numerical range falling within that wider range, as if these narrower numerical ranges were explicitly stated herein.

[0081] When used in this paper, the expression "A and B" includes three cases: (1) A; (2) B; (3) A and B. The meanings of similar expressions can be inferred by analogy.

[0082] Crystalline form and / or salt form

[0083] In a first aspect, this disclosure provides crystalline forms of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone or pharmaceutically acceptable solvates thereof and / or salt forms of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone.

[0084] In some embodiments, (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone has crystal form A, and the X-ray powder diffraction pattern of crystal form A has characteristic peaks at 2θ angles of 7.798°±0.2°, 15.103°±0.2°, 18.215°±0.2° and 18.436°±0.2°.

[0085] As used herein, the terms "X-ray powder diffraction pattern," "XRPD pattern," or "XRD pattern" refer to the X-ray powder diffraction pattern obtained when X-rays are incident at a grazing angle θ (the complementary angle of the incident angle, also known as the Bragg angle) onto an atomic plane of a crystal or partially crystalline sample with a lattice spacing of d, according to Bragg's law 2d sinθ = nλ (where λ is the wavelength of the X-rays, and the diffraction order n is any positive integer, typically the first-order diffraction peak, n = 1). Those skilled in the art will understand that the peak position (2θ) can indicate variability between certain apparatuses or some experimental error, typically up to 0.2°. Furthermore, those skilled in the art will understand that the relative peak intensity will indicate variability between apparatuses and variability due to crystallinity, preferred orientation, the prepared sample surface, and other factors known to those skilled in the art, and should be used only as a qualitative measurement. Those skilled in the art of X-ray powder diffraction can readily determine from an X-ray powder diffraction pattern whether a given sample originates from the same crystal form as a reference sample.

[0086] When used in this document, the term “2θ” or “2θ angle” refers to the diffraction angle, where θ is the Bragg angle, and the unit is ° or degree. The error range of 2θ is ±0.2 or ±0.1.

[0087] In this paper, the terms "interplanar spacing" or "d-value" refer to the spacing between crystal planes. Three non-parallel unit vectors, a, b, and c, are chosen to connect adjacent points in a space lattice. These vectors divide the lattice into juxtaposed parallelepiped units. The space lattice is divided according to these defined parallelepiped units, resulting in a linear grid called a space lattice or crystal lattice. Lattices and crystal lattices respectively represent the periodicity of crystal structures using geometric points and lines. Different crystal planes have different interplanar spacings (i.e., the distance between two adjacent parallel crystal planes); the unit is 1 / 2π. Or E.

[0088] In some implementations, X-ray powder diffraction patterns are obtained by using Cu-Ka radiation in an X-ray powder diffractometer, resulting in patterns expressed in terms of 2θ angles and interplanar spacing.

[0089] In some embodiments, the X-ray powder diffraction pattern of crystal form A has characteristic peaks at 2θ angles of 7.798°±0.2°, 15.103°±0.2°, 15.784°±0.2°, 18.215°±0.2° and 18.436°±0.2°.

[0090] In some embodiments, the X-ray powder diffraction pattern of crystal form A has characteristic peaks at 2θ angles of 7.798°±0.2°, 15.103°±0.2°, 15.784°±0.2°, 18.215°±0.2°, 18.436°±0.2°, 21.340°±0.2°, 22.079°±0.2°, 23.899°±0.2°, 25.763°±0.2°, and 32.159°±0.2°.

[0091] In some embodiments, the X-ray powder diffraction pattern of crystal form A is as follows: Figure 1 As shown.

[0092] In some embodiments, the X-ray powder diffraction pattern of crystal form A is compared with... Figure 1 They are basically the same.

[0093] When used herein, the term "substantially identical" means that for characteristics such as endothermic, endothermic peaks, exothermic, baseline shift, etc., their values ​​may vary slightly, taking into account instrumentation, different batches of samples, and operational errors. Regarding X-ray diffraction peak positions, "substantially identical" means taking into account the variability in typical peak positions and intensities. For DSC, observed temperature variations may be related to the rate of temperature change, as well as sample preparation techniques and the specific instrument used. Therefore, the endothermic / melting point values ​​for DSC and TGA disclosed herein may vary by ±3°C (and are still considered characteristic of the specific crystal form described herein), and other characteristics such as weight percentage (by weight%) and mass percentage (by mass%) may vary by ±0.004% (and are still considered characteristic of the specific crystal form described herein).

[0094] In some embodiments, the differential scanning calorimetry spectrum of crystal form A has an endothermic peak in the range of 172.94℃±3℃.

[0095] When used in this document, the terms "differential scanning calorimetry" or "DSC spectrum" refer to a spectrum obtained by measuring the temperature difference and heat flow difference between the sample and a reference material during sample heating or isothermal processes to characterize all physical and chemical changes related to thermal effects, thus providing information on the phase transition of the sample. DSC of crystal forms may be subject to experimental error. Specifically, the initial melting point, maximum endothermic peak (melting peak point), and final melting point may vary slightly between different instruments and between different samples. The experimental error or difference may be less than or equal to 3°C, less than or equal to 2°C, or less than or equal to 1°C. Therefore, the peak position or peak value of the DSC endothermic peak should not be considered absolute.

[0096] In some embodiments, when heated from 30°C to 300°C at a heating rate of 20°C / min, the initial melting point of crystal form A is 170.53°C ± 3°C, the peak endothermic temperature is 172.94°C ± 3°C, and the final melting point is 176.34°C ± 3°C.

[0097] In some embodiments, the differential scanning calorimeter of crystal form A is as follows: Figure 2 As shown. In some embodiments, the differential scanning calorimetry (DSC) spectrum of crystal form A is compared with... Figure 2 They are basically the same.

[0098] In some implementations, the thermogravimetric analysis (TGA) spectrum of crystal form A is as follows: Figure 3 As shown. In some embodiments, the thermogravimetric analysis spectrum of crystal form A is... Figure 3 They are basically the same.

[0099] As used herein, the term "thermogravimetric analysis (TGA) spectrum" refers to a graph obtained by measuring the mass of a substance against temperature or time under programmed temperature control, showing the relationship between the mass of the substance and temperature change. Thermogravimetric analysis can reflect the composition, thermal stability, and / or thermal decomposition of a sample and its potential intermediates. DSC analysis of crystalline forms may be subject to experimental error; specifically, the endothermic curves or weight loss rates may vary slightly between different instruments and between different samples. The experimental error or difference may be less than or equal to 0.004%, or less than or equal to 0.003%, or less than or equal to 0.002%, or less than or equal to 0.001%. Therefore, the TGA curve or its weight loss rate should not be considered absolute.

[0100] In some embodiments, the A crystal form does not experience significant weight loss before being heated from 30°C to the decomposition temperature of the A crystal form at a heating rate of 20°C / min.

[0101] In some embodiments, (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is a tetrahydrofuran solvate, which has a B crystal form. The X-ray powder diffraction pattern of the B crystal form has characteristic peaks at 2θ angles of 12.640°±0.2°, 16.584°±0.2°, and 18.101°±0.2°.

[0102] In some embodiments, the X-ray powder diffraction pattern of the B crystal form has characteristic peaks at 2θ angles of 8.181°±0.2°, 11.978°±0.2°, 12.640°±0.2°, 14.099°±0.2°, 16.584°±0.2° and 18.101°±0.2°.

[0103] In some embodiments, the X-ray powder diffraction pattern of the B crystal form has characteristic peaks at 2θ angles of 5.870°±0.2°, 8.181°±0.2°, 11.978°±0.2°, 12.640°±0.2°, 14.099°±0.2°, 16.584°±0.2°, and 18.101°±0.2°.

[0104] In some embodiments, the X-ray powder diffraction pattern of the B crystal form has characteristic peaks at 2θ angles of 5.870°±0.2°, 6.899°±0.2°, 8.181°±0.2°, 11.978°±0.2°, 12.640°±0.2°, 14.099°±0.2°, 16.584°±0.2°, and 18.101°±0.2°.

[0105] In some embodiments, the X-ray powder diffraction pattern of the B crystal form has characteristic peaks at 2θ angles of 5.870°±0.2°, 6.899°±0.2°, 8.181°±0.2°, 11.978°±0.2°, 12.640°±0.2°, 14.099°±0.2°, 16.584°±0.2°, 18.101°±0.2°, 20.833°±0.2°, 23.201°±0.2°, 23.976°±0.2°, and 25.193°±0.2°.

[0106] In some embodiments, the X-ray powder diffraction pattern of crystal type B is as follows: Figure 4 As shown. In some embodiments, the X-ray powder diffraction pattern of crystal form B is... Figure 4 They are basically the same.

[0107] In some embodiments, the differential scanning calorimetry spectrum of the B crystal form has the maximum endothermic peak value in the range of 165.08℃±3℃.

[0108] In some embodiments, the differential scanning calorimetry (DSC) spectrum of the B crystal form exhibits endothermic peaks in the ranges of 165.08℃±3℃ and 172.34℃±3℃.

[0109] In some embodiments, when heated from 30°C to 300°C at a heating rate of 20°C / min, the B crystal form exhibits two endothermic peaks. In some embodiments, the initial melting point of the first endothermic peak of the B crystal form is 162.94°C ± 3°C, the peak endothermic peak is 165.08°C ± 3°C, and the final melting point of the first endothermic peak is 168.17°C ± 3°C; and / or, the initial melting point of the second endothermic peak of the B crystal form is 170.64°C ± 3°C, the peak endothermic peak is 172.34°C ± 3°C, and the final melting point of the second endothermic peak is 175.39°C ± 3°C.

[0110] In some embodiments, the differential scanning calorimetry (DSC) spectrum of the B crystal form is as follows: Figure 5 As shown. In some embodiments, the differential scanning calorimetry (DSC) spectrum of crystal form B is compared with... Figure 5 They are basically the same.

[0111] In some implementations, the thermogravimetric analysis (TGA) spectrum of the B crystal form is as follows: Figure 6 As shown. In some embodiments, the thermogravimetric analysis (TGA) spectrum of crystal form B is... Figure 6 They are basically the same.

[0112] In some embodiments, when heated from 30°C to 150°C at a heating rate of 20°C / min, the weight loss of B crystal form during drying is 1.33%. In some embodiments, when heated from 150°C to 190°C at a heating rate of 20°C / min, the weight loss of B crystal form during drying is 1.11%.

[0113] As used herein, the term "solvent" refers to a crystalline form that further comprises molecules, atoms, and / or ions of one or more solvents incorporated into a crystal lattice structure. Solvent molecules in a solvate may exist in a regular and / or disordered arrangement. A solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. For example, a solvate with non-stoichiometric amounts of solvent molecules may arise from the partial loss of solvent from the solvate. A solvate may occur in a crystal lattice structure as a dimer or oligomer comprising more than one molecule or compound.

[0114] In some embodiments, (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is in the form of hydrobromide.

[0115] In some embodiments, the hydrobromide form has a crystalline form. In some embodiments, in the crystalline form of the hydrobromide, the molar ratio of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone to hydrobromic acid is 1:1.

[0116] In some embodiments, the X-ray powder diffraction pattern of the hydrobromide crystalline form has characteristic peaks at 2θ angles of 9.334°±0.2°, 10.112°±0.2°, 22.083°±0.2°, 22.677°±0.2°, 24.299°±0.2°, 25.905°±0.2°, and 27.674°±0.2°.

[0117] In some embodiments, the X-ray powder diffraction patterns of the hydrobromide crystalline form are at 2θ angles of 8.717°±0.2°, 9.334°±0.2°, 10.112°±0.2°, 12.031°±0.2°, 12.560°±0.2°, 13.298°±0.2°, 14.950°±0.2°, 15.291°±0.2°, 15.847°±0.2°, 16.404°±0.2°, 17.398°±0.2°, 18.358°±0.2°, and 18.687°±0.2°. Characteristic peaks are found at 19.058°±0.2°, 20.087°±0.2°, 22.083°±0.2°, 22.677°±0.2°, 23.274°±0.2°, 24.299°±0.2°, 24.649°±0.2°, 25.207°±0.2°, 25.905°±0.2°, 26.997°±0.2°, 27.674°±0.2°, 28.927°±0.2°, 30.495°±0.2°, 30.758°±0.2°, and 31.051°±0.2°.

[0118] In some embodiments, the X-ray powder diffraction patterns of the hydrobromide crystalline form are at 2θ angles of 8.717°±0.2°, 9.334°±0.2°, 10.112°±0.2°, 11.679°±0.2°, 12.031°±0.2°, 12.560°±0.2°, 12.893°±0.2°, 13.298°±0.2°, and 14.950°. ±0.2°, 15.291°±0.2°, 15.847°±0.2°, 16.404°±0.2°, 17.398°±0.2°, 18.132°±0.2°, 18.358°±0.2°, 18.687°±0.2°, 19.058°±0.2°, 19.738°±0.2°, 20.087°±0.2°, 21.687 °±0.2°, 22.083°±0.2°, 22.677°±0.2°, 23.274°±0.2°, 24.299°±0.2°, 24.649°±0.2°, 25.207°±0.2°, 25.905°±0.2°, 26.704°±0.2°, 26.997°±0.2°, 27.674°±0.2°, 28.12 Characteristic peaks are found at 4°±0.2°, 28.493°±0.2°, 28.927°±0.2°, 29.136°±0.2°, 30.101°±0.2°, 30.495°±0.2°, 30.758°±0.2°, 31.051°±0.2°, 32.510°±0.2°, 33.148°±0.2°, and 35.426°±0.2°.

[0119] In some embodiments, the X-ray powder diffraction pattern of the hydrobromide crystalline form is as follows: Figure 8 As shown. In some embodiments, the X-ray powder diffraction pattern of the hydrobromide crystalline form is... Figure 8 They are basically the same.

[0120] In some embodiments, the differential scanning calorimeter of the hydrobromide crystalline form exhibits endothermic peaks in the ranges of 118.68±3℃, 152.26±3℃, and 158.59±3℃.

[0121] In some embodiments, when heated from 30°C to 300°C at a heating rate of 20°C / min, the crystalline form of hydrobromide exhibits three endothermic peaks. In some embodiments, the first endothermic peak of the crystalline form of hydrobromide has an initial melting point of 112.63°C, a peak endothermic peak of 118.68°C, and a final melting point of 122.93°C; the second endothermic peak has an initial melting point of 146.89°C, a peak endothermic peak of 152.26°C, and a final melting point of 155.56°C; and the third endothermic peak has an initial melting point of 155.89°C, a peak endothermic peak of 158.59°C, and a final melting point of 162.63°C.

[0122] In some embodiments, the differential scanning calorimeter of the hydrobromide crystalline form is as follows: Figure 10 As shown. In some embodiments, the differential scanning calorimeter of the hydrobromide crystalline form is compared with... Figure 10 They are basically the same.

[0123] In some embodiments, the thermogravimetric analysis (TGA) spectrum of the hydrobromide crystalline form is as follows: Figure 9 As shown. In some embodiments, the thermogravimetric analysis (TGA) spectrum of the hydrobromide crystalline form is compared with... Figure 9 They are basically the same.

[0124] In some embodiments, when heated from 21°C to 123°C at a heating rate of 20°C / min, the weight loss of the hydrobromide crystalline form during drying is 1.04%. In some embodiments, when heated from 123.00°C to 163.00°C at a heating rate of 20°C / min, the weight loss of the hydrobromide crystalline form during drying is 4.40%.

[0125] In some embodiments, (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is in the form of a hydrochloride salt. In some embodiments, the hydrochloride salt form has a crystalline hydrochloride salt form. In some embodiments, in the crystalline hydrochloride salt form, the molar ratio of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone to hydrochloric acid is 1:1.

[0126] In some embodiments, the X-ray powder diffraction pattern of the hydrochloride crystalline form has characteristic peaks at 2θ angles of 8.793°±0.2°, 10.133°±0.2°, 10.321°±0.2°, 10.483°±0.2°, 10.834°±0.2°, 17.249°±0.2°, 22.204°±0.2°, 22.474°±0.2°, 24.178°±0.2°, and 24.590°±0.2°.

[0127] In some embodiments, the X-ray powder diffraction patterns of the hydrochloride crystalline form are at 2θ angles of 8.793°±0.2°, 10.133°±0.2°, 10.321°±0.2°, 10.483°±0.2°, 10.834°±0.2°, 12.624°±0.2°, 13.037°±0.2°, 16.780°±0.2°, 17.249°±0.2°, 17.826°±0.2°, and 18.422°. Characteristic peaks are observed at 0°±0.2°, 19.222°±0.2°, 19.430°±0.2°, 20.047°±0.2°, 20.455°±0.2°, 21.034°±0.2°, 22.204°±0.2°, 22.474°±0.2°, 23.441°±0.2°, 24.178°±0.2°, 24.590°±0.2°, 25.395°±0.2°, and 26.236°±0.2°.

[0128] In some embodiments, the X-ray powder diffraction patterns of the hydrochloride crystalline form are at 2θ angles of 7.080°±0.2°, 8.793°±0.2°, 10.133°±0.2°, 10.321°±0.2°, 10.483°±0.2°, 10.834°±0.2°, 12.624°±0.2°, 13.037°±0.2°, 16.153°±0.2°, 16.780°±0.2°, 17.249°±0.2°, and 17.826°. Characteristic peaks are observed at ±0.2°, 18.422°±0.2°, 19.222°±0.2°, 19.430°±0.2°, 20.047°±0.2°, 20.455°±0.2°, 21.034°±0.2°, 22.204°±0.2°, 22.474°±0.2°, 23.081°±0.2°, 23.441°±0.2°, 24.178°±0.2°, 24.590°±0.2°, and 25.395°±0.2°.

[0129] In some embodiments, the X-ray powder diffraction pattern of the hydrochloride crystalline form is as follows: Figure 20As shown. In some embodiments, the X-ray powder diffraction pattern of the hydrochloride crystalline form is... Figure 20 They are basically the same.

[0130] In some embodiments, the differential scanning calorimeter of the hydrochloride crystalline form exhibits endothermic peaks in the ranges of 142.07±3℃, 169.34±3℃, and 195.96±3℃.

[0131] In some embodiments, when heated from 30°C to 300°C at a heating rate of 20°C / min, the hydrochloride crystalline form exhibits three endothermic peaks. In some embodiments, the first endothermic peak of the hydrochloride crystalline form has an initial melting point of 130.10°C, an endothermic peak of 142.07°C, and a final melting point of 153.54°C; the second endothermic peak has an initial melting point of 161.86°C, an endothermic peak of 169.34°C, and a final melting point of 182.37°C; and the first endothermic peak has an initial melting point of 184.59°C, an endothermic peak of 195.96°C, and a final melting point of 207.88°C.

[0132] In some embodiments, the differential scanning calorimeter of the hydrochloride crystalline form is as follows: Figure 22 As shown. In some embodiments, the differential scanning calorimeter of the hydrochloride crystalline form is compared with... Figure 22 They are basically the same.

[0133] In some embodiments, the thermogravimetric analysis (TGA) spectrum of the hydrochloride crystalline form is as follows: Figure 21 As shown. In some embodiments, the thermogravimetric analysis (TGA) spectrum of the hydrochloride crystalline form is compared with... Figure 21 They are basically the same.

[0134] In some embodiments, when heated from 21°C to 130°C at a heating rate of 20°C / min, the crystalline form of the hydrochloride exhibits a drying weight loss of 4.12%. In some embodiments, when heated from 130°C to 210°C at a heating rate of 20°C / min, the crystalline form of the hydrochloride exhibits a drying weight loss of 9.8%.

[0135] In some embodiments, (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is in the form of p-toluenesulfonate. In some embodiments, the p-toluenesulfonate form has a crystalline p-toluenesulfonate form. In some embodiments, in the crystalline p-toluenesulfonate form, the molar ratio of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone to p-toluenesulfonic acid is 1:1.

[0136] In some embodiments, the X-ray powder diffraction pattern of the crystalline form of p-toluenesulfonate has characteristic peaks at 2θ angles of 4.173°±0.2°, 4.357°±0.2°, 7.090°±0.2°, 8.737°±0.2°, 10.399°±0.2°, and 19.037°±0.2°.

[0137] In some embodiments, the X-ray powder diffraction pattern of the crystalline form of p-toluenesulfonate exhibits characteristic peaks at 2θ angles of 4.173°±0.2°, 4.357°±0.2°, 7.090°±0.2°, 8.364°±0.2°, 8.737°±0.2°, 10.093°±0.2°, 10.399°±0.2°, 12.047°±0.2°, 13.860°±0.2°, 17.542°±0.2°, 19.037°±0.2°, 20.910°±0.2°, 21.156°±0.2°, 22.700°±0.2°, and 23.663°±0.2°.

[0138] In some embodiments, the X-ray powder diffraction patterns of the crystalline form of p-toluenesulfonate are as follows at 2θ angles of 4.173°±0.2°, 4.357°±0.2°, 7.090°±0.2°, 8.364°±0.2°, 8.737°±0.2°, 10.093°±0.2°, 10.399°±0.2°, 12.047°±0.2°, 12.727°±0.2°, 13.860°±0.2°, 14.271°±0.2°, 16.038°±0.2°, and 16.757°±0.2°. Characteristic peaks are found at 17.542°±0.2°, 18.504°±0.2°, 19.037°±0.2°, 19.611°±0.2°, 20.144°±0.2°, 20.910°±0.2°, 21.156°±0.2°, 21.445°±0.2°, 21.818°±0.2°, 22.700°±0.2°, 23.027°±0.2°, 23.663°±0.2°, 24.427°±0.2°, 26.214°±0.2°, and 28.680°±0.2°.

[0139] In some embodiments, the X-ray powder diffraction pattern of the crystalline form of p-toluenesulfonate is as follows: Figure 12 As shown. In some embodiments, the X-ray powder diffraction pattern of the crystalline form of p-toluenesulfonate is compared with... Figure 12 They are basically the same.

[0140] In some embodiments, the differential scanning calorimeter of the crystalline form of p-toluenesulfonate has an endothermic peak in the range of 145.48 ± 3 °C.

[0141] In some embodiments, when heated from 30°C to 300°C at a heating rate of 20°C / min, the crystalline form of p-toluenesulfonate exhibits an endothermic peak. In some embodiments, the initial melting point of the endothermic peak in the crystalline form of p-toluenesulfonate is 139.10°C, the peak endothermic peak is 145.48°C, and the final melting point is 150.04°C.

[0142] In some embodiments, the differential scanning calorimetry (DSC) spectrum of the crystalline form of toluenesulfonate is as follows: Figure 14 As shown. In some embodiments, the differential scanning calorimeter of the crystalline form of toluenesulfonate is compared with... Figure 14 They are basically the same.

[0143] In some embodiments, the thermogravimetric analysis (TGA) spectrum of the crystalline form of toluenesulfonate is as follows: Figure 13 As shown. In some embodiments, the thermogravimetric analysis spectrum of the crystalline form of toluenesulfonate is compared with... Figure 13 They are basically the same.

[0144] In some embodiments, the weight loss of p-toluenesulfonate crystalline form during drying is 0.07% when heated from 21°C to 117°C at a heating rate of 20°C / min. In some embodiments, the weight loss of p-toluenesulfonate crystalline form during drying is 0.35% when heated from 117°C to 150°C at a heating rate of 20°C / min.

[0145] In some embodiments, (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is in the form of a 1,5-naphthalenedisulfonate. In some embodiments, the 1,5-naphthalenedisulfonate form is in crystalline form. In some embodiments, in the crystalline form of the 1,5-naphthalenedisulfonate, the molar ratio of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone to 1,5-naphthalenedisulfonate is 1:0.5.

[0146] In some embodiments, the X-ray powder diffraction pattern of the crystalline form of 1,5-naphthalenedisulfonate has characteristic peaks at 2θ angles of 8.923°±0.2°, 12.830°±0.2°, 14.328°±0.2°, and 17.824°±0.2°.

[0147] In some embodiments, the X-ray powder diffraction pattern of the crystalline form of 1,5-naphthalenedisulfonate has characteristic peaks at 2θ angles of 8.159°±0.2°, 8.923°±0.2°, 9.496°±0.2°, 10.056°±0.2°, 12.830°±0.2°, 14.328°±0.2°, 16.282°±0.2°, 17.019°±0.2°, 17.824°±0.2°, and 20.192°±0.2°.

[0148] In some embodiments, the X-ray powder diffraction patterns of the crystalline form of 1,5-naphthalenedisulfonate are at 2θ angles of 8.159°±0.2°, 8.923°±0.2°, 9.496°±0.2°, 10.056°±0.2°, 10.857°±0.2°, 11.079°±0.2°, 11.572°±0.2°, and 12.8°. Characteristic peaks are found at 30°±0.2°, 14.328°±0.2°, 15.870°±0.2°, 16.282°±0.2°, 17.019°±0.2°, 17.824°±0.2°, 19.267°±0.2°, 20.192°±0.2°, 23.873°±0.2°, and 26.209°±0.2°.

[0149] In some embodiments, the X-ray powder diffraction pattern of the crystalline form of 1,5-naphthalenedisulfonate is as follows: Figure 16 As shown. In some embodiments, the X-ray powder diffraction pattern of the crystalline form of 1,5-naphthalenedisulfonate is... Figure 16 They are basically the same.

[0150] In some embodiments, the differential scanning calorimeter of the crystalline form of 1,5-naphthalenedisulfonate has endothermic peaks in the ranges of 58.67℃±3℃, 111.99℃±3℃, 116.99℃±3℃, and 209.00℃±3℃.

[0151] In some embodiments, when heated from 30°C to 300°C at a heating rate of 20°C / min, the crystalline form of 1,5-naphthalenedisulfonate exhibits four endothermic peaks. In some embodiments, the first endothermic peak of the crystalline form of 1,5-naphthalenedisulfonate has an initial melting point of 57.40°C, a peak endothermic peak of 58.67°C, and a final melting point of 61.37°C; the second endothermic peak has an initial melting point of 109.67°C, a peak endothermic peak of 111.99°C, and a final melting point of 114.35°C; the third endothermic peak has an initial melting point of 114.96°C, a peak endothermic peak of 116.99°C, and a final melting point of 120.35°C; and the fourth endothermic peak has an initial melting point of 196.82°C, a peak endothermic peak of 209.00°C, and a final melting point of 229.14°C.

[0152] In some embodiments, the differential scanning calorimeter of the crystalline form of 1,5-naphthalenedisulfonate is as follows: Figure 18 As shown. In some embodiments, the differential scanning calorimeter of the crystalline form of 1,5-naphthalenedisulfonate is compared with... Figure 18 They are basically the same.

[0153] In some embodiments, the thermogravimetric analysis (TGA) spectrum of the crystalline form of 1,5-naphthalenedisulfonate is as follows: Figure 17As shown. In some embodiments, the thermogravimetric analysis (TGA) spectrum of the crystalline form of 1,5-naphthalenedisulfonate is compared with... Figure 17 They are basically the same.

[0154] In some embodiments, when heated from 21°C to 195°C at a heating rate of 20°C / min, the crystalline form of 1,5-naphthalenedisulfonate showed a drying weight loss of 3.63%.

[0155] In some embodiments, (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is in the form of β-naphthalenesulfonate. In some embodiments, the β-naphthalenesulfonate form has a crystalline form. In some embodiments, in the crystalline form of β-naphthalenesulfonate, the molar ratio of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone to β-naphthalenesulfonic acid is 1:1.

[0156] In some embodiments, the X-ray powder diffraction pattern of the β-naphthalenesulfonate crystalline form has characteristic peaks at 2θ angles of 3.999°±0.2°, 7.977°±0.2°, 18.160°±0.2°, 18.540°±0.2°, 20.199°±0.2°, 20.479°±0.2°, and 24.844°±0.2°.

[0157] In some embodiments, the X-ray powder diffraction pattern of the crystalline form of β-naphthalenesulfonate has characteristic peaks at 2θ angles of 3.999°±0.2°, 7.977°±0.2°, 16.781°±0.2°, 18.160°±0.2°, 18.540°±0.2°, 18.637°±0.2°, 20.199°±0.2°, 20.479°±0.2°, 20.754°±0.2°, 23.130°±0.2°, 23.205°±0.2°, 24.844°±0.2°, 25.503°±0.2°, and 28.416°±0.2°.

[0158] In some embodiments, the X-ray powder diffraction patterns of the β-naphthalenesulfonate crystalline form are as follows: 2θ angles of 3.999°±0.2°, 4.716°±0.2°, 4.973°±0.2°, 6.716°±0.2°, 7.977°±0.2°, 9.639°±0.2°, 11.301°±0.2°, 13.378°±0.2°, 16.781°±0.2°, 18.160°±0.2°, 18.540°±0.2°, 18.637°±0.2°, 20.199°±0.2°, 2 Characteristic peaks are observed at 0.479°±0.2°, 20.754°±0.2°, 22.088°±0.2°, 22.599°±0.2°, 23.130°±0.2°, 23.205°±0.2°, 23.734°±0.2°, 24.844°±0.2°, 25.503°±0.2°, 28.139°±0.2°, 28.416°±0.2°, 29.950°±0.2°, 33.632°±0.2°, 34.778°±0.2°, and 37.897°±0.2°.

[0159] In some embodiments, the X-ray powder diffraction pattern of the β-naphthalenesulfonate crystalline form is as follows: Figure 24 As shown. In some embodiments, the X-ray powder diffraction pattern of the β-naphthalenesulfonate crystalline form is... Figure 24 They are basically the same.

[0160] In some embodiments, the differential scanning calorimeter of the β-naphthalenesulfonate crystalline form exhibits an endothermic peak in the range of 144.83 °C ± 3 °C.

[0161] In some embodiments, the differential scanning calorimeter of the β-naphthalenesulfonate crystalline form is as follows: Figure 26 As shown. In some embodiments, the differential scanning calorimeter of the β-naphthalenesulfonate crystalline form is compared with... Figure 26 They are basically the same.

[0162] In some embodiments, the thermogravimetric analysis (TGA) spectrum of the β-naphthalenesulfonate crystalline form is as follows: Figure 25 As shown. In some embodiments, the thermogravimetric analysis spectrum of the β-naphthalenesulfonate crystalline form is compared with... Figure 25 They are basically the same.

[0163] In some embodiments, when heated from 21°C to 129.00°C at a heating rate of 20°C / min, the crystalline form of β-naphthalenesulfonate exhibits a drying weight loss of 0.08%. In some embodiments, when heated from 129.00°C to 154.00°C at a heating rate of 20°C / min, the crystalline form of β-naphthalenesulfonate exhibits a drying weight loss of 0.05%.

[0164] In some embodiments, (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is in the form of hydroiodide, sulfate, methanesulfonate, benzenesulfonate, nitrate, and / or camphorsulfonate.

[0165] Preparation method

[0166] In a second aspect, this disclosure provides a method for preparing crystalline form and / or salt form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone or a pharmaceutically acceptable solvate thereof, as described in the first aspect of this disclosure.

[0167] Preparation method of A crystal form

[0168] In some embodiments, (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone has crystal form A, and the method for crystal form A includes the following steps:

[0169] Dichloromethane was added to (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone, and the mixture was heated until the (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone dissolved to obtain the first solution;

[0170] Methyl tert-butyl ether was added to the first solution to obtain crystal form A.

[0171] The method for preparing crystal form A disclosed herein is simple to operate, has good repeatability, and has a good crystallization yield, making it suitable for industrial-scale production.

[0172] In some embodiments, the method includes the following steps: adding dichloromethane (DCM) to (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone, heating to reflux, and dissolving (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone to obtain a first solution.

[0173] In some embodiments, the reflux internal temperature is the boiling point of dichloromethane. In some embodiments, the reflux internal temperature is 39°C.

[0174] In some implementations, a heating reflux apparatus is used to prepare the A-type crystal.

[0175] In some embodiments, the method includes the following steps: adding methyl tert-butyl ether (MTBE) to a first solution, cooling, stirring, and obtaining crystal form A.

[0176] In some embodiments, methyl tert-butyl ether is added slowly to the first solution. In some embodiments, methyl tert-butyl ether is added dropwise to the first solution.

[0177] In some embodiments, cooling is performed until the internal temperature is room temperature. In some embodiments, cooling is performed until the internal temperature is 20°C.

[0178] In some embodiments, the stirring time is 1-2 hours. In some embodiments, the stirring time is 1 hour, 1.2 hours, 1.4 hours, 1.6 hours, 1.8 hours, 2.0 hours, or a range of any two of the above times, or a value within that range.

[0179] In some embodiments, the volume ratio of dichloromethane to methyl tert-butyl ether is (1:1) to (1:5). In some embodiments, the volume ratio of dichloromethane to methyl tert-butyl ether can be 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, or a range of any two of the above volume ratios, or a value within that range. In some embodiments, the volume ratio of dichloromethane to methyl tert-butyl ether is 1:5.

[0180] In some embodiments, the method includes the following steps: adding methyl tert-butyl ether (MTBE) to a first solution, cooling, stirring, filtering to obtain a filter cake, and rinsing the filter cake with methyl tert-butyl ether to obtain crystal form A.

[0181] In some embodiments, the volume of methyl tert-butyl ether used to wash the filter cake can be selected according to conventional amounts used in the art.

[0182] In some implementations, the method includes the following steps:

[0183] Dichloromethane (DCM) was added to (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone and heated to reflux. The (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone dissolved and became clear, yielding the first solution.

[0184] Methyl tert-butyl ether (MTBE) was added to the first solution, cooled, stirred, and filtered to obtain a filter cake, wherein the volume ratio of dichloromethane to methyl tert-butyl ether was (1:1)-(1:5).

[0185] The filter cake was washed with methyl tert-butyl ether to obtain crystal form A.

[0186] Preparation method of B crystal form

[0187] In some embodiments, (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone has a B crystal form, and the preparation method of the B crystal form includes the following steps:

[0188] A second solution was obtained by dissolving tetrahydrofuran in (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone.

[0189] The solvent in the second solution is evaporated to obtain crystal form B.

[0190] In some embodiments, the method for preparing the B crystal form includes the following steps:

[0191] Add (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone to the first container;

[0192] After adding tetrahydrofuran (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone to the first container and dissolving it, a second solution is obtained;

[0193] Filter the second solution and place the filtered solution into the second container;

[0194] Seal the second container and create a hole in the second container for the tetrahydrofuran to evaporate;

[0195] The solvent in the solution was evaporated at room temperature to obtain a solid, which was then dried to obtain crystal form B.

[0196] When used in this article, the term "room temperature" refers to the temperature of an indoor environment, typically between 15°C and 25°C.

[0197] In some embodiments, the mass ratio of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone to tetrahydrofuran is (20:0.5) to (20:10), where mass is expressed in milligrams (mg) and volume in milliliters (mL). In some embodiments, the mass ratio of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone to tetrahydrofuran is 20:1.

[0198] In some implementations, the first container and / or the second container includes a beaker or a glass bottle.

[0199] In some embodiments, the filtered solution includes membrane filtration. In some embodiments, the membrane size includes 0.45 μm.

[0200] In some embodiments, the temperature for drying the solid is 30°C-60°C. In some embodiments, the temperature for drying the solid is 40°C. In some embodiments, the drying time for the solid is 8h-15h. In some embodiments, the drying time for the solid is 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, or a range of any two of the above times, or a value within such a range.

[0201] In some embodiments, the method for preparing crystal form B includes the following steps: adding (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone to a first glass bottle, then adding tetrahydrofuran, and dissolving the (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone to obtain a second solution; filtering the second solution through a 0.45 μm filter membrane, and placing the filtered second solution in a second glass bottle; covering the mouth of the second glass bottle with aluminum foil and punching holes in the aluminum foil; evaporating the solvent of the second solution at room temperature to obtain a solid, and drying the solid to obtain crystal form B.

[0202] The method for preparing B crystal form disclosed herein is simple to operate and has good reproducibility.

[0203] Preparation method of hydrobromide crystal form

[0204] In some embodiments, (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is in the form of hydrobromide, and the hydrobromide form has a crystalline form. A method for preparing the crystalline form of hydrobromide includes the following steps:

[0205] (2-Pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is added to acetone, and after mixing, hydrobromic acid is added. The mixture is then stirred to obtain a first slurry, wherein (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is the A crystal form. The first slurry is separated to obtain a first solid. The first solid is dried to obtain the hydrobromate crystal form.

[0206] Optionally, the pulping time is 24h-150h, and more preferably, the pulping time is 80h-120h.

[0207] The method for preparing crystalline form of hydrobromide provided in this disclosure is simple to operate, has good reproducibility, and is suitable for industrial-scale production.

[0208] As used herein, the term "pulping" refers to suspension stirring, which can specifically involve mixing a sample and a solvent and then stirring them. In some embodiments, the sample and solvent are mixed to form a suspension.

[0209] In some implementations, the mixing temperature is room temperature.

[0210] In some embodiments, the pulping time can be 24h, 36h, 48h, 60h, 72h, 84h, 96h, 108h, 120h, 144h, 150h, or a range of any two of the above times, or a value within such a range. In some embodiments, the pulping temperature is room temperature.

[0211] In some embodiments, the drying temperature is 20°C-50°C and the drying time is 1h-48h.

[0212] In some embodiments, the drying temperature is 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, or 50°C, or a range of any two of the above temperatures, or a value within that range. In some embodiments, the drying time is 1h, 3h, 5h, 8h, 10h, 12h, 15h, 18h, 20h, 24h, 26h, 28h, 30h, 32h, 34h, 36h, 38h, 40h, 42h, 44h, 46h, or 48h, or a range of any two of the above times, or a value within that range.

[0213] In some embodiments, the method for obtaining the crystalline form of hydrobromide includes the following steps: adding (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone in crystal form A to acetone, mixing at room temperature, adding 1.05 eq of hydrobromic acid, and slurrying for 72 h or 96 h to obtain a first slurry, centrifuging the first slurry to obtain a first solid, and placing the first solid under vacuum drying at 40 °C for 4 h to obtain the crystalline form of hydrobromide.

[0214] Preparation method of hydrochloride crystal form

[0215] In some embodiments, (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is in the form of a hydrochloride salt, which has a crystalline form, and the method includes the following steps:

[0216] (2-Pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is added to acetone, tetrahydrofuran, or acetonitrile, and hydrochloric acid is added after mixing. The mixture is then stirred to obtain a second slurry, wherein (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is crystal form A. The second slurry is separated to obtain a second solid. The second solid is dried to obtain the crystalline form of the hydrochloride salt.

[0217] Optionally, the pulping time is 12h-150h, and more preferably, the pulping time is 24h-120h.

[0218] The method for preparing the crystalline form of hydrochloride provided in this disclosure is simple to operate, has good reproducibility, and is suitable for industrial-scale production. Using tetrahydrofuran or acetonitrile as the solvent is more conducive to obtaining the crystalline form of hydrochloride with excellent crystallinity.

[0219] In some implementations, the mixing temperature is room temperature.

[0220] In some embodiments, the pulping time can be 12h, 24h, 36h, 48h, 60h, 72h, 84h, 96h, 108h, 120h, 144h, 150h, or a range of any two of the above times, or a value within such a range. In some embodiments, the pulping temperature is room temperature.

[0221] In some embodiments, the drying temperature is 20°C-50°C and the drying time is 1h-48h.

[0222] In some embodiments, the drying temperature is 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, or 50°C, or a range of any two of the above temperatures, or a value within that range. In some embodiments, the drying time is 1h, 3h, 5h, 8h, 10h, 12h, 15h, 18h, 20h, 24h, 26h, 28h, 30h, 32h, 34h, 36h, 38h, 40h, 42h, 44h, 46h, or 48h, or a range of any two of the above times, or a value within that range.

[0223] In some embodiments, the preparation method of the hydrochloride crystalline form includes the following steps: adding (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone A crystal form to tetrahydrofuran, mixing at room temperature, adding 1.05 eq hydrochloric acid, slurrying for 24 h or 72 h to obtain a second slurry, centrifuging the second slurry to obtain a second solid, and placing the second solid at 40 °C under vacuum drying for 4 h to obtain the hydrochloride crystalline form.

[0224] In some embodiments, the preparation method of the hydrochloride crystalline form includes the following steps: adding (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone A crystal form to acetonitrile, mixing at room temperature, adding 1.05 eq. hydrochloric acid, slurrying for 72 h or 96 h to obtain a second slurry, centrifuging the second slurry to obtain a second solid, and placing the second solid at 40 °C under vacuum drying for 4 h to obtain the hydrochloride crystalline form.

[0225] In some embodiments, the preparation method of the hydrochloride crystalline form includes the following steps: adding (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone in crystal form A to acetone, mixing at room temperature, adding 1.05 eq. hydrochloric acid, slurrying for 96 h to obtain a second slurry, centrifuging the second slurry to obtain a second solid, and placing the solid at 40 °C under vacuum drying for 4 h to obtain the hydrochloride crystalline form.

[0226] Preparation method of p-toluenesulfonate crystalline form

[0227] In some embodiments, (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is in the form of p-toluenesulfonate, which has a crystalline form. The method for preparing the crystalline form of p-toluenesulfonate includes the following steps:

[0228] (2-Pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is added to acetone, and after mixing, p-toluenesulfonic acid or its hydrate is added. After slurrying, a third slurry is obtained, wherein (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is the A crystal form; the third slurry is separated to obtain a third solid; the third solid is dried to obtain the p-toluenesulfonate crystalline form.

[0229] Optionally, the pulping time is 24h-150h, and more preferably, the pulping time is 80h-120h.

[0230] The method for preparing crystalline p-toluenesulfonate provided in this disclosure is simple to operate, has good reproducibility, and is suitable for industrial-scale production.

[0231] In some implementations, the mixing temperature is room temperature.

[0232] In some embodiments, the pulping time can be 24h, 36h, 48h, 60h, 72h, 84h, 96h, 108h, 120h, 144h, 150h, or a range of any two of the above times, or a value within such a range. In some embodiments, the pulping temperature is room temperature.

[0233] In some embodiments, the drying temperature is 20°C-50°C and the drying time is 1h-48h.

[0234] In some embodiments, the drying temperature is 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, or 50°C, or a range of any two of the above temperatures, or a value within that range. In some embodiments, the drying time is 1h, 3h, 5h, 8h, 10h, 12h, 15h, 18h, 20h, 24h, 26h, 28h, 30h, 32h, 34h, 36h, 38h, 40h, 42h, 44h, 46h, or 48h, or a range of any two of the above times, or a value within that range.

[0235] In some embodiments, p-toluenesulfonic acid is p-toluenesulfonic acid monohydrate.

[0236] In some embodiments, the preparation method of p-toluenesulfonate crystalline form includes the following steps: adding (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone in crystal form A to acetone, mixing at room temperature, adding 1.05 eq of p-toluenesulfonic acid monohydrate, slurrying for 72 h or 96 h to obtain a third slurry, centrifuging the third slurry to obtain a third solid, and placing the third solid under vacuum drying at 40 °C for 4 h to obtain p-toluenesulfonate crystalline form.

[0237] Preparation method of crystalline form of 1,5-naphthalenedisulfonate

[0238] In some embodiments, (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is in the form of 1,5-naphthalenedisulfonate, which has a crystalline form. The preparation method of the crystalline form of 1,5-naphthalenedisulfonate includes the following steps:

[0239] (2-Pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone was added to dichloromethane, and after mixing, 1,5-naphthalenedisulfonic acid was added. The mixture was then stirred to obtain a fourth slurry, wherein (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone was crystal form A. The fourth slurry was separated to obtain a fourth solid. The fourth solid was dried to obtain the crystalline form of 1,5-naphthalenedisulfonate.

[0240] Optionally, the pulping time is 6h-150h, and more preferably, the pulping time is 12h-120h.

[0241] The method for preparing crystalline 1,5-naphthalenedisulfonate provided in this disclosure is simple to operate, has good reproducibility, and is suitable for industrial-scale production.

[0242] In some implementations, the mixing temperature is room temperature.

[0243] In some embodiments, the pulping time can be 6h, 12h, 24h, 36h, 48h, 60h, 72h, 84h, 96h, 108h, 120h, 144h, 150h, or a range of any two of the above times, or a value within such a range. In some embodiments, the pulping temperature is room temperature.

[0244] In some embodiments, the drying temperature is 20°C-50°C and the drying time is 1h-48h.

[0245] In some embodiments, the drying temperature is 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, or 50°C, or a range of any two of the above temperatures, or a value within that range. In some embodiments, the drying time is 1h, 3h, 5h, 8h, 10h, 12h, 15h, 18h, 20h, 24h, 26h, 28h, 30h, 32h, 34h, 36h, 38h, 40h, 42h, 44h, 46h, or 48h, or a range of any two of the above times, or a value within that range.

[0246] In some embodiments, the preparation method of crystalline form of 1,5-naphthalenedisulfonate includes the following steps: adding (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone in crystal form A to dichloromethane, mixing at room temperature, adding 0.525 eq of 1,5-naphthalenedisulfonic acid, slurrying for 12 h or 72 h to obtain a fourth slurry, centrifuging the fourth slurry to obtain a fourth solid, and placing the fourth solid under vacuum drying at 40 °C for 4 h to obtain crystalline form of 1,5-naphthalenedisulfonate.

[0247] Preparation method of crystalline form of β-naphthalenesulfonate

[0248] In some embodiments, (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is in the form of β-naphthalenesulfonate, which has a crystalline form. The method for preparing the crystalline form of β-naphthalenesulfonate includes the following steps:

[0249] (2-Pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone in crystal form A is added to dichloromethane, and β-naphthalenesulfonic acid is added after mixing. After the first slurrying, a fifth slurry is obtained. The fifth slurry is dried to obtain a fifth solid, wherein (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is crystal form A.

[0250] Tetrahydrofuran was added to the fifth solid, and the sixth slurry was obtained after a second pulping.

[0251] Separate the sixth slurry to obtain the sixth solid;

[0252] The β-naphthalenesulfonate crystalline form was obtained by drying the sixth solid.

[0253] Optionally, the first pulping time is 24h-150h;

[0254] Optionally, the second pulping time is 12h-150h.

[0255] The method for preparing crystalline β-naphthalenesulfonate provided in this disclosure is simple to operate, has good reproducibility, and is suitable for industrial-scale production.

[0256] In some embodiments, the time for the first pulping can be 24h, 36h, 48h, 60h, 72h, 84h, 96h, 108h, 120h, 144h, 150h, or a range of any two of the above times, or a value within such a range. In some embodiments, the temperature for the first pulping is room temperature.

[0257] In some embodiments, the temperature for drying the first slurry is 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, or 50°C, or a range of any two of the above temperatures, or a value within that range. In some embodiments, the drying time is 1 hour, 3 hours, 5 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 24 hours, 26 hours, 28 hours, 30 hours, 32 hours, 34 hours, 36 hours, 38 hours, 40 hours, 42 hours, 44 hours, 46 hours, or 48 hours, or a range of any two of the above times, or a value within that range.

[0258] In some embodiments, the second pulping time can be 12h, 24h, 36h, 48h, 60h, 72h, 84h, 96h, 108h, 120h, 144h, 150h, or a range of any two of the above times, or a value within such a range. In some embodiments, the temperature for the second pulping is room temperature.

[0259] In some embodiments, the temperature for drying the solid is 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, or 50°C, or a range of any two of the above temperatures, or a value within that range. In some embodiments, the drying time for the solid is 1h, 3h, 5h, 8h, 10h, 12h, 15h, 18h, 20h, 24h, 26h, 28h, 30h, 32h, 34h, 36h, 38h, 40h, 42h, 44h, 46h, or 48h, or a range of any two of the above times, or a value within that range.

[0260] In some embodiments, the preparation method of β-naphthalenesulfonate crystalline form includes the following steps: adding (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone to dichloromethane, mixing at room temperature, adding 1.05 eq β-naphthalenesulfonic acid, and after the first slurrying for 96 h, obtaining the fifth slurry, and placing the fifth slurry under vacuum drying at 40 °C for 4 h to obtain the fifth solid;

[0261] Tetrahydrofuran was added to the fifth solid, and the mixture was pulped for a second time for 48 hours to obtain the sixth slurry. The sixth slurry was separated by centrifugation to obtain the sixth solid, which was then vacuum dried at 40°C for 4 hours to obtain crystalline β-naphthalenesulfonate.

[0262] Pharmaceutical Composition

[0263] Thirdly, this disclosure provides a pharmaceutical composition comprising, as in the crystalline form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone or a pharmaceutically acceptable solvate thereof as in the first aspect of this disclosure, and / or a salt form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone, as prepared by the method of the second aspect of this disclosure, and a pharmaceutically acceptable carrier.

[0264] As used herein, the term "pharmaceuticalally acceptable carrier" refers to a pharmaceutically acceptable raw material, component, or carrier that imparts morphology or consistency to the pharmaceutical composition. When mixed, each carrier is compatible with the other components of the pharmaceutical composition, thereby avoiding significant reduction in the potency of the crystal form disclosed herein when administered to a subject and avoiding interactions between pharmaceutically unacceptable pharmaceutical components.

[0265] In some embodiments, pharmaceutically acceptable carriers include, but are not limited to: diluents, fillers, binders, disintegrants, lubricants, flow aids, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, thickeners, antioxidants, preservatives, stabilizers, surfactants, or buffers. Those skilled in the art may selectively use the above-mentioned pharmaceutically acceptable carriers depending on the dosage form of the pharmaceutical composition.

[0266] Uses and treatments

[0267] Fourthly, this disclosure provides the use of crystalline forms and / or salt forms of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) ketone or pharmaceutically acceptable solvates thereof as in the first aspect of this disclosure, crystalline forms and / or salt forms of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) ketone prepared by the method of the second aspect of this disclosure, and / or the use of pharmaceutical compositions as in the third aspect of this disclosure in the preparation of medicaments for the prevention, treatment and / or relief of diseases, symptoms and / or disorders.

[0268] In some embodiments, the disease, symptom, or disorder includes neurodegenerative diseases, psychosis, epilepsy, seizures, stroke, and pain. In some embodiments, neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, and cognitive impairment, and pain includes chronic inflammatory pain.

[0269] When used in this document, the term “treatment” means to alleviate or improve a disease or disorder (i.e., to slow or stop the development of the disease or at least one clinical symptom); or to alleviate or improve at least one physical parameter or biomarker associated with the disease or disorder.

[0270] When used herein, the term “prevention” means a method implemented to block, reduce, inhibit, prevent and / or delay the occurrence of a disease or condition or symptom (e.g., cancer, metastatic cancer cells, respiratory diseases and symptoms, infections or autoimmune diseases) in a subject, or a method to reduce the incidence of infectious diseases in said subject.

[0271] Fifthly, this disclosure also provides a method for diagnosing, preventing, and / or treating a disease, the method comprising administering to a subject in need a therapeutically effective dose of crystalline form and / or a pharmaceutically acceptable solvate of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) ketone or the like of the first aspect of this disclosure, crystalline form and / or a salt form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) ketone prepared by the method of the second aspect of this disclosure, and / or a pharmaceutical composition as described in the third aspect of this disclosure.

[0272] As used herein, the term "subject" refers to a primate (e.g., a human), a dog, a rabbit, a guinea pig, a pig, a rat, and a mouse. In some embodiments, the subject is a primate. In some specific embodiments, the subject is a human.

[0273] In this paper, a subject is considered "needing" the treatment if the subject benefits from it biologically, medically, or in terms of quality of life.

[0274] As used herein, the term "therapeutic effective dose" refers to an amount that results in benefit or treatment of a disease compared to a corresponding subject who did not receive that amount, but is sufficiently low within the range of reasonable medical judgment to avoid serious side effects. The therapeutic effective doses of the crystalline and salt forms of this disclosure will vary depending on factors such as the specific crystalline and salt forms chosen; the chosen route of administration; the disease being treated; the severity of the disease being treated; the age, body type, weight, and physical condition of the patient being treated; the patient's medical history; the duration of treatment; the nature of concurrent treatments; and the desired therapeutic effect, but can still be determined by those skilled in the art in a conventional manner.

[0275] The various embodiments and preferences described above with respect to this disclosure can be combined with each other (as long as they are not inherently contradictory to each other), and all embodiments formed by such combinations are considered as part of this disclosure.

[0276] The technical solutions of this disclosure will be illustrated more clearly and explicitly below with reference to embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of protection of this disclosure. The scope of protection of this disclosure is defined only by the claims.

[0277] Example

[0278] The embodiments described below are exemplary and are only used to explain this application, and should not be construed as limiting this application. Where specific techniques or conditions are not specified in the embodiments, they shall be performed in accordance with the techniques or conditions described in the literature in this field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0279] Instruments and their testing methods

[0280] 1. X-ray powder diffraction (XRPD)

[0281] 1.1. The equipment model is Shimadzu XRD-6000. Scan the sample according to the following parameters:

[0282] The radiation source is a Cu-Kα target.

[0283] The minimum operating voltage and current of the fluorescent tube are 40kV and 30mA, respectively.

[0284] The 2θ value of the sample scanning range is from 2° to 50°, and the scanning speed is 5 deg / min.

[0285] 1.2 The equipment model is Bruker D8 Advance. Scan the sample according to the following parameters:

[0286] The radiation source is a Cu-Kα target.

[0287] The minimum operating voltage and current of the optical tube are 40kV and 40mA, respectively.

[0288] The 2θ value of the sample scanning range is from 3° to 40°, and the scanning speed is 5 deg / min.

[0289] 2. Differential Scanning Calorimeter (DSC)

[0290] 2.1 Both crystal form A and crystal form B are tested using DSC3 (Mettler) equipment;

[0291] The test method was as follows: Approximately 5 mg of powder sample was weighed and placed in a sealed aluminum crucible, with a pinhole punched in the crucible lid. Under nitrogen protection, the temperature was increased from 30 °C to 300 °C for differential calorimetry scanning. The heating rate was 20 °C / min, and the differential scanning calorimetry spectrum was obtained.

[0292] 2.2 The salt-type crystallization method uses equipment model DSC3 (Mettler);

[0293] The test method is as follows: Weigh approximately 1–2 mg of powder sample and place it in a sealed aluminum crucible. Make a pinhole in the crucible lid. Under nitrogen protection, perform a differential thermal scan by heating from 30°C to 350°C. The heating rate is 20°C / min.

[0294] 3. Thermogravimetric analyzer (TGA)

[0295] The device model is Pyris1 TGA (Platinum Elmer);

[0296] The test method is as follows: Weigh 5 mg of sample into a crucible, protect with nitrogen, heat from 30 °C to 350 °C at a heating rate of 20 °C / min, hold at 350 °C for 1 min, and obtain the thermogravimetric analysis spectrum.

[0297] 4. Nuclear magnetic resonance hydrogen spectrum ( 1 H-NMR)

[0298] Dissolve 3-5 mg of sample in 0.5 mL of deuterated reagent, and test the 1H NMR spectrum of the sample using a BRUKER AVANCE III (400 M) instrument.

[0299] 5. Dynamic Moisture Adsorption (DVS)

[0300] Under a relative humidity (RH) cycle of 0%–95%–0%, approximately 10 mg of sample was weighed and subjected to a moisture absorption / desorption characteristic test at 25°C. The parameters are as follows:

[0301]

[0302] 6. Ion chromatography (IC)

[0303] Ion chromatography was commissioned to Ingel Testing Technology Service (Shanghai) Co., Ltd. to be performed according to conventional testing methods in this field, as follows: 2g of sample was dissolved in 20mL of solvent to prepare a sample solution, and ion chromatography was performed using a Dionex INTEGRION HPIC instrument (Thermo). The chromatographic column was a Dionex IonPac™ AS18 REICTM4×250mm Analytical (Thermo).

[0304] Example 1: Preparation of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone A crystal form

[0305] 400 mL of dichloromethane was added to 100 g of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone (provided by Guangzhou Shenyuan Huikang Biomedical Technology Co., Ltd.). The mixture was heated to a reflux internal temperature of 39 °C, and after complete dissolution, it was heated to reflux. 2000 mL of methyl tert-butyl ether was added dropwise, and a solid precipitated. The mixture was cooled to an internal temperature of 20 °C and stirred for 2 h. After filtration, the filter cake was washed with 100 mL of methyl tert-butyl ether to obtain crystal form A. The crystallization yield was 88%, and the method showed good reproducibility.

[0306] Using the testing instruments and methods described in section 1.1, the X-ray powder diffraction pattern of crystal form A is shown below. Figure 1 The specific characteristic peak positions are shown in the table below:

[0307]

[0308] Differential scanning calorimetry (DSC) spectra of crystal form A are as follows: Figure 2 As shown, the differential scanning calorimetry (DSC) spectrum reveals an endothermic peak in crystal form A, with an initial melting point of 170.53℃, a peak endothermic point of 172.94℃, and a final melting point of 176.34℃. The thermogravimetric analysis (TGA) spectrum of crystal form A is shown below. Figure 3 As shown, the thermogravimetric analysis spectrum indicates that the A crystal form did not experience significant weight loss before being heated from 30°C to its decomposition temperature.

[0309] Example 2: Preparation of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone A crystal form

[0310] 1 g of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone was added to 20 eq of anhydrous ethanol, and the mixture was heated to a reflux internal temperature of 79 °C. After the solution was cleared, the mixture was heated to reflux. 10 eq of water was added dropwise, and the mixture was stirred for 30 min after the addition was complete. The mixture was cooled to room temperature (25 °C), stirred overnight (10 h), filtered, and dried to obtain crystals. The crystallization yield was 60%, and the method was not reproducible.

[0311] The X-ray powder diffraction pattern, differential scanning calorimetry pattern, and thermogravimetric analysis pattern of the crystal obtained by the preparation method in Example 2 are basically consistent with those in Example 1.

[0312] Example 3: Preparation of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone B crystal form

[0313] Weigh 40 mg of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone into a 4 ml glass bottle, then add tetrahydrofuran to dissolve the compound. Filter the solution through a 0.45 μm nylon membrane and transfer it to a new glass bottle. Cover the bottle opening with perforated aluminum foil and place the sample in a fume hood to evaporate naturally at room temperature. After the solvent has completely evaporated, a solid precipitates. Dry the solid under reduced pressure in a vacuum drying oven at 40 °C overnight to obtain crystal form B. 1 H-NMR results show (attached) Figure 7 In the B crystal form, the mass percentage of tetrahydrofuran is 2.06%.

[0314] Using the testing instruments and methods described in section 1.1, the X-ray powder diffraction pattern of crystal form B is shown below. Figure 4 The specific characteristic peak positions are shown in the table below:

[0315]

[0316] Differential scanning calorimetry (DSC) spectra of B-type crystals are as follows: Figure 5 As shown, the differential scanning calorimetry (DSC) spectrum reveals that crystal form B has two endothermic peaks. The first endothermic peak has an initial melting point of 162.94℃, a peak endothermic point of 165.08℃, and a final melting point of 168.17℃. The second endothermic peak has an initial melting point of 170.64℃, a peak endothermic point of 172.34℃, and a final melting point of 175.39℃. The thermogravimetric analysis (TGA) spectrum of crystal form B is shown below. Figure 6 As shown, the thermogravimetric analysis spectrum indicates that the B crystal form loses 1.33% of its weight when heated from 30℃ to 150℃ and 1.11% of its weight when heated from 150℃ to 190℃.

[0317] Example 4: Screening and characterization of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) ketone salts

[0318] 4.1 Salt type screening and characterization of the acetone system

[0319] Approximately 30 mg of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone A crystal form (prepared according to the method in Example 1) was weighed into a 4 mL glass bottle, and 0.9 mL of acetone was added. The mixture was stirred at room temperature. 1.05 eq of ligand acids (including hydroiodic acid, hydrobromic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid monohydrate, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, β-naphthalenesulfonic acid, benzenesulfonic acid, 1,2-ethanedisulfonic acid dihydrate, camphorsulfonic acid, citric acid, fumaric acid, tartaric acid, succinic acid, and phosphoric acid) were added separately. The experimental phenomena were observed and recorded, as shown in Table 1. In the acetone system, the crystalline salts of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone could be obtained using hydrobromic acid and p-toluenesulfonic acid ligands, while the salt obtained using hydrochloric acid ligand had low crystallinity. Products obtained with other ligands showed no diffraction peaks by XRPD characterization, indicating no crystalline form was obtained.

[0320] Table 1: Salt formation experiments in the acetone system

[0321]

[0322]

[0323]

[0324] 4.2 Salt type screening and characterization of the dichloromethane system

[0325] Approximately 330 mg of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone A crystal form (prepared according to the method in Example 1) was weighed into a 4 mL glass bottle. 3.3 mL of dichloromethane was added, and the solution was stirred and dissolved at room temperature. The solution was filtered to obtain a clear solution, with an actual volume of 3.75 mL. 0.34 mL of this solution was dispensed into 4 mL glass vials, and 1.05 eq. of ligand acids (including hydroiodic acid, hydrobromic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid monohydrate, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, β-naphthalenesulfonic acid, benzenesulfonic acid, and 1,2-ethanedisulfonic acid dihydrate) was added to each. The experimental phenomena were observed and recorded, as shown in Table 2. In the dichloromethane system, the crystalline salt of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone can be obtained using the 1,5-naphthalenedisulfonic acid ligand. The products obtained with other ligands showed no diffraction peaks upon XRPD characterization and no crystalline form was obtained.

[0326] Table 2: Salt formation experiments of dichloromethane system

[0327]

[0328]

[0329] NA indicates that the sample has not undergone XRPD testing, usually because the sample condition is not suitable for XRPD testing, such as when the sample is oily.

[0330] 4.3 Salt type screening and characterization of acetonitrile system

[0331] Approximately 30 mg of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone A crystal form (prepared in Example 1) was weighed into a 4 mL glass bottle, and 1.0 mL of acetonitrile was added. The mixture was stirred at room temperature. 1.05 eq. of ligand acids (including hydrochloric acid, sulfuric acid, oxalic acid, maleic acid, nitric acid, methanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, citric acid, fumaric acid, tartaric acid, succinic acid, and phosphoric acid) were added. The experimental phenomena were observed and recorded, as shown in Table 3. In the acetonitrile system, the crystalline salt of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone was obtained using the hydrochloric acid ligand. Products obtained with other ligands showed no diffraction peaks by XRPD characterization, indicating no crystalline form was obtained.

[0332] Preparation of 1 mol / L hydrochloric acid acetonitrile solution: Accurately measure 417 μL into a 5 mL volumetric flask, add acetonitrile to the mark, shake, and mix well.

[0333] Preparation of 1 mol / L sulfuric acid acetonitrile solution: Accurately measure 278 μL into a 5 mL volumetric flask, add acetonitrile to the mark, shake, and mix well.

[0334] Preparation of 2 mol / L nitric acid solution: Accurately measure 1307 μL into a 10 mL volumetric flask, add water to the mark, shake, and mix well.

[0335] Table 3: Salt formation experiments of acetonitrile system

[0336]

[0337]

[0338]

[0339] 4.4 Salt type screening and characterization of the tetrahydrofuran system

[0340] Approximately 30 mg of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone A crystal form (prepared in Example 1) was weighed into a 4 mL glass bottle, and 1.0 mL of tetrahydrofuran was added. The mixture was stirred at room temperature. 1.05 eq. of ligand acids (including hydrochloric acid, sulfuric acid, oxalic acid, maleic acid, nitric acid, and β-naphthalenesulfonic acid) was added, and the experimental phenomena were observed and recorded as shown in Table 4. In the tetrahydrofuran system, the crystalline salt of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone could be obtained using hydrochloric acid ligands and β-naphthalenesulfonic acid ligands. Products obtained with other ligands showed no diffraction peaks by XRPD characterization, indicating that no crystalline form was obtained.

[0341] Table 4: Salt formation experiments of the tetrahydrofuran system

[0342]

[0343]

[0344] 4.5 Pulping and Crystallization

[0345] Based on the above experimental phenomena and results, and using ligands (hydroiodic acid, methanesulfonic acid, β-naphthalenesulfonic acid, benzenesulfonic acid), the product obtained in the acetone system was slurried in 0.5 mL of acetonitrile, and the product obtained in the dichloromethane system was slurried in 0.5 mL of tetrahydrofuran. The experimental phenomena were observed and recorded, as shown in Table 5. The crystalline form of β-naphthalenesulfonate of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone can be obtained by using the slurry-to-crystallization method (original solvent: dichloromethane, slurry solvent: tetrahydrofuran). Other products showed no diffraction peaks upon XRD characterization.

[0346] Table 5: Pulping and Crystallization Experiments

[0347]

[0348] 4.6 Characterization data of salt crystallization form

[0349] 4.6.1 Characterization data of hydrobromide crystal form

[0350] This summary covers the crystalline forms of hydrobromide obtained from the acetone system, including XRPD, TGA, and DSC. 1 The results of H-NMR and IC characterization are as follows. The testing instruments and methods described in section 1.2 were used. The XRPD spectrum is shown below. Figure 8 As shown in the table below, the specific peak positions are as follows:

[0351]

[0352]

[0353] TGA curve as follows Figure 9As shown, the hydrobromide crystalline form lost 1.04% of its weight during the heating process from 21.31℃ to 123.00℃, and 4.40% during the heating process from 123.00℃ to 163.00℃. The DSC curves are shown below. Figure 10 As shown, the hydrobromide crystalline form exhibits three endothermic peaks. The first endothermic peak has an initial melting point of 112.63℃, an endothermic peak of 118.68℃, and a final melting point of 122.93℃. The second endothermic peak has an initial melting point of 146.89℃, an endothermic peak of 152.26℃, and a final melting point of 155.56℃. The third endothermic peak has an initial melting point of 155.89℃, an endothermic peak of 158.59℃, and a final melting point of 162.63℃. 1 H-NMR spectrum as shown Figure 11 As shown, there is a chemical shift in the hydrobromide crystal form compared to crystal form A. IC results indicate that the bromide ion content in the hydrobromide crystal form is 17.1%, therefore the molar ratio of the salt is 1:1.

[0354] 4.6.2 Characterization data of the crystalline form of p-toluenesulfonate

[0355] This paper summarizes the XRPD, TGA, and DSC methods used to obtain p-toluenesulfonate crystalline forms from the acetone system. 1 The results of the 1H-NMR characterization were obtained. The testing instruments and methods described in section 1.2 of the instrument and testing methods section were used. The XRPD spectra are shown below. Figure 12 As shown in the table below, the specific peak positions are as follows:

[0356]

[0357]

[0358] The TGA curves show that the crystalline form of p-toluenesulfonate lost 0.07% weight during the heating process from 21.44℃ to 117.00℃, and 0.35% weight during the heating process from 117.00℃ to 150.00℃. (Specific details are as follows...) Figure 13 As shown in the figure. The DSC curve shows that the crystalline form of p-toluenesulfonate has a sharp endothermic peak, with an initial melting point of 139.10℃, an endothermic peak of 145.48℃, and a final melting point of 150.04℃. (Details are as follows...) Figure 14 As shown. 1 The H-NMR spectrum shows characteristic peaks for p-toluenesulfonic acid, indicating a salt formation ratio of 1:1. (Specific details are as follows...) Figure 15 As shown.

[0359] 4.6.3 Characterization data of the crystalline form of 1,5-naphthalenedisulfonate

[0360] This paper summarizes the XRPD, TGA, DSC, and other methods used to obtain 1,5-naphthalenedisulfonate crystal forms from the dichloromethane system. 1 The characterization results of H-NMR were obtained. The testing instruments and methods described in section 1.2 of the instrument and testing methods section were used. The XRPD spectra are shown below. Figure 16 As shown in the table below, the specific peak positions are as follows:

[0361]

[0362] The TGA curve shows that the crystalline form of 1,5-naphthalenedisulfonate lost 3.63% of its weight during the heating process from 21.32℃ to 195.00℃. (Specific details are as follows...) Figure 17 As shown in the figure. The DSC curve shows that the crystalline form of 1,5-naphthalenedisulfonate has four endothermic peaks. The first endothermic peak has an initial melting point of 57.40℃, a peak endothermic point of 58.67℃, and a final melting point of 61.37℃. The second endothermic peak has an initial melting point of 109.67℃, a peak endothermic point of 111.99℃, and a final melting point of 114.35℃. The third endothermic peak has an initial melting point of 114.96℃, a peak endothermic point of 116.99℃, and a final melting point of 120.35℃. The fourth endothermic peak has an initial melting point of 196.82℃, a peak endothermic point of 209.00℃, and a final melting point of 229.14℃. (Details are as follows...) Figure 18 As shown. 1 The H-NMR spectrum shows characteristic peaks for 1,5-naphthalenedisulfonic acid, with a salt formation ratio of 1:0.5, as detailed below. Figure 19 As shown.

[0363] 4.6.4 Characterization data of hydrochloride crystal form

[0364] This summary covers the crystalline forms of hydrochloride obtained from the tetrahydrofuran system, including XRPD, TGA, and DSC. 1 The results were characterized by H-NMR and IC. The testing instruments and methods described in section 1.2 were used. The XRPD spectrum is shown below. Figure 20 As shown in the table below, the specific peak positions are as follows:

[0365]

[0366]

[0367] The TGA curves show that the hydrochloride crystals lost 4.12% of their weight during the heating process from 21.28℃ to 130.00℃, and 9.80% during the heating process from 130.00℃ to 210.00℃. (Specific details are as follows...) Figure 21As shown in the figure. The DSC curve shows that the hydrochloride crystal form has three endothermic peaks. The first endothermic peak has an initial melting point of 130.10℃, an endothermic peak of 142.07℃, and a final melting point of 153.54℃. The second endothermic peak has an initial melting point of 161.86℃, an endothermic peak of 169.34℃, and a final melting point of 182.37℃. The first endothermic peak has an initial melting point of 184.59℃, an endothermic peak of 195.96℃, and a final melting point of 207.88℃. (Details are as follows...) Figure 22 As shown. 1 The H-NMR spectrum shows a chemical shift in the hydrochloride crystal form compared to crystal form A, specifically as follows: Figure 23 As shown in the figure. IC results show that the chloride ion content in the crystalline form of hydrochloride is 10.8%, therefore the molar ratio of salt formation is 1:1.

[0368] The XRPD, TGA, DSC, 1H-NMR, and IC characterization results of the hydrochloride crystals obtained in the acetone and acetonitrile systems are basically consistent with those of the hydrochloride crystals obtained in the tetrahydrofuran system.

[0369] 4.6.5 Characterization data of β-naphthalenesulfonate crystal form

[0370] This paper summarizes the methods for XRPD, TGA, DSC, and other assays on the crystalline forms of β-naphthalenesulfonate obtained through a pulping and crystallization process. 1 H-NMR characterization. The testing instruments and methods described in section 1.1 of the instrument and testing methods section were used. The XRPD spectrum is shown below. Figure 24 As shown in the table below, the specific peak positions are as follows:

[0371]

[0372]

[0373] The TGA curves show that the β-naphthalenesulfonate crystal form lost 0.08% weight during the heating process from 21.23℃ to 129.00℃, and 0.05% weight during the heating process from 129.00℃ to 154.00℃. (Specific details are as follows...) Figure 25 As shown in the figure. The DSC curve shows that the crystalline form of β-naphthalenesulfonate has an endothermic peak, with an initial melting point of 129.29℃, an endothermic peak of 144.83℃, and a final melting point of 153.41℃. (Details are as follows...) Figure 26 As shown. 1 The H-NMR spectrum shows characteristic peaks for β-naphthalenesulfonic acid, indicating a salt molar ratio of 1:1. (Specific details are as follows...) Figure 27 As shown.

[0374] 4.7 Summary of Screening for (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) ketone salts

[0375] The screening results for (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone salts are shown in Table 7.

[0376] Table 7: Summary of Screening for (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) ketone salts

[0377]

[0378]

[0379] Test Example 1: Solubility Test

[0380] 1.1 Solubility test of crystal form A in organic solvents

[0381] Test method: Weigh about 4 mg of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone A crystal form, add an appropriate volume of solvent step by step, shake or sonicate for 15 seconds, observe whether it dissolves, record the volume that can be completely dissolved and the volume of solvent that cannot be completely dissolved in the previous test, and calculate its solubility.

[0382] Test results:

[0383] solvent Crystal form A mass (mg) solvent volume Solubility (mg / mL) methanol 4.33 1.0-1.5 2.9-4.3 Acetonitrile 4.43 0.5-1.0 4.4-8.9 acetone 4.42 0.4-0.5 8.8-11.1 2-Butanone 4.23 0.3-0.4 10.6-14.1 Tetrahydrofuran 4.07 0.1-0.2 20.4-40.7 Toluene 4.71 1.0-1.5 3.1-4.7 1,4-Dioxane 4.15 0.3-0.4 10.4-13.8 dichloromethane 4.38 0.05-0.1 43.8-87.6 dimethyl sulfoxide 4.49 0.08-0.1 44.9-56.1

[0384] The table above shows the solubility of crystal form A in different solvents. As can be seen from the table, crystal form A has good solubility in the above solvents.

[0385] 1.2 Solubility test of salt form

[0386] 1.2.1 Solubility test of salt-type crystal form

[0387] The solubility of crystal forms A, hydrobromide, hydrochloride, p-toluenesulfonate, and 1,5-naphthalenedisulfonate in water, simulated gastric juice (SGF), simulated intestinal juice under fasting conditions (FaSSIF), and simulated intestinal juice under feeding conditions (FeSSIF) were tested at 37℃. The specific test methods are as follows:

[0388] Approximately 12 mg of the above sample was weighed into a 4 mL glass bottle, and 3 mL of solvent (water, SGF, FeSSIF, FaSSIF) was added. The mixture was stirred on a magnetic stirrer at 37 °C, and samples were taken at 1 h and 24 h. The sample solution was filtered to obtain a clear liquid, and its concentration was determined by HPLC. The results are shown in Table 8.

[0389] The results showed that, compared with the A crystal form, the salt crystal form had significantly higher solubility in water and SGF, and slightly higher solubility in FeSSIF and FaSSIF.

[0390] Table 8: Solubility Test Results

[0391]

[0392] Note: Solubility is calculated based on crystal form A; LOQ is 0.40 μg / mL. *: Hydrobromide is a clear solution in SGF after 1 hour.

[0393] 1.2.2 Solubility test of amorphous salts

[0394] The solubility of amorphous benzenesulfonate (prepared in Example 4.1.9), amorphous sulfate (prepared in Example 4.1.4), and amorphous β-naphthalenesulfonate (prepared in Example 4.1.8) in water, SGF, FaSSIF, and FeSSIF was tested at 37°C using the following methods.

[0395] Approximately 12 mg of the above sample was weighed into a 4 mL glass bottle, and 3 mL of solvent (water, SGF, FaSSIF, FeSSIF) was added. The mixture was stirred on a magnetic stirrer at 37 °C, and samples were taken at 1 h and 24 h. The sample solution was filtered to obtain a clear liquid, and its concentration was determined by HPLC, as shown in Table 9.

[0396] The results showed that, compared with the A crystal form, the amorphous salt form had significantly higher solubility in water and SGF, while its solubility in FeSSIF and FaSSIF was slightly increased.

[0397] Table 9: Solubility Test Results

[0398]

[0399] Note: Solubility is calculated based on crystal form A; LOQ is 0.40 μg / mL.

[0400] Test Example 2: Stability Test

[0401] 2.1 Stability Tests of Crystal Forms A and B

[0402] Test Method: Weigh 10 mg of sample (crystal form A and crystal form B) into 40 mL glass bottles and place them open under high temperature and high humidity conditions: high humidity condition: 40℃ / 75% humidity; high temperature condition: 60℃. Cover the mouth of all open sample bottles with perforated aluminum foil to avoid cross-contamination. Seal all sealed samples with sealing film after capping. Samples were taken at the initial time, two weeks, and four weeks for purity analysis using high-performance liquid chromatography (HPLC). The HPLC method is shown below:

[0403]

[0404] Test results:

[0405]

[0406] As shown in the table above, the purity of both crystal forms A and B did not decrease significantly after being placed under high humidity (40℃ / 75% humidity) and high temperature (60℃) conditions for 4 weeks. (See attached table.) Figure 28 and attached Figure 29 The X-ray powder diffraction patterns of crystal forms A and B under different stability conditions are shown in the table above (using the testing instruments and methods described in section 1.1 of the Instruments and Testing Methods section). Figures 28-29 It can be seen that the crystal morphology of crystal forms A and B remains stable. In summary, crystal forms A and B have good stability.

[0407] 2.2 Stability test of salt crystal form

[0408] The stability of the hydrobromide crystal form (prepared according to the preparation method of Example 4.1.2), the hydrochloride crystal form (prepared according to the preparation method of Example 4.4.1), the p-toluenesulfonate crystal form (prepared according to the preparation method of Example 4.1.5), and the 1,5-naphthalenedisulfonate crystal form (prepared according to the preparation method of Example 4.2.7) under open conditions at 40°C / 75% RH was tested.

[0409] Approximately 60 mg of the above sample was weighed into 4 mL glass bottles and placed at 40℃ / 75% RH. All bottle openings were covered with perforated aluminum foil to prevent cross-contamination. All sealed samples were then sealed with sealing film after capping. Samples were taken at the initial time, week 2, and week 4, and changes in appearance were recorded. The physical and chemical stability of the samples were investigated using X-ray diffraction and high-performance liquid chromatography.

[0410] Table 10: Stability Test (HPLC) Results

[0411]

[0412] As shown in Table 10, under high humidity conditions, the chemical purity of the hydrobromide crystal form was high and did not change significantly, the chemical purity of the hydrochloride crystal form decreased only slightly during storage, the chemical purity of the 1,5-naphthalenedisulfonate crystal form decreased by 1.5%, and the p-toluenesulfonate crystal form showed a certain degree of degradation.

[0413] Under open conditions of 40℃ / 75%RH, by the attached Figure 30It can be seen that the crystal forms of hydrochloride and 1,5-naphthalenedisulfonate show no significant changes, while the hydrobromide crystal form transforms into a hydrate, and the p-toluenesulfonate crystal form remains a colloidal substance. The XRPD spectra of the hydrobromide crystal form under open-air conditions at 40℃ / 75% RH are shown below. Figure 30 XRPD spectrum of hydrochloride crystal form under open conditions at 40℃ / 75%RH, as shown in Figure A. Figure 30 As shown in B; the XRPD spectrum of the crystal form of 1,5-naphthalenedisulfonate under open conditions at 40℃ / 75%RH is as follows. Figure 30 As shown in C, this part of the XRPD spectrum was tested using the testing instruments and methods described in section 1.1 of the section on instruments and testing methods.

[0414] Test Example 3: Hygroscopicity Test

[0415] 3.1 Hygroscopicity Test Method for Crystal Forms A and B: The hygroscopicity of the samples was tested using the Dynamic Moisture Adsorption (DVS) method. Specifically, 10 mg of the sample (crystal form A and crystal form B) was weighed and tested for hygroscopic / desorption characteristics at 25°C under a cyclic environment of 0%–95%–0% relative humidity (RH). The hygroscopicity classification is shown in the table below.

[0416]

[0417]

[0418] *: Under conditions of 25±1℃ and 80±2%RH (European Pharmacopoeia 10.0);

[0419] "W": Moisture gain at 80% RH.

[0420] Test results:

[0421] Appendix Figure 31 - Appendix Figure 32 The DVS isotherms of crystal forms A and B of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) ketone are shown. Figure 31 It can be seen that the moisture absorption weight gain of crystal form A at 80% RH is less than 0.2%, indicating that crystal form A is not easily hygroscopic. From... Figure 32 It can be seen that the weight gain of crystal form B at 80% RH is about 2%, which indicates that crystal form B has a certain degree of hygroscopicity.

[0422] Appendix Figure 33 and attached Figure 34 X-ray powder diffraction patterns of crystal forms A and B before and after DVS testing are shown (tested using the testing instruments and methods described in section 1.1 of the Instrumentation and Testing Methods section). Figures 33-34It can be seen that the crystal forms of crystal form A and crystal form B did not change after the DVS test.

[0423] In summary, both crystal forms A and B of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) ketone exhibit good stability. Furthermore, crystal form A is less hygroscopic. The preparation method for crystal form A is simple, reproducible, and has a good crystallization yield, making it suitable for industrial-scale production. The method for preparing crystal form B is also simple and reproducible.

[0424] 3.2 Hygroscopicity test of salt crystal form

[0425] Under a relative humidity (RH) cycle of 0% to 95% to 0%, a 10 mg sample was weighed and subjected to a moisture absorption / desorption characteristic test at 25°C.

[0426] 3.2.1 Crystalline form of hydrobromide

[0427] DVS results are as follows Figure 35 As shown in the test results, during the process of increasing the relative humidity from 0%RH to 80%RH at 25℃, the hygroscopic weight gain of hydrobromide crystals was 1.13%, indicating that hydrobromide crystals have slight hygroscopicity.

[0428] 3.2.2 Crystalline Forms of Hydrochloride

[0429] DVS results are as follows Figure 36 As shown in the test results, during the process of increasing the relative humidity from 0%RH to 80%RH at 25℃, the hydrochloric acid crystalline form experienced a hygroscopic weight gain of 5.61%, indicating that the hydrochloric acid crystalline form exhibits a certain degree of hygroscopicity. After DVS testing, the sample crystal form showed no significant change. The XRPD spectrum is shown below. Figure 37 As shown, the XRPD spectrum was tested using the testing instruments and methods described in section 1.1 of the section on instruments and testing methods.

[0430] 3.2.3 Crystalline Forms of p-Toluenesulfonate

[0431] DVS results are as follows Figure 38 As shown in the test results, during the process of increasing the relative humidity from 0%RH to 80%RH at 25℃, the hygroscopic weight gain of the p-toluenesulfonate crystalline form was 19.73%, indicating that the p-toluenesulfonate crystalline form is highly hygroscopic. After DVS testing, the crystal form of the sample did not change significantly, but the crystallinity decreased. The XRPD spectrum is shown below. Figure 39 As shown, the XRPD spectrum was tested using the testing instruments and methods described in section 1.1 of the section on instruments and testing methods.

[0432] 3.2.4 Crystalline form of 1,5-naphthalenedisulfonate

[0433] DVS results are as follows Figure 40 As shown in the test results, during the process of increasing the relative humidity from 0%RH to 80%RH at 25℃, the hygroscopic weight gain of the 1,5-naphthalenedisulfonate crystalline form was 14.03%, indicating that the 1,5-naphthalenedisulfonate crystalline form is hygroscopic. After DVS testing, the crystal form of the sample did not change significantly, but the crystallinity improved. The XRPD spectrum is shown below. Figure 41 As shown, the XRPD spectrum was tested using the testing instruments and methods described in section 1.1 of the section on instruments and testing methods.

[0434] In summary, the hydrobromide crystalline form is slightly hygroscopic (1.13%); the hydrochloride crystalline form is somewhat hygroscopic (5.61%); the p-toluenesulfonate crystalline form is extremely hygroscopic (19.73%); and the 1,5-naphthalenedisulfonate crystalline form is hygroscopic (14.03%).

[0435] Test Example 4: Pharmacokinetic Study in Rats

[0436] To investigate the metabolism of the A crystal form, hydrobromide crystal form, and hydrochloride crystal form of this application in rats, 6-8 week old male SD rats (from Zhejiang Vital River Laboratory Animal Technology Co., Ltd.) were selected and orally administered (PO, solvent: water (0.5% dichloromethane + 0.2% Tween 80), 3 mice per group, dose: 25 mg / kg). Blood samples were collected at different time points to detect the drug concentration in plasma: 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h after administration.

[0437] LC-MS / MS (Sciex Triple Quad 5500) for quantifying drug plasma exposure. Chromatographic separation was performed using...

[0438] C18 2.6μm The column (50 mm × 2.1 mm) used a mobile phase of 0.1% formic acid aqueous solution (phase A) and 0.1% formic acid acetonitrile solution (phase B) at a flow rate of 0.6 mL / min and a column temperature of 40 °C, with gradient elution. Mass spectrometry detection was performed using an electrospray ionization (ESI) source in positive ion mode at a temperature of 500 °C and a spray voltage of ±4500 V, with data acquisition in multiple reaction monitoring (MRM) mode. The concentration of the analyte was calculated using the standard curve, and pharmacokinetic parameters from three rats were calculated using WinNolin software.

[0439] Table 11 shows the in vivo pharmacokinetic results for crystal form A, Table 12 shows the results for the hydrobromide crystal form, and Table 13 shows the results for the hydrochloride crystal form. The results indicate that the peak plasma concentration (C) of the hydrochloride crystal form after administration was [missing data].max The concentration of α-form A was significantly higher than that of α-form A, the exposure value (AUC) was higher than that of α-form A, and the time to peak concentration (t) was faster than that of α-form A. max ); Peak plasma concentration (C) of hydrobromide crystals max It has a higher peak time than crystal form A and a faster peak time (t) than crystal form A. max However, the exposure level (AUC) is lower than that of crystal form A.

[0440] Table 11: Results of in vivo pharmacokinetic studies of crystal form A

[0441]

[0442]

[0443] Continued from Table 11

[0444] Group 1: Crystal form A <![CDATA[AUC last Last blood draw time (hr) <![CDATA[Calculating T 1 / 2 (hr) blood collection time point]]> Correlation coefficient squared Rsq rat 1 8.00 2,4,8 0.999 rat 2 24.0 4,8,24 1.00 rat 3 24.0 4,8,24 0.998

[0445] Table 12: Results of in vivo pharmacokinetic studies of crystalline hydrobromide form

[0446]

[0447] Continued from Table 12

[0448]

[0449] Table 13: Results of in vivo pharmacokinetic studies of the crystalline form of hydrochloride

[0450]

[0451] Continued from Table 13

[0452]

[0453] The changes in plasma drug concentrations over time after administration of crystal form A, hydrobromide crystal form, and hydrochloride crystal form are shown in Tables 14, 15, and 16, respectively. The changes in plasma drug concentrations over time (24 h) after administration of crystal form A, hydrobromide crystal form, and hydrochloride crystal form are shown in Tables 14, 15, and 16, respectively. Figure 42 As shown in Figure A, the change in plasma drug concentration over time (8 hours) is as follows: Figure 42 As shown in Figure B. The results indicated that after administration, the peak plasma concentration of the hydrochloride crystalline form was significantly higher than that of the A crystalline form, and the peak plasma concentration of the hydrobromide crystalline form was also higher than that of the A crystalline form. Both showed a faster time to peak concentration compared to the A crystalline form. Within 8 hours, the duration of plasma concentration maintenance for the hydrochloride crystalline form was similar to that of the A crystalline form, both being longer than that of the hydrobromide crystalline form. The hydrochloride crystalline form also showed a higher peak concentration and exposure than the A crystalline form. It is anticipated that the hydrochloride crystalline form can reduce the dosage used in clinical practice, thereby reducing side effects and improving safety.

[0454] Table 14: Changes in plasma drug concentration over time after administration of crystal form A

[0455]

[0456] Table 15: Changes in plasma drug concentration over time after administration of hydrobromide crystalline form

[0457]

[0458] Table 16: Changes in plasma drug concentration over time after administration of crystalline hydrochloride.

[0459]

[0460]

[0461] Note: BLOQ = below LLOQ, LLOQ = 1 ng / mL, N / A indicates that BLOQ is present and cannot be calculated.

[0462] This article uses specific examples to illustrate the principles and implementation methods of this disclosure. The description of the above embodiments is only for the purpose of helping to understand the technical solutions and core ideas of this disclosure. Those skilled in the art should understand that they can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. These modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this disclosure.

Claims

1. The salt form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) ketone, wherein, (2-Pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone exists in hydrochloride form, wherein the hydrochloride form has a crystalline form, and the X-ray powder diffraction pattern of the crystalline form has characteristic peaks at 2θ angles of 8.793°±0.2°, 10.133°±0.2°, 10.321°±0.2°, 10.483°±0.2°, 10.834°±0.2°, 17.249°±0.2°, 22.204°±0.2°, 22.474°±0.2°, 24.178°±0.2°, and 24.590°±0.2°.

2. The salt form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone according to claim 1, wherein, In the crystalline form of the hydrochloride salt, the molar ratio of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone to hydrochloric acid is 1:

1.

3. The salt form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone according to claim 1, characterized in that, The X-ray powder diffraction pattern of the hydrochloride crystal form is as follows: at 2θ angles of 8.793°±0.2°, 10.133°±0.2°, 10.321°±0.2°, 10.483°±0.2°, 10.834°±0.2°, 12.624°±0.2°, 13.037°±0.2°, 16.780°±0.2°, 17.249°±0.2°, 17.826°±0.2°, and 18.422°±0.2°. Characteristic peaks are found at 2°, 19.222°±0.2°, 19.430°±0.2°, 20.047°±0.2°, 20.455°±0.2°, 21.034°±0.2°, 22.204°±0.2°, 22.474°±0.2°, 23.441°±0.2°, 24.178°±0.2°, 24.590°±0.2°, 25.395°±0.2°, and 26.236°±0.2°.

4. The salt form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone according to claim 1, characterized in that, The X-ray powder diffraction patterns of the hydrochloride crystalline form are at 2θ angles of 7.080°±0.2°, 8.793°±0.2°, 10.133°±0.2°, 10.321°±0.2°, 10.483°±0.2°, 10.834°±0.2°, 12.624°±0.2°, 13.037°±0.2°, 16.153°±0.2°, 16.780°±0.2°, 17.249°±0.2°, and 17.826°±0.2°. Characteristic peaks are found at 2°, 18.422°±0.2°, 19.222°±0.2°, 19.430°±0.2°, 20.047°±0.2°, 20.455°±0.2°, 21.034°±0.2°, 22.204°±0.2°, 22.474°±0.2°, 23.081°±0.2°, 23.441°±0.2°, 24.178°±0.2°, 24.590°±0.2°, and 25.395°±0.2°.

5. The salt form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone according to any one of claims 1-4, characterized in that, The X-ray powder diffraction pattern of the hydrochloride crystal form is shown in Figure 20.

6. The salt form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone according to any one of claims 1-4, characterized in that, The differential scanning calorimetry (DSC) spectrum of the hydrochloride crystal form exhibits endothermic peaks in the ranges of 142.07±3℃, 169.34±3℃, and 195.96±3℃.

7. The salt form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone according to any one of claims 1-4, characterized in that, The differential scanning calorimeter of the hydrochloride crystal form is shown in Figure 22.

8. The salt form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone according to any one of claims 1-4, characterized in that, The thermogravimetric analysis (TGA) spectrum of the hydrochloride crystal form is shown in Figure 21.

9. A method for preparing the salt form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone as described in any one of claims 1-8, characterized in that, (2-Pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is in hydrochloride form, said hydrochloride form having said crystalline form, and the method for preparing said crystalline form includes the following steps: (2-Pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is added to acetone, tetrahydrofuran, or acetonitrile, mixed, and then hydrochloric acid is added. After slurrying, a second slurry is obtained. The (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is in crystal form A. The X-ray powder diffraction pattern of crystal form A has characteristic peaks at 2θ angles of 7.798°±0.2°, 15.103°±0.2°, 18.215°±0.2°, and 18.436°±0.2°. The slurrying time is 12h-150h. The second slurry is separated to obtain a second solid; The second solid is dried to obtain the hydrochloride crystalline form, wherein the drying temperature is 20℃-50℃.

10. The method according to claim 9, characterized in that, The pulping time is 24h-120h.

11. The method according to claim 9, characterized in that, The X-ray powder diffraction pattern of the A-type crystal has characteristic peaks at 2θ angles of 7.798°±0.2°, 15.103°±0.2°, 15.784°±0.2°, 18.215°±0.2°, 18.436°±0.2°, 21.340°±0.2°, 22.079°±0.2°, 23.899°±0.2°, 25.763°±0.2°, and 32.159°±0.2°.

12. The method according to claim 9, characterized in that, The X-ray powder diffraction pattern of the A-type crystal is shown in Figure 1; And / or, The differential scanning calorimetry spectrum of the A-type crystal is shown in Figure 2; And / or, The thermogravimetric analysis spectrum of the A-type crystal is shown in Figure 3.

13. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the salt form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone as described in any one of claims 1-8, and a pharmaceutically acceptable carrier.

14. Use of the salt form of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone as described in any one of claims 1-8 or the pharmaceutical composition as described in claim 13 in the preparation of a medicament for the prevention, treatment and / or relief of diseases, symptoms and / or disorders, wherein the diseases, symptoms or disorders are selected from at least one of neurodegenerative diseases, psychosis, epilepsy, seizures, stroke and pain, wherein the pain is selected from chronic inflammatory pain.

15. The use according to claim 14, characterized in that, The neurodegenerative disease is selected from at least one of Alzheimer's disease, Parkinson's disease, and cognitive impairment.

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