A co-crystal of an amide compound and a preparation method thereof

Abstract

The present application mainly provides a co-crystal of an amide compound and a preparation method thereof, and belongs to the technical field of medicines. The co-crystal provided by the present application has good stability and solubility, is easy to obtain, and can be applied to pharmaceutical preparations.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemical industry, and particularly relates to a cocrystal of an amide compound and a preparation method thereof. Background Art

[0002] Aticaprant (CAS No. 1174130-61-0) is a central nervous system-penetrating kappa opioid receptor antagonist currently in clinical trials for the treatment of major depressive disorder.

[0003] The structure of Aticaprant is shown below:

[0004]

[0005] Because the crystalline form of a drug significantly impacts its preparation, formulation, storage, application, dissolution, and bioavailability, different crystalline forms can differ in many aspects, potentially leading to significant differences in the efficacy, safety, and application of drug formulations, or even failure to meet quality requirements. Therefore, research on the crystalline form of a drug is necessary. The inventors have conducted research on the crystalline forms of Aticaprant and discovered a new crystalline form that can be used. Summary of the Invention

[0006] Definition of terms

[0007] The present invention is intended to encompass all alternatives, modifications, and equivalent technical solutions, which are all included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0008] It will be further appreciated that certain features of the invention, which, for clarity, are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which, for brevity, are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0009] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0010] Unless otherwise indicated, the following definitions used herein shall apply. For purposes of the present invention, chemical elements are referred to in accordance with the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry may be found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0011] The term "include" or "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0012] The term "substantially as shown" refers to a substantially pure "crystalline form" whose X-ray powder diffraction pattern comprises at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% of the peaks appearing in the given X-ray powder diffraction pattern. As the content of a crystalline form in a sample gradually decreases, some diffraction peaks attributable to that crystalline form in its X-ray powder diffraction pattern may become less frequent due to the sensitivity of the instrument.

[0013] The term "relative intensity" refers to the ratio of the intensity of other peaks to the intensity of the first strongest peak in a group of diffraction peaks belonging to a certain crystal form, when the intensity of the first strongest peak is defined as 100%.

[0014] In the context of the present invention, the 2θ (also known as 2Theta or diffraction peak) values ​​in the X-ray powder diffraction pattern are all in degrees (°).

[0015] When referring to a spectrum and / or data therein, the term "diffraction peak" refers to a feature that one skilled in the art would not attribute to background noise.

[0016] The X-ray powder diffraction peaks of the crystals, the measurement of 2θ or diffraction peaks in their X-ray powder diffraction patterns have experimental errors. The measurements of 2θ or diffraction peaks in the X-ray powder diffraction patterns may vary slightly between one machine and another and between one sample and another. The numerical value of the experimental error or difference may be + / - 0.2 units or + / - 0.1 units or + / - 0.05 units. Therefore, the numerical value of the 2θ or diffraction peak cannot be considered absolute.

[0017] The differential scanning calorimetry (DSC) curve of the crystal has experimental errors. The position and peak value of the endothermic peak may be slightly different between one machine and another, and between one sample and another. The numerical value of the experimental error or difference may be less than or equal to 4°C, or less than or equal to 3°C, or 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 cannot be considered absolute.

[0018] The thermogravimetric analysis (TGA) curve of the crystal has experimental errors. The endothermic curve or weight loss rate may be slightly different between one machine and another, and between one sample and another. The numerical value of the experimental error or difference may be less than or equal to 0.004% or 0.003% or 0.002% or 0.001%. Therefore, the thermogravimetric analysis curve or its weight loss rate cannot be considered absolute.

[0019] In the context of the present invention, all numerical values ​​disclosed herein are approximate, regardless of whether the word "about" or "approximately" is used. The numerical value of each numerical value may vary by + / -1%, + / -2%, or + / -5%, etc., based on the original value. When "about" is used to describe the 2θ value (also known as 2Theta or diffraction peak) of an X-ray powder diffraction peak, "about" means that the 2θ value may vary by + / -0.2 units, + / -0.1 units, or + / -0.05 units.

[0020] "Room temperature" refers to a temperature between about 20°C and 35°C, or about 23°C and 28°C, or about 25°C. Detailed Description of the Invention

[0022] In one aspect, the inventors have developed a co-crystal of aticaprant and an amide compound, wherein the amide compound is benzamide, cinnamamide, isonicotine, or propionamide. The co-crystal of aticaprant and the amide compound has a molar ratio of aticaprant to the amide compound of 1:1.

[0023] After research, the inventors developed an Aticaprant-benzamide cocrystal, in which the molar ratio of Aticaprant to benzamide is 1:1.

[0024] An aticaprant-benzamide cocrystal has an X-ray powder diffraction pattern with diffraction peaks at 2θ (unit: degree, error ±0.2 degree) of 3.6, 10.4, 11.4, 13.9, 15.8, 17.5, 18.1, 18.3, 18.7, 19.9, 21.0, 21.9, 22.9, 24.0, 24.5, 24.9, 25.2 and 27.8 degrees.

[0025] In some embodiments, the Aticaprant-benzamide cocrystal has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 3.6, 7.0, 10.4, 11.4, 13.9, 15.8, 16.1, 17.5, 18.1, 18.3, 18.7, 19.4, 19.6, 19.9, 21.0, 21.9, 22.9, 24.0, 24.5, 24.9, 25.2 and 27.8 degrees.

[0026] In some embodiments, the Aticaprant-benzamide cocrystal has an X-ray powder diffraction pattern with diffraction peaks at 2θ of 3.6, 7.0, 10.4, 11.4, 13.9, 15.8, 16.1, 17.5, 18.1, 18.3, 18.7, 19.4, 19.6, 19.9, 21.0, 21.9, 22.9, 24.0, 24.5, 24.9, 25.2, 27.8, 30.6, 32.0 and 34.5 degrees.

[0027] In some embodiments, the X-ray powder diffraction pattern of the Aticaprant-benzamide cocrystal has diffraction peaks at 2θ of 3.6, 7.0, 10.4, 11.4, 12.5, 13.9, 15.2, 15.8, 16.1, 16.5, 17.5, 18.1, 18.3, 18.7, 19.4, 19.6, 19.9, 21.0, 21.9, 22.9, 24.0, 24.5, 24.9, 25.2, 26.2, 26.5, 27.0, 27.8, 29.2, 29.8, 30.6, 32.0, 34.5 and 38.3 degrees.

[0028] In some embodiments, the X-ray powder diffraction (XRPD) pattern of the Aticaprant-benzamide cocrystal is as follows: Figure 1 shown.

[0029] The Aticaprant-benzamide cocrystal also has the following characteristics: its differential scanning calorimetry (DSC) curve has an endothermic peak at 100°C-125°C. In some embodiments, the differential scanning calorimetry (DSC) curve of the Aticaprant-benzamide cocrystal has an endothermic peak at 110°C-120°C. In some embodiments, the differential scanning calorimetry (DSC) curve of the Aticaprant-benzamide cocrystal has an endothermic peak at 113°C-120°C, with a peak value of 117.9°C. In some embodiments, the differential scanning calorimetry (DSC) curve of the Aticaprant-benzamide cocrystal is as follows: Figure 2 shown.

[0030] The thermogravimetric analysis curve of the Aticaprant-benzamide co-crystal shows a weight loss of less than 1.0% between 105° C. and 150° C. In some embodiments, the thermogravimetric analysis curve of the Aticaprant-benzamide co-crystal shows a slight weight loss of about 0.39% between 105° C. and 150° C.

[0031] In some embodiments, the thermogravimetric analysis (TGA) curve of the Aticaprant-benzamide cocrystal is as follows: Figure 3 shown.

[0032] According to the stability test study of influencing factors, it was found that the Aticaprant-benzamide cocrystal was stable under high temperature, high humidity or light conditions and did not undergo crystal form transformation. It was a stable cocrystal with good thermal stability.

[0033] The Aticaprant-benzamide cocrystal has almost no hygroscopicity (less than 1%), has good stability, and has good solubility, which is conducive to the preparation of pharmaceutical preparations and improves the bioavailability of the drug.

[0034] After research, the inventors have also developed a crystalline form A of Aticaprant-cinnamamide cocrystal.

[0035] In the X-ray powder diffraction pattern of the crystalline form A, there are diffraction peaks at 2θ (unit: degree, °, error ±0.2 degree) of 12.7, 15.9, 18.9, 20.1, 21.6, 22.9, 23.5, 25.0, 26.5, 27.3 and 28.1 degrees.

[0036] In some embodiments, the X-ray powder diffraction pattern of the crystalline form A comprises diffraction peaks at 2θ of 12.7, 15.9, 18.2, 18.9, 19.6, 20.1, 20.6, 21.1, 21.6, 22.3, 22.9, 23.5, 24.2, 25.0, 26.5, 27.3, 28.1 and 28.9 degrees.

[0037] In some embodiments, the X-ray powder diffraction pattern of the crystalline form A comprises diffraction peaks at 2θ of 12.7, 15.9, 18.2, 18.7, 18.9, 19.3, 19.6, 20.1, 20.6, 21.1, 21.6, 22.3, 22.9, 23.5, 24.2, 25.0, 25.6, 26.5, 27.3, 28.1 and 28.9 degrees.

[0038] In some embodiments, the X-ray powder diffraction pattern of the crystalline form A comprises diffraction peaks at 2θ of 9.7, 12.7, 15.9, 18.2, 18.7, 18.9, 19.3, 19.6, 20.1, 20.6, 21.1, 21.6, 22.3, 22.9, 23.5, 24.2, 25.0, 25.6, 26.5, 27.3, 28.1 and 28.9 degrees.

[0039] In some embodiments, the X-ray powder diffraction pattern of the crystalline form A has a diffraction peak at a position of 15.9 degrees 2θ, and its relative intensity is greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.

[0040] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form A is as follows: Figure 4 shown.

[0041] The crystalline form A also has the following characteristics, and its differential scanning calorimetry curve (DSC) has an endothermic peak at 90°C-120°C. In some embodiments, the differential scanning calorimetry curve (DSC) of the crystalline form A has an endothermic peak at 95°C-113°C. In some embodiments, the differential scanning calorimetry curve (DSC) of the crystalline form A has an endothermic peak at 98°C-110°C, and the peak value is 105.1°C. In some embodiments, the differential scanning calorimetry curve (DSC) of the crystalline form A is as follows: Figure 5 shown.

[0042] The crystal form A also has the following characteristics: its thermogravimetric analysis curve (TGA) shows a weight loss between 50°C and 150°C, with a weight loss of approximately 1.03%. In some embodiments, the thermogravimetric analysis curve (TGA) of the crystal form A is as follows: Figure 6 shown.

[0043] After research, it was found that the crystal form A is a stable crystal form, which is stable under high temperature, high humidity or light conditions and will not undergo crystal form transformation.

[0044] The inventors have also developed a crystalline form B of Aticapran-cinnamic amide cocrystal.

[0045] In the X-ray powder diffraction pattern of the crystalline form B, there are diffraction peaks at 2θ (unit: degree, °, error ±0.2 degree) of 3.8, 7.4, 10.6, 11.1, 14.8, 15.4, 18.5, 19.0, 20.2, 20.7, 21.1, 22.2, 23.4, 24.2, 24.7, 25.5, 27.3, 29.3 and 30.3 degrees.

[0046] In some embodiments, the X-ray powder diffraction pattern of the crystalline form B has diffraction peaks at 2θ of 3.8, 7.4, 9.8, 10.6, 11.1, 14.8, 15.4, 17.4, 18.3, 18.5, 19.0, 20.2, 20.7, 21.1, 22.2, 23.4, 24.2, 24.7, 25.5, 27.3, 29.3 and 30.3 degrees.

[0047] In some embodiments, the X-ray powder diffraction pattern of the crystalline form B comprises diffraction peaks at 2θ of 3.8, 7.4, 9.8, 10.6, 11.1, 11.7, 12.9, 13.9, 14.8, 15.4, 15.6, 17.1, 17.4, 18.3, 18.5, 19.0, 19.4, 19.8, 20.2, 20.7, 21.1, 22.2, 23.4, 24.2, 24.7, 25.5, 26.1, 26.4, 27.3, 28.0, 28.2, 28.8, 29.3 and 30.3 degrees.

[0048] In some embodiments, the crystalline form B has an X-ray powder diffraction pattern with a diffraction peak at 2θ of 23.4 degrees, and its relative intensity is greater than 80%, or greater than 90%, or greater than 99%.

[0049] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form B is as follows: Figure 7 shown.

[0050] The crystal form B also has the following characteristics: its differential scanning calorimetry (DSC) curve has an endothermic peak at 50°C-80°C. In some embodiments, the differential scanning calorimetry (DSC) curve of the crystal form B has an endothermic peak at 60°C-75°C, with a peak value of 69.5°C. In some embodiments, the differential scanning calorimetry (DSC) curve of the crystal form B is as follows: Figure 8 shown.

[0051] The crystal form B also has the following characteristics: its thermogravimetric analysis curve (TGA) shows a weight loss between 55°C and 150°C, with a weight loss of approximately 6.98%. In some embodiments, the thermogravimetric analysis curve (TGA) of the crystal form B is as follows: Figure 9 shown.

[0052] According to the DSC and TGA test results of Form B, Form B is considered to be a crystalline form containing residual solvents in an uncertain stoichiometric ratio.

[0053] After stability studies, it was found that Form B was thermally unstable and underwent a crystal transformation under high temperature conditions, and could be transformed into the aforementioned Form A. It is believed that Form B is a metastable form of Form A.

[0054] After research, the inventors also developed an Aticapran-propionamide cocrystal.

[0055] An aticapran-propionamide cocrystal has an X-ray powder diffraction pattern showing diffraction peaks at 2θ (unit: degree, error ±0.2 degree) of 6.5, 8.9, 9.9, 10.2, 11.8, 12.2, 12.9, 15.8, 16.2, 17.4, 17.9, 18.2, 18.7, 19.1, 19.5, 20.2, 20.7, 21.5, 21.7, 23.9, 24.2 and 27.0 degrees.

[0056] In some embodiments, the Aticapran-propionamide cocrystal has an X-ray powder diffraction pattern comprising diffraction peaks at 2θ of 6.5, 8.9, 9.9, 10.2, 11.8, 12.2, 12.9, 14.2, 15.8, 16.2, 17.4, 17.9, 18.2, 18.7, 19.1, 19.5, 20.2, 20.7, 21.5, 21.7, 22.5, 23.9, 24.2, 24.6, 26.0, 26.5, 27.0, 27.7 and 28.4 degrees.

[0057] In some embodiments, the Aticapran-propionamide cocrystal has an X-ray powder diffraction pattern comprising diffraction peaks at 2θ of 6.5, 8.9, 9.9, 10.2, 11.8, 12.2, 12.9, 14.2, 15.8, 16.2, 17.4, 17.9, 18.2, 18.7, 19.1, 19.5, 20.2, 20.7, 21.5, 21.7, 22.1, 22.5, 23.9, 24.2, 24.6, 26.0, 26.5, 27.0, 27.7 and 28.4 degrees.

[0058] The Aticapran-propionamide cocrystal has a diffraction peak at a position of 9.9 degrees in its X-ray powder diffraction pattern, and its relative intensity is greater than 80%, or greater than 90%, or greater than 99%.

[0059] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Aticapran-propionamide cocrystal is as follows: Figure 10 shown.

[0060] The Aticapran-propionamide co-crystal also has the following characteristics, and in its differential scanning calorimetry curve (DSC), as the temperature rises, it first absorbs heat, then releases heat, and then absorbs heat twice again. In some embodiments, the differential scanning calorimetry curve (DSC) of the Aticapran-propionamide co-crystal has an endothermic peak at 60°C-75°C, and the peak value is 71.6°C. In some embodiments, the differential scanning calorimetry curve (DSC) of the Aticapran-propionamide co-crystal has an endothermic peak at 93°C-98°C, and the peak value is 96.9°C. In some embodiments, the differential scanning calorimetry curve (DSC) of the Aticapran-propionamide co-crystal has an endothermic peak at 100°C-115°C, and the peak value is 112.1°C. In some embodiments, the differential scanning calorimetry curve (DSC) of the Aticapran-propionamide co-crystal is as follows Figure 11 shown.

[0061] The Aticapran-propionamide co-crystal also has the following characteristics: its thermogravimetric analysis (TGA) curve shows a weight loss of about 8.92% between 75°C and 150°C. In some embodiments, the thermogravimetric analysis (TGA) curve of the Aticapran-propionamide co-crystal is as follows: Figure 12 As shown. Figure 10-12 , comprehensive analysis shows that the Aticapran-propionamide cocrystal is not a solvate. Figure 12 The weight loss is due to the separation and degradation of the eutectic components. The Aticapran-propionamide eutectic is thermally unstable and the crystalline form may change under high temperature conditions.

[0062] The present invention also provides an Aticaprant-isonicotine cocrystal.

[0063] An aticaprant-isonicotine cocrystal has an X-ray powder diffraction pattern showing diffraction peaks at 2θ (unit: degree, error ±0.2 degree) of 3.8, 10.6, 14.8, 15.5, 18.5, 19.0, 20.2, 21.1, 22.2, 23.0, 23.4, 24.3, 27.3 and 30.3 degrees.

[0064] In some embodiments, the Aticaprant-isonicotine cocrystal has an X-ray powder diffraction pattern comprising diffraction peaks at 2θ of 3.8, 7.4, 9.8, 10.6, 11.1, 11.5, 14.8, 15.5, 16.4, 17.4, 18.0, 18.5, 19.0, 19.4, 20.2, 20.7, 21.1, 22.2, 23.0, 23.4, 24.3, 27.3 and 30.3 degrees.

[0065] In some embodiments, the Aticaprant-isonicotine cocrystal has an X-ray powder diffraction pattern with a diffraction peak at 2θ of 23.0 degrees, and the relative intensity thereof is greater than 80%, or greater than 90%, or greater than 99%.

[0066] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Aticaprant-isonicotine cocrystal is as follows: Figure 13 shown.

[0067] The Aticaprant-isonicotine cocrystal also has the following characteristics, and its differential scanning calorimetry curve (DSC) has an endothermic peak at 55°C-75°C. In some embodiments, the differential scanning calorimetry curve (DSC) of the Aticaprant-isonicotine cocrystal has an endothermic peak at 57°C-75°C, and the peak top value is 69.2°C. In some embodiments, the differential scanning calorimetry curve (DSC) of the Aticaprant-isonicotine cocrystal has an endothermic peak at 113°C-130°C. In some embodiments, the differential scanning calorimetry curve (DSC) of the Aticaprant-isonicotine cocrystal has an endothermic peak at 120°C-127°C, and the peak top value is 124.4°C. In some embodiments, the differential scanning calorimetry curve (DSC) of the Aticaprant-isonicotine cocrystal is as follows Figure 14 shown.

[0068] The Aticaprant-isonicotine co-crystal also has the following characteristics: its thermogravimetric analysis (TGA) curve shows a weight loss of about 4.33% between 60°C and 140°C. In some embodiments, the thermogravimetric analysis (TGA) curve of the Aticaprant-isonicotine co-crystal is as follows: Figure 15 According to the chromatographic analysis, the Aticaprant-isonicotine cocrystal is believed to be a solvate, and the stoichiometric ratio of the cocrystal to the solvent is a non-integer ratio.

[0069] Studies have found that the Aticaprant-isonicotine cocrystal is thermally unstable and may undergo crystal transformation under high temperature conditions.

[0070] Comprehensive analysis shows that the crystalline form A of the aticaprant-benzamide cocrystal and the aticaprant-cinnamic amide cocrystal of the present invention has good stability, which is convenient for storage, transfer, and operation in the production process.

[0071] In another aspect, the present invention provides a method for preparing the aforementioned co-crystal.

[0072] A method for preparing a co-crystal of aticaprant and an amide compound comprises: mixing equimolar amounts of aticaprant and an amide compound with a solvent, and evaporating the solvent to precipitate the co-crystal to obtain the co-crystal; wherein the solvent is methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, or a combination thereof; and the amide compound is benzamide, cinnamamide, propionamide, or isonicotine.

[0073] The mass volume ratio of aticaprant to the solvent may be 1 mg / ml to 1 g / ml. In some embodiments, the mass volume ratio of aticaprant to the solvent may be 50 mg / ml to 1 g / ml. In some embodiments, the mass volume ratio of aticaprant to the solvent may be 50 mg / ml to 500 mg / ml. In some embodiments, the mass volume ratio of aticaprant to the solvent may be 100 mg / ml to 500 g / ml. In some embodiments, the mass volume ratio of aticaprant to the solvent may be 500 mg / ml to 1 g / ml.

[0074] In some embodiments, the solvent is methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate or a combination thereof to obtain Aticaprant-benzamide cocrystal.

[0075] In some embodiments, the solvent is acetone, and Aticaprant-cinnamic acid amide cocrystal Form A is obtained.

[0076] In some embodiments, the solvent is tetrahydrofuran, and Aticaprant-cinnamic acid amide cocrystal Form B is obtained.

[0077] In some embodiments, the solvent is acetone, and Aticaprant-propionamide cocrystals are obtained.

[0078] In some embodiments, the solvent is tetrahydrofuran, and Aticaprant-isonicotine cocrystals are obtained.

[0079] In another aspect, the present invention also provides a pharmaceutical composition.

[0080] A pharmaceutical composition comprising: a therapeutically effective amount of at least one crystal form of the aforementioned co-crystal of Aticaprant and an amide compound and pharmaceutically acceptable excipients.

[0081] A therapeutically effective amount of a co-crystal of aticaprant and an amide compound is mixed or contacted with one or more pharmaceutically acceptable excipients to form a pharmaceutical composition or formulation, which is prepared using methods well known in the pharmaceutical art. The pharmaceutical composition or formulation can be used to treat depression or depression-related diseases.

[0082] In some embodiments, the co-crystal comprises at least 5% by weight of the composition, calculated by weight of aticaprant. In some embodiments, the co-crystal comprises at least 1% by weight of the composition, calculated by weight of aticaprant. In some embodiments, the co-crystal comprises at least 0.5% by weight of the composition, calculated by weight of aticaprant.

[0083] In some embodiments, the co-crystal in the composition comprises no more than 10% of the total weight of the composition, calculated by weight of aticaprant. In some embodiments, the co-crystal in the composition comprises no more than 6% of the total weight of the composition, calculated by weight of aticaprant. In some embodiments, the co-crystal in the composition comprises no more than 5% of the total weight of the composition, calculated by weight of aticaprant. In some embodiments, the co-crystal in the composition comprises no more than 3% of the total weight of the composition, calculated by weight of aticaprant. In some embodiments, the co-crystal in the composition comprises no more than 1% of the total weight of the composition, calculated by weight of aticaprant. In some embodiments, the co-crystal in the composition comprises no more than 0.5% of the total weight of the composition, calculated by weight of aticaprant.

[0084] In some embodiments, the co-crystal comprises at least 0.05% to 95% or 1% to 95% of the total weight of the composition, calculated by weight of aticaprant. In some embodiments, the co-crystal comprises at least 0.5% to 10% of the total weight of the composition, calculated by weight of aticaprant. In some embodiments, the co-crystal comprises at least 5% to 10% of the total weight of the composition, calculated by weight of aticaprant.

[0085] In some embodiments, the co-crystal in the composition is an Aticaprant-benzamide co-crystal.

[0086] The pharmaceutically acceptable excipients may include diluents, disintegrants, binders, or lubricants.

[0087] The composition can be prepared according to conventional methods in the field of formulation. BRIEF DESCRIPTION OF THE DRAWINGS

[0088] Figure 1 shows the X-ray powder diffraction pattern of Aticaprant-benzamide cocrystal;

[0089] Figure 2 shows the differential scanning calorimetry (DSC) curve of Aticaprant-benzamide cocrystal;

[0090] Figure 3 Figure 4 shows the thermogravimetric analysis (TGA) curve of Aticaprant-benzamide cocrystal.

[0091] Figure 4 shows the X-ray powder diffraction pattern of Aticaprant-cinnamic amide cocrystal Form A;

[0092] Figure 5 shows the differential scanning calorimetry (DSC) curve of Aticaprant-cinnamic amide cocrystal Form A;

[0093] Figure 6 Shown is the thermogravimetric analysis curve (TGA) of Aticaprant-cinnamic amide cocrystal Form A.

[0094] Figure 7 shows the X-ray powder diffraction pattern of Aticaprant-cinnamic amide cocrystal Form B;

[0095] Figure 8 shows the differential scanning calorimetry (DSC) curve of Aticaprant-cinnamic amide cocrystal Form B;

[0096] Figure 9 Shown is the thermogravimetric analysis curve (TGA) of Aticaprant-cinnamic amide cocrystal Form B.

[0097] Figure 10 shows the X-ray powder diffraction pattern of Aticaprant-propionamide cocrystal;

[0098] Figure 11 shows the differential scanning calorimetry (DSC) curve of Aticaprant-propionamide cocrystal;

[0099] Figure 12 Figure 4 shows the thermogravimetric analysis (TGA) curve of Aticaprant-propionamide cocrystal.

[0100] Figure 13 shows the X-ray powder diffraction pattern of Aticaprant-isonicotine;

[0101] Figure 14shows the differential scanning calorimetry (DSC) curve of Aticaprant-isonicotine;

[0102] Figure 15 Shown is the thermogravimetric analysis (TGA) curve of Aticaprant-isonicotine.

[0103] In each of the drawings, 2Theta (°) represents 2θ, and the unit is degree (°); Intensity (counts) represents intensity (counts); Temperature (°C) represents temperature, and the unit is °C; Heat Flow (W / g) represents heat flow, and the unit is watt / gram; and Weight (%) represents weight (%). DETAILED DESCRIPTION

[0104] In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to further illustrate the present invention in detail.

[0105] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0106] In the present invention, mg represents milligram, mL represents milliliter, rpm represents revolutions per minute, h represents hour, and RH represents relative humidity.

[0107] In the present invention, the DSC spectrum of the Aticaprant raw material used has an endothermic peak between 91°C and 102°C, with the peak top at 97°C.

[0108] Instrument parameters

[0109] Unless otherwise specified in the parameters, all analyses below were performed at room temperature.

[0110] X-ray powder diffraction (XRPD) studies

[0111] X-ray powder diffraction (XRPD) patterns were collected on a PANalytical Empyrean X-ray diffractometer equipped with an automated 3*15 zero-background sample holder and a transflective sample stage. The radiation sources used were (Cu, kα, Kα1 1.540598; Kα2 1.544426; Kα2 / Kα1 intensity ratio: 0.50), where the voltage was set at 45KV and the current was set at 40mA. The beam divergence of the X-rays, that is, the effective size of the X-ray confinement on the sample, was 6.6mm. A θ-θ continuous scanning mode was used to obtain an effective 2θ range of 3° to 60°. Take an appropriate amount of sample and place it under ambient conditions (about 18℃ to 32℃) on the circular groove of the zero background sample holder, gently press it with a clean glass slide to obtain a flat surface, and fix the zero background sample holder. The sample was scanned at a step size of 0.0167° to generate a traditional XRPD pattern in the range of 3 to 60° 2θ±0.2°. The software used for data collection was Data Collector, and the data were analyzed and displayed using Data Viewer and HighScore Plus.

[0112] Differential Scanning Calorimetry (DSC)

[0113] DSC measurements were performed on a TA Instruments™ model Q2000 using a sealed pan setup. Samples (approximately 1-3 mg) were weighed into aluminum pans, sealed with a Tzero seal, and recorded to the nearest hundredth of a milligram. The sample was then transferred to the instrument for measurement. The instrument was purged with nitrogen at 50 mL / min. Data were collected between 30°C and 300°C at a heating rate of 10°C / min. Plots were plotted with the endothermic peak downward, and data were analyzed and displayed using a TA Universal Analysis.

[0114] Thermogravimetric analysis (TGA)

[0115] TGA data were collected on a TA Instruments Q500. The instrument temperature was calibrated using certified nickel. Typically, 8-12 mg of sample was loaded into a pre-weighed platinum crucible and heated from 30°C to 300°C at 10°C / min. A nitrogen purge of 60 mL / min was maintained over the sample. In the TGA graphs, the abscissa represents temperature (°C) and the ordinate represents weight loss (%).

[0116] Dynamic Vapor Sorption (DVS)

[0117] Under 25°C ambient conditions, starting from a relative humidity of 0%, the humidity is gradually increased by 5%, and the mass of the sample is tested at each humidity condition; then, starting from a relative humidity of 95%, the humidity is gradually decreased by 5%, and the mass of the sample is tested at each humidity condition; when the absolute value of the sample weight change per unit time dm / dt is less than 0.1% under a specific relative humidity condition, equilibrium is considered to have been reached, and the next relative humidity is entered; then, a DVS curve is drawn. Description of hygroscopic characteristics and definition of hygroscopic weight gain (Chinese Pharmacopoeia 2010 Edition Appendix: Guidance for Hygroscopicity Test of Drugs, experimental conditions: 25±0.2°C, 80% relative humidity):

[0118] Deliquescent: Absorbs sufficient water to form a liquid;

[0119] Highly hygroscopic: weight gain due to moisture absorption is not less than 15%;

[0120] Hygroscopic: weight gain due to moisture absorption is less than 15% but not less than 2%;

[0121] Slightly hygroscopic: weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0122] No or almost no hygroscopicity: weight gain due to moisture is less than 0.2%.

[0123] Example 1

[0124] 50 mg of Aticaprant raw material was added to 0.5 ml of acetone and dissolved. After the solution was clear, 14.5 mg of benzamide was added and the benzamide was also dissolved. The lid was opened and stirred for 16 hours to obtain 40 mg of cocrystal product. The X-ray powder diffraction pattern of the cocrystal product was the same as that of the cocrystal product. Figure 1 Basically consistent, its DSC spectrum is Figure 2 Basically consistent, TGA spectrum and Figure 3 Basically the same.

[0125] Example 2

[0126] 50 mg of Aticaprant raw material was added to 0.5 ml of ethanol and dissolved. After the solution was clear, 14.5 mg of benzamide was added and the benzamide was also dissolved. The lid was opened and stirred for 16 hours to obtain 42 mg of cocrystal product. The X-ray powder diffraction pattern of the cocrystal product was the same as that of the cocrystal product. Figure 1 Basically consistent, its DSC spectrum is Figure 2 Basically consistent, TGA spectrum and Figure 3 Basically the same.

[0127] Example 3

[0128] 20 mg of Aticaprant raw material and 6 mg of benzamide were added to 0.2 mL of ethyl acetate and dissolved. After the solution was clear, the mixture was opened and stirred for 16 hours to obtain 15 mg of cocrystal product. The X-ray powder diffraction pattern of the cocrystal product was the same as that of the cocrystal product. Figure 1 Basically consistent, its DSC spectrum is Figure 2 Basically consistent, TGA spectrum and Figure 3 Basically the same.

[0129] Example 4

[0130] 20 mg of Aticaprant raw material and 6 mg of benzamide were added to 0.2 mL of tetrahydrofuran and dissolved. After the solution was clear, the mixture was opened and stirred for 16 hours to obtain 16 mg of cocrystal product. The X-ray powder diffraction pattern of the cocrystal product was the same as that of the cocrystal product. Figure 1 Basically consistent, its DSC spectrum is Figure 2 Basically consistent, TGA spectrum and Figure 3 Basically the same.

[0131] Example 5

[0132] 20 mg of Aticaprant raw material and 6 mg of benzamide were added to 0.2 mL of tetrahydrofuran and dissolved. After the solution was clear, the mixture was opened and stirred for 16 hours to obtain 16 mg of cocrystal product. The X-ray powder diffraction pattern of the cocrystal product was the same as that of the cocrystal product. Figure 1 Basically consistent, its DSC spectrum is Figure 2 Basically consistent, TGA spectrum and Figure 3 Basically the same.

[0133] Example 6

[0134] 200 mg of Aticaprant raw material was added to 1 mL of methanol to dissolve, and 50 μL of methanol solution was dispensed. 3 mg of benzamide was added to the solution. After dissolution, the solution was opened and stirred for 16 hours to obtain 7 mg of cocrystal product. The X-ray powder diffraction pattern of the cocrystal product was the same as that of the cocrystal product. Figure 1 Basically consistent, its DSC spectrum is Figure 2 Basically consistent, TGA spectrum and Figure 3 Basically the same.

[0135] Example 7

[0136] 50 mg of Aticaprant and 18.25 mg of cinnamamide were added to 0.5 ml of acetone and dissolved. After dissolution, the mixture was opened and stirred for 16 hours to obtain 40 mg of cocrystal product. The X-ray powder diffraction pattern of the cocrystal product was the same as that of the cinnamamide. Figure 4 Basically consistent, its DSC spectrum is Figure 5 Basically consistent, TGA spectrum and Figure 6 Basically the same.

[0137] Example 8

[0138] 60 mg of Aticaprant and 21 mg of cinnamamide were added to 1 ml of tetrahydrofuran and dissolved. After dissolution, the mixture was opened and stirred for 16 hours to obtain 45 mg of cocrystal product. The X-ray powder diffraction pattern of the cocrystal product was the same as that of the cinnamamide. Figure 7 Basically consistent, its DSC spectrum is Figure 8 Basically consistent, TGA spectrum and Figure 9 Basically the same.

[0139] Example 9

[0140] 60 mg of Aticaprant and 12 mg of propionamide were added to 3 ml of acetone and dissolved. After dissolution, the mixture was opened and allowed to evaporate for 16 hours to obtain 42 mg of cocrystal product. The X-ray powder diffraction pattern of the cocrystal product was the same as that of the cocrystal product. Figure 10 Basically consistent, its DSC spectrum is Figure 11 Basically consistent, TGA spectrum and Figure 12 Basically the same.

[0141] Example 10

[0142] 60 mg of Aticaprant and 18 mg of isonicotine were added to 0.6 ml of tetrahydrofuran and dissolved. After dissolution, the mixture was opened and allowed to evaporate for 16 hours to obtain 45 mg of cocrystal product. The X-ray powder diffraction pattern of the cocrystal product was the same as that of the cocrystal product. Figure 13 Basically consistent, its DSC spectrum is Figure 14 Basically consistent, TGA spectrum and Figure 15 Basically the same.

[0143] Example 11: Stability Test

[0144] According to the guidelines for drug preparation stability testing, samples were subjected to influencing factor experiments, including high temperature test, high humidity test and strong light irradiation test, to investigate the stability of each crystal form under different conditions. The results are shown in Table 1 below.

[0145] Experimental conditions:

[0146] High temperature test: Take appropriate amounts of samples, lay them flat in weighing bottles, leave them uncovered, and place them in a constant temperature and humidity chamber at 60±5°C and RH75±5%. Then, take about 10 mg of the above samples at 0, 5, and 15 days, and test their crystal forms using powder X-ray diffraction (XRPD) and differential scanning calorimetry (DSC).

[0147] High humidity test: Take appropriate amounts of samples, lay them flat in weighing bottles, leave them uncovered, and place them in a constant temperature and humidity chamber at 25°C and RH 92.5±5%. Then, about 10 mg of the above samples were taken at 0, 5, and 15 days, and their crystal forms were tested by powder X-ray diffraction (XRPD) and differential scanning calorimetry (DSC).

[0148] Illumination test: Take an appropriate amount of each sample, spread it flat into a weighing bottle, open it, and place it in a constant temperature and humidity chamber (25°C, RH60%±5%) with visible light 4500Lux±500Lux (VIS) and ultraviolet light 1.7W*h / m2 (UV). Then, about 10 mg of the above samples were taken at 0, 5 and 15 days, and their crystal forms were tested by powder X-ray diffraction (XRPD) and differential scanning calorimetry (DSC).

[0149] Experimental results: The test results of each sample are shown in Table 1.

[0150] Table 1: Stability test results

[0151] 0-day crystal form High temperature stability Light stability High humidity stability Aticaprant-benzamide cocrystal Unchanged Unchanged Unchanged Aticaprant-cinnamic acid cocrystal Form A Unchanged Unchanged Unchanged Aticaprant-cinnamic acid cocrystal Form B After 5 days of testing, it turned into crystal form A Unchanged Unchanged Aticaprant-propionamide cocrystal After 5 days of testing, the crystal form changed Unchanged Unchanged Aticaprant-isonicotine cocrystal After 5 days of testing, the crystal form changed Unchanged Unchanged

[0152] Example 12: Moisture absorption test

[0153] The hygroscopicity of each eutectic sample was tested using the DVS test method. Based on the DVS curve results, it was found that the hygroscopicity of each eutectic was relatively low, less than 1%, indicating that it was only slightly hygroscopic.

[0154] Example 13: Solubility Test

[0155] method:

[0156] Add 5 mg of aticaprant and 6 mg of each cocrystal to a glass test tube. Place the test tube in an Easymax thermostat jacket and maintain the temperature at 37°C. Add a small amount of acetate buffer (prepared by adding 2.99 g of sodium acetate trihydrate and 1.85 ml of glacial acetic acid to 1 L of purified water, pH = 4.5). Magnetic stir each test tube and observe whether the sample dissolves clearly. If not, add additional small amounts of buffer until the sample dissolves clearly.

[0157] Test results:

[0158] When 4 ml of buffer was added, the aticaprant-benzamide cocrystal dissolved clearly; when 9 ml of buffer was added, the aticaprant dissolved clearly; the solubility of the aticaprant-benzamide cocrystal was 1.5 mg / ml, which was 0.0028 mol / ml based on aticaprant. Under the same conditions, the solubility of aticaprant was 0.56 mg / ml, which was 0.0013 mol / ml. Other cocrystals adhered to the bottom of the glass test tube and could not be suspended after adding buffer, so the solubility test could not be performed and the sample was discarded.

[0159] Table 2: Solubility of cocrystal samples (calculated based on the total mass of the cocrystal)

[0160] Eutectic sample Solubility (mg / mL) Aticaprant raw material 0.56 Aticaprant-benzamide cocrystal 1.5 Aticaprant-cinnamic acid cocrystal Form A / Aticaprant-cinnamic acid cocrystal Form B / Aticaprant-propionamide cocrystal / Aticaprant-isonicotine cocrystal /

[0161] According to the above stability, hygroscopicity and solubility test results, the Aticaprant-benzamide cocrystal has relatively good physical and chemical properties, which is conducive to the preparation of pharmaceutical preparations.

[0162] The methods of the present invention have been described through preferred embodiments. It is apparent that those skilled in the art will be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and spirit of the present invention to implement and apply the technology of the present invention. Those skilled in the art may refer to the disclosure herein and appropriately modify the process parameters to achieve the desired effect. It is particularly important to note that all similar substitutions and modifications apparent to those skilled in the art are considered encompassed by the present invention.

Claims

1. An Aticaprant-benzamide cocrystal, wherein The molar ratio of Aticaprant to benzamide is 1:1; The X-ray powder diffraction pattern of the Aticaprant-benzamide cocrystal has diffraction peaks at positions 2θ of 3.6, 10.4, 11.4, 13.9, 15.8, 17.5, 18.1, 18.3, 18.7, 19.9, 21.0, 21.9, 22.9, 24.0, 24.5, 24.9, 25.2 and 27.8 degrees.

2. The co-crystal of claim 1 , wherein the co-crystal has diffraction peaks at 2θ of 3.6, 7.0, 10.4, 11.4, 13.9, 15.8, 16.1, 17.5, 18.1, 18.3, 18.7, 19.4, 19.6, 19.9, 21.0, 21.9, 22.9, 24.0, 24.5, 24.9, 25.2 and 27.8 degrees in its X-ray powder diffraction pattern.

3. The co-crystal of claim 1 , wherein the co-crystal has diffraction peaks at 2θ of 3.6, 7.0, 10.4, 11.4, 13.9, 15.8, 16.1, 17.5, 18.1, 18.3, 18.7, 19.4, 19.6, 19.9, 21.0, 21.9, 22.9, 24.0, 24.5, 24.9, 25.2, 27.8, 30.6, 32.0 and 34.5 degrees in its X-ray powder diffraction pattern.

4. The co-crystal of claim 1 , wherein the co-crystal has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 3.6, 7.0, 10.4, 11.4, 12.5, 13.9, 15.2, 15.8, 16.1, 16.5, 17.5, 18.1, 18.3, 18.7, 19.4, 19.6, 19.9, 21.0, 21.9, 22.9, 24.0, 24.5, 24.9, 25.2, 26.2, 26.5, 27.0, 27.8, 29.2, 29.8, 30.6, 32.0, 34.5 and 38.3 degrees. The co-crystal according to claim 1 , wherein the X-ray powder diffraction pattern of the co-crystal is as shown in FIG1 .

6. The co-crystal according to any one of claims 1 to 5, wherein the differential scanning calorimetry curve of the co-crystal has an endothermic peak at 110°C-120°C; and / or the thermogravimetric analysis curve of the co-crystal has a weight loss of less than 1.0% between 105°C and 150°C.

7. A composition comprising the co-crystal according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.

8. The composition according to claim 7, wherein the eutectic accounts for 0.5% to 10% of the total weight of the composition, calculated based on the weight of Aticaprant.

9. A method for preparing the cocrystal according to any one of claims 1 to 6, comprising: Aticaprant and benzamide in equal molar amounts are dissolved in a solvent, and the solvent is evaporated to remove the solvent to precipitate a cocrystal, thereby obtaining the cocrystal; wherein the solvent is methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate or a combination thereof.

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