Cariprazine medicinal salts and their crystalline forms, pharmaceutical compositions, methods of manufacture and uses

Abstract

The present invention relates to a 1-hydroxy-2-naphthoate or pamoate salt of cariprazine, a new solid form thereof, and a pharmaceutical composition, preparation method and use thereof. The salt of cariprazine and the solid form thereof, particularly the cariprazine 1-hydroxy-2-naphthoate salt in the poorly soluble cariprazine salt, have the characteristics of a long-acting sustained-release preparation and can be developed into a suspension injection, while at the same time overcoming the problems of the conventional salt-type dissociation risk or lack of sustained release effect such as cariprazine hydrochloride, and can achieve the effect of long-acting administration, greatly improving the patient compliance and the bioavailability and administration safety of the drug.

Description

Detailed Description of the Invention

[0001] This application claims priority to the applicant's prior application, bearing application number 202210162007.8 and entitled "Cariprazine medicinal salts and crystalline forms thereof, pharmaceutical compositions, preparation methods and uses," filed with the State Intellectual Property Office of the People's Republic of China on February 22, 2022. The above-mentioned prior application is hereby incorporated by reference in its entirety.

[0002] [Technical field] The present invention belongs to the field of chemical medicine, specifically to cariprazine medicinal salts and their crystalline forms, pharmaceutical compositions, preparation methods and uses.

[0003] [Background technology] Cariprazine, whose chemical structure is shown below, is a novel atypical antipsychotic drug that has antagonistic effects on dopamine D3, dopamine D2 and 5-serotonin 2B receptors and can be used to treat schizophrenia and bipolar I disorder. Currently available cariprazine hydrochloride capsules are oral preparations that need to be administered daily to maintain the drug concentration in the blood, but the frequent administration poses a problem of poor patient compliance.

[0004] [ka]

[0005] Patent document CN101679315A discloses various salts of cariprazine, including the monohydrochloride, dihydrochloride, monohydrobromide, maleate and mesylate salts.

[0006] Patent document CN105218484A discloses cariprazine tartrate and provides the solubilities of cariprazine tartrate, cariprazine hydrochloride, cariprazine maleate, cariprazine besylate and cariprazine phosphate, all of which are greater than 3 mg / mL.

[0007] Patent document WO2020056929A discloses a new crystalline form of cariprazine hydrochloride, in which it is described that cariprazine hydrochloride is rapidly dissociated into a free base in a buffer solution of pH 6.5.

[0008] Patent document CN108261394A discloses cariprazine hydrochloride injection formulations, including aqueous suspension and lyophilized formulations, which can obtain sustained release for at least one week. However, the inventors found in the course of research that the stability of the aqueous solution of cariprazine hydrochloride is not ideal, and dissociation occurs under weakly acidic to alkaline conditions, so there is a risk of dissociation in the aqueous suspension, which results in the property and quality of the product being easily changed, the solubility and absorbability of the drug being changed, affecting the efficacy of the drug and the safety of drug use in patients, and making it unsuitable for use in long-acting sustained-release formulations. In addition, the cariprazine concentration, administration concentration, and blood drug concentration in animal pK experiments of the cariprazine hydrochloride injection formulation disclosed in patent document CN108261394A are too high, and previous research data shows that the elimination of cariprazine varies greatly between species (about 2 to 4 hours in rats and 3 to 9 days in humans), so if the blood drug concentration is too high, the toxicity and side effects will be relatively large, and the drug may accumulate excessively in the human body.

[0009] There have been no reports to date of an injectable cariprazine poorly soluble salt formulation with improved performance.

[0010] In view of the deficiencies of the prior art, finding cariprazine pharmaceutical salts and crystalline forms thereof that have low solubility, are suitable for long-acting administration, are highly stable, have good clinical efficacy, and / or are suitable for commercialization is a technical problem that is currently urgently needed to be solved in the field.

[0011] Summary of the Invention In order to solve the above problems existing in the prior art, the present invention provides a pharma- ceutically acceptable salt of cariprazine, in particular 1-hydroxy-2-naphthoate salt of cariprazine or cariprazine pamoate salt, and / or a new solid form thereof, and a pharmaceutical composition, preparation method and use thereof.

[0012] According to an embodiment of the present invention, the 1-hydroxy-2-naphthoic acid salt of cariprazine is selected from cariprazine mono-1-hydroxy-2-naphthoic acid salt represented by the following formula (I) or cariprazine bis-1-hydroxy-2-naphthoic acid represented by the following formula (II).

[0013] [ka]

[0014] According to an embodiment of the present invention, the cariprazine 1-hydroxy-2-naphthoate is crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate, preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, in which the X-ray powder diffraction pattern of crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate, preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, has characteristic peaks at 2θ values ​​of 15.6°±0.2°, 19.7°±0.2°, 20.7°±0.2°, etc.

[0015] Furthermore, the X-ray powder diffraction pattern of crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate, preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, has characteristic peaks at 2θ values ​​of 12.7°±0.2°, 15.6°±0.2°, 17.3°±0.2°, 19.7°±0.2°, 20.2°±0.2°, 20.7°±0.2°, and the like.

[0016] Furthermore, the X-ray powder diffraction pattern of crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate, preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, has characteristic peaks at 2θ values ​​of 12.7°±0.2°, 15.6°±0.2°, 17.3°±0.2°, 18.8°±0.2°, 19.7°±0.2°, 20.2°±0.2°, 20.7°±0.2°, 24.3°±0.2°, and the like.

[0017] Furthermore, the X-ray powder diffraction pattern of the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate, preferably the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, has 2θ values ​​of 4.4°±0.2°, 8.6°±0.2°, 9.7°±0.2°, 11 It has absorption peaks at 0.4°±0.2°, 12.7°±0.2°, 15.6°±0.2°, 16.5°±0.2°, 16.9°±0.2°, 17.3°±0.2°, 18.8°±0.2°, 19.7°±0.2°, 20.2°±0.2°, 20.7°±0.2°, 23.3°±0.2°, 24.3°±0.2°, 24.9°±0.2°, and 29.5°±0.2°.

[0018] Furthermore, the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate, preferably the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, has an X-ray powder diffraction pattern essentially as shown in FIG.

[0019] Preferably, the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate, preferably the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, has a differential scanning calorimetry pattern essentially as shown in FIG. 2.

[0020] Preferably, the melting point of the crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate, preferably the crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate hydrate, more preferably the crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate, is about 101.3°C.

[0021] Preferably, said crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate, preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, has a thermogravimetric analysis pattern essentially as shown in FIG. 2, in which a weight loss of about 4.82% is exhibited before 100° C.

[0022] Preferably, the crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate is crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate hydrate, more preferably crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate.

[0023] Furthermore, in the above-mentioned crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate, preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, a salt is formed between cariprazine and 1-hydroxy-2-naphthoic acid in a molar ratio of 1:1, and its 1H-NMR spectrum is basically as shown in FIG. 3.

[0024] The present invention further provides a single crystal of crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate, the X-ray diffraction pattern of which has characteristic peaks at 2θ values ​​of 17.5°±0.2°, 19.7°±0.2°, 20.8°±0.2°, etc.

[0025] Furthermore, the X-ray diffraction pattern of the above single crystal has characteristic peaks at 2θ values ​​of 17.5°±0.2°, 19.0°±0.2°, 19.7°±0.2°, 20.3°±0.2°, 20.8°±0.2°, 23.4°±0.2°, etc.

[0026] Furthermore, the X-ray diffraction pattern of the above single crystal has characteristic peaks at 2θ values ​​of 12.7°±0.2°, 15.7°±0.2°, 17.5°±0.2°, 19.0°±0.2°, 19.7°±0.2°, 20.3°±0.2°, 20.8°±0.2°, 23.4°±0.2°, etc.

[0027] Furthermore, the X-ray diffraction pattern of the above single crystal has absorption peaks at 2θ values ​​of 11.5°±0.2°, 12.7°±0.2°, 15.7°±0.2°, 16.6°±0.2°, 16.9°±0.2°, 17.5°±0.2°, 18.1°±0.2°, 19.0°±0.2°, 19.7°±0.2°, 20.0°±0.2°, 20.3°±0.2°, 20.8°±0.2°, 21.3°±0.2°, 23.4°±0.2°, 23.6°±0.2°, 24.4°±0.2°, 24.9°±0.2°, and 29.6°±0.2°.

[0028] According to an embodiment of the present invention, there is further provided a method for preparing crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate, preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, comprising the steps of: (a1) Cariprazine is dissolved in an aqueous phosphoric acid solution, and the solution A is obtained by filtration. An aqueous 1-hydroxy-2-naphthoic acid solution and an aqueous sodium hydroxide solution are mixed with the solution A, and the solution B is obtained by filtration. (a2) Solution B is added to solution A in a solute molar ratio of 1:1, and stirred at room temperature to obtain crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate, preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate.

[0029] Alternatively, a method for preparing the above-mentioned crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate, preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, comprises the following steps: (a3) Cariprazine and 1-hydroxy-2-naphthoic acid are mixed in a molar ratio of 1:1 with a solvent. (a4) Stirring at 25 to 70°C gives crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate, preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate.

[0030] According to an embodiment of the present invention, the solvent is a mixture of methanol, ethanol or acetone with water. Preferably, the volume ratio of methanol, ethanol or acetone to water may be 2:1 to 1:2, for example, 1:1.

[0031] Preferably, the mass / volume ratio of cariprazine to the total volume of the solvent system is 1 g:5-30 mL, for example, 1 g:5-20 mL, for example, 1 g:10 mL.

[0032] According to an embodiment of the present invention, the cariprazine 1-hydroxy-2-naphthoate is crystalline form B of cariprazine mono-1-hydroxy-2-naphthoate, of which the X-ray powder diffraction pattern of crystalline form B of cariprazine mono-1-hydroxy-2-naphthoate has characteristic peaks at 2θ values ​​of 14.6°±0.2°, 18.8°±0.2°, 19.5°±0.2°, etc.

[0033] Furthermore, the X-ray powder diffraction pattern of crystalline form B of cariprazine mono 1-hydroxy-2-naphthoate has characteristic peaks at 2θ values ​​of 5.5°±0.2°, 11.5°±0.2°, 14.6°±0.2°, 18.8°±0.2°, 19.5°±0.2°, 23.7°±0.2°, etc.

[0034] Furthermore, the X-ray powder diffraction pattern of crystalline form B of cariprazine mono-1-hydroxy-2-naphthoate has characteristic peaks at 2θ values ​​of 5.5°±0.2°, 11.5°±0.2°, 13.0°±0.2°, 14.6°±0.2°, 16.9°±0.2°, 18.8°±0.2°, 19.5°±0.2°, 23.7°±0.2°, etc.

[0035] Furthermore, according to an embodiment of the present invention, the X-ray powder diffraction pattern of crystalline form B of cariprazine mono-1-hydroxy-2-naphthoate has characteristic peaks at 2θ values ​​of 5.5°±0.2°, 9.2°±0.2°, 11.1°±0.2°, 11.5°±0.2°, 13.0°±0.2°, 13.9°±0.2°, 14.6°±0.2°, 16.6°±0.2°, 16.9°±0.2°, 18.5°±0.2°, 18.8°±0.2°, 19.5°±0.2°, 19.9°±0.2°, 20.3°±0.2°, 21.2°±0.2°, 23.7°±0.2°, 24.3°±0.2°, and the like.

[0036] Furthermore, the crystalline form B of cariprazine mono 1-hydroxy-2-naphthoate has an X-ray powder diffraction pattern essentially as shown in FIG.

[0037] Preferably, the crystalline form B of cariprazine mono 1-hydroxy-2-naphthoate has a differential scanning calorimetry pattern essentially as shown in FIG.

[0038] Preferably, the melting point of the crystalline form B of cariprazine mono 1-hydroxy-2-naphthoate is about 106.8°C.

[0039] Furthermore, in the crystalline form B of the above cariprazine mono-1-hydroxy-2-naphthoate, a salt is formed between cariprazine and 1-hydroxy-2-naphthoic acid in a molar ratio of 1:1, and its 1H-NMR spectrum is essentially as shown in FIG.

[0040] According to an embodiment of the present invention, the method for preparing crystalline form B of cariprazine mono 1-hydroxy-2-naphthoate comprises the following steps: (b1) Cariprazine and 1-hydroxy-2-naphthoic acid are mixed in a molar ratio of 1:1 with a solvent. (b2) Stirring at 25 to 70° C. gives crystalline form B of the above cariprazine mono-1-hydroxy-2-naphthoate.

[0041] According to an embodiment of the present invention, the solvent is a mixture of methanol, ethanol or acetone with water. Preferably, the volume ratio of methanol, ethanol or acetone to water may be 2:1 to 1:2, for example, 1.5:1.

[0042] Preferably, the mass / volume ratio of cariprazine to the total volume of the solvent system is 1 g:0.5-10 mL, for example, 1 g:0.5-1.5 mL, for example, 1 g:1 mL.

[0043] According to an embodiment of the present invention, the cariprazine 1-hydroxy-2-naphthoate is crystalline form C of cariprazine mono-1-hydroxy-2-naphthoate, of which the X-ray powder diffraction pattern of crystalline form C of cariprazine mono-1-hydroxy-2-naphthoate has characteristic peaks at 2θ values ​​of 17.8°±0.2°, 19.9°±0.2°, 21.1°±0.2°, etc. Furthermore, the X-ray powder diffraction pattern of crystalline form C of cariprazine mono 1-hydroxy-2-naphthoate has characteristic peaks at 2θ values ​​of 4.4°±0.2°, 15.6°±0.2°, 17.8°±0.2°, 19.9°±0.2°, 21.1°±0.2°, 23.7°±0.2°, etc.

[0044] Furthermore, the X-ray powder diffraction pattern of crystalline form C of cariprazine mono 1-hydroxy-2-naphthoate has characteristic peaks at 2θ values ​​of 4.4°±0.2°, 12.8°±0.2°, 15.6°±0.2°, 17.8°±0.2°, 19.9°±0.2°, 20.2°±0.2°, 21.1°±0.2°, 23.7°±0.2°, etc.

[0045] Furthermore, according to an embodiment of the present invention, the X-ray powder diffraction pattern of crystalline form C of cariprazine mono-1-hydroxy-2-naphthoate has characteristic peaks at 2θ values ​​of 4.4°±0.2°, 8.6°±0.2°, 9.7°±0.2°, 11.5°±0.2°, 12.8°±0.2°, 13.2°±0.2°, 15.6°±0.2°, 16.6°±0.2°, 17.8°±0.2°, 19.3°±0.2°, 19.9°±0.2°, 20.2°±0.2°, 21.1°±0.2°, 22.4°±0.2°, 23.7°±0.2°, 24.2°±0.2°, 24.9°±0.2°, and the like.

[0046] Furthermore, the crystalline form C of cariprazine mono 1-hydroxy-2-naphthoate has an X-ray powder diffraction pattern essentially as shown in FIG.

[0047] Preferably, the crystalline form C of cariprazine mono 1-hydroxy-2-naphthoate has a differential scanning calorimetry pattern essentially as shown in FIG.

[0048] Preferably, the melting point of the crystalline form C of cariprazine mono 1-hydroxy-2-naphthoate is about 103.4°C.

[0049] According to an embodiment of the present invention, in the crystalline form C of the above cariprazine mono 1-hydroxy-2-naphthoate, cariprazine and 1-hydroxy-2-naphthoic acid form a salt in a molar ratio of 1:1, and its 1H-NMR spectrum is essentially as shown in FIG. 9.

[0050] According to an embodiment of the present invention, the method for preparing crystalline form C of cariprazine mono 1-hydroxy-2-naphthoate comprises the following steps: (c1) Cariprazine and 1-hydroxy-2-naphthoic acid are mixed in a molar ratio of 1:1 with a solvent. (c2) Stirring at 25 to 70° C. gives the above crystalline form C of cariprazine mono 1-hydroxy-2-naphthoate.

[0051] According to an embodiment of the present invention, the solvent is a mixture of methanol, ethanol or acetone with water. Preferably, the volume ratio of methanol, ethanol or acetone to water may be 2:1 to 1:2, for example, 1.5:1.

[0052] Preferably, the mass / volume ratio of cariprazine to the total volume of the solvent system is 1 g:5-30 mL, for example, 1 g:5-20 mL, for example, 1 g:10 mL.

[0053] According to an embodiment of the present invention, the cariprazine 1-hydroxy-2-naphthoate is cariprazine bis-1-hydroxy-2-naphthoate as shown in the above formula (II), in which the molar ratio of cariprazine to 1-hydroxy-2-naphthoic acid is 1:2.

[0054] According to an embodiment of the present invention, the cariprazine bis 1-hydroxy-2-naphthoate may be in a solid form, such as an amorphous or crystalline form. According to an embodiment of the present invention, the cariprazine bis-1-hydroxy-2-naphthoate is crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate, in which the X-ray powder diffraction pattern of crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate has characteristic peaks at 2θ values ​​of 4.7°±0.2°, 9.4°±0.2°, 20.8°±0.2°, etc.

[0055] Furthermore, the X-ray powder diffraction pattern of the crystalline form A of cariprazine bis(1-hydroxy-2-naphthoate) has characteristic peaks at 2θ values ​​of 4.7°±0.2°, 9.4°±0.2°, 12.7°±0.2°, 20.1°±0.2°, 20.8°±0.2°, 27.4°±0.2°, etc.

[0056] Furthermore, the X-ray powder diffraction pattern of crystalline form A of cariprazine bis(1-hydroxy-2-naphthoate) has characteristic peaks at 2θ values ​​of 4.7°±0.2°, 9.4°±0.2°, 12.7°±0.2°, 17.1°±0.2°, 19.1°±0.2°, 20.1°±0.2°, 20.8°±0.2°, 27.4°±0.2°, etc.

[0057] Furthermore, according to an embodiment of the present invention, the X-ray powder diffraction pattern of crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate has characteristic peaks at 2θ values ​​of 4.7°±0.2°, 8.8°±0.2°, 9.4°±0.2°, 12.7°±0.2°, 16.5°±0.2°, 17.1°±0.2°, 18.4°±0.2°, 19.1°±0.2°, 19.9°±0.2°, 20.1°±0.2°, 20.8°±0.2°, 21.1°±0.2°, 21.9°±0.2°, 24.1°±0.2°, 24.8°±0.2°, 25.6°±0.2°, 27.4°±0.2°, and the like.

[0058] Furthermore, the crystalline form A of the cariprazine bis(1-hydroxy-2-naphthoate) has an X-ray powder diffraction pattern essentially as shown in FIG.

[0059] Preferably, the crystalline form A of cariprazine bis 1-hydroxy-2-naphthoate has a differential scanning calorimetry pattern essentially as shown in FIG.

[0060] Preferably, the melting point of the crystalline form A of the cariprazine bis 1-hydroxy-2-naphthoate salt is about 86.3°C.

[0061] Preferably, the thermogravimetric analysis pattern of the crystalline form A of said cariprazine bis 1-hydroxy-2-naphthoate is essentially as shown in FIG. 11, which shows a weight loss of about 1.31% before 100°C.

[0062] Preferably, the crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate is a hydrate of cariprazine bis-1-hydroxy-2-naphthoate.

[0063] Preferably, the H-NMR spectrum of the crystalline form A of the cariprazine bis-1-hydroxy-2-naphthoic acid salt is essentially as shown in FIG. 12, which shows that the salt is formed between cariprazine and 1-hydroxy-2-naphthoic acid in a molar ratio of 1:2.

[0064] According to an embodiment of the present invention, the method for preparing crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate comprises the following steps:

[0065] Cariprazine and 1-hydroxy-2-naphthoic acid are added to a solvent in a molar ratio of 1:2 and stirred at 25 to 70° C. to obtain crystalline form A of the cariprazine bis-1-hydroxy-2-naphthoate.

[0066] The solvent is a mixture of methanol, ethanol or acetone with water. The volume ratio of methanol, ethanol or acetone to water is preferably 2:1 to 1:2, for example, 1:1.

[0067] Preferably, the mass / volume ratio of cariprazine to the total volume of the solvent system is 1 g:5-40 mL, for example, 1 g:10-30 mL, for example, 1 g:20 mL.

[0068] According to an embodiment of the present invention, the cariprazine pamoate salt has the structure shown in formula (III):

[0069] [ka]

[0070] According to an embodiment of the present invention, in the cariprazine pamoate salt, the molar ratio of cariprazine to pamoic acid is 1:1.

[0071] According to an embodiment of the present invention, the cariprazine pamoate is crystalline form H of cariprazine pamoate, and the X-ray powder diffraction pattern of the crystalline form H of cariprazine pamoate has characteristic peaks at 2θ values ​​of 7.3°±0.2°, 8.8°±0.2°, 9.4°±0.2°, 14.6°±0.2°, 17.4°±0.2°, 18.1°±0.2°, 18.6°±0.2°, 19.2°±0.2°, 22.9°±0.2°, etc.

[0072] Furthermore, the crystalline form H of cariprazine pamoate has an X-ray powder diffraction pattern essentially as shown in FIG.

[0073] According to an embodiment of the present invention, the cariprazine pamoate salt is amorphous and preferably has an X-ray powder diffraction pattern essentially as shown in FIG.

[0074] According to an embodiment of the present invention, the solid form may be a crystalline or non-crystalline (amorphous) form of a pharma- ceutically acceptable salt of cariprazine, and may be an anhydrate, hydrate or solvate. If present, the molar ratio of the salt to water or solvent molecules in the solid form may vary within the range of 1:0.5 to 1:5 (e.g., 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3), and the molar ratio may be determined by methods known to those skilled in the art.

[0075] The present invention further provides a combination of pharma- ceutically acceptable salts of cariprazine comprising at least one, e.g. two or three, of the pharma- ceutically acceptable salts or solid forms thereof described above, and optionally other pharma- ceutically acceptable salts of cariprazine present, or other forms of cariprazine mono 1-hydroxy-2-naphthoate, cariprazine bis 1-hydroxy-2-naphthoate or cariprazine pamoate described above.

[0076] According to an embodiment of the present invention, in the total weight of the pharma- ceutically acceptable salts of cariprazine in the above combination, the weight percentage content of the crystalline form of cariprazine mono-1-hydroxy-2-naphthoate or cariprazine bis-1-hydroxy-2-naphthoate described above is greater than the content of other salt forms or crystalline forms of cariprazine.

[0077] For example, the weight percentage content of the crystalline form of cariprazine mono 1-hydroxy-2-naphthoate or cariprazine bis 1-hydroxy-2-naphthoate described above in the total weight of the pharma- ceutically acceptable salts of cariprazine in the above combination is 80% or more, preferably 90% or more, and more preferably 95% or 99% or more.

[0078] The present invention further provides a pharmaceutical composition comprising a pharma- ceutically acceptable salt of cariprazine as described above, preferably comprising cariprazine mono 1-hydroxy-2-naphthoate, cariprazine bis 1-hydroxy-2-naphthoate, cariprazine pamoate or one of the crystalline forms thereof.

[0079] The present invention further provides a pharmaceutical composition of cariprazine comprising solid particles of cariprazine having a particle size Dv(10)≦30 microns, Dv(50)≦50 microns and Dv(90)≦100 microns, preferably ≦50 microns.

[0080] The solid cariprazine particles may be one selected from the above-mentioned cariprazine mono 1-hydroxy-2-naphthoate, cariprazine bis 1-hydroxy-2-naphthoate, cariprazine pamoate, or a crystalline form thereof.

[0081] According to an embodiment of the present invention, the pharma- ceutically acceptable salts of cariprazine include, but are not limited to, cariprazine mono 1-hydroxy-2-naphthoate, cariprazine bis 1-hydroxy-2-naphthoate, and cariprazine pamoate.

[0082] According to an embodiment of the present invention, the solid cariprazine particles may be in amorphous or crystalline form.

[0083] According to an embodiment of the present invention, the pharmaceutical composition of cariprazine may further comprise an auxiliary agent, which may be one or more selected from a suspending agent, a wetting agent, an osmotic pressure adjusting agent, a solvent, and a buffering agent.

[0084] According to an embodiment of the present invention, the concentration range of the suspending agent is 0 to 10 mg / mL, preferably 3.5 mg / mL to 7.5 mg / mL, for example 5.0 mg / mL or 7.5 mg / mL.

[0085] According to an embodiment of the present invention, the suspending agent is one or more selected from sodium carboxymethylcellulose, methylcellulose and polyvinylpyrrolidone, and is preferably sodium carboxymethylcellulose.

[0086] According to an embodiment of the present invention, the concentration range of the wetting agent is 0.2 to 10 mg / mL, preferably 1 mg / mL to 5 mg / mL, for example 1 mg / mL, 1.5 mg / mL, 2.0 mg / mL, 2.5 mg / mL, 3.0 mg / mL, 3.5 mg / mL, 4.0 mg / mL, 4.5 mg / mL or 5.0 mg / mL.

[0087] According to an embodiment of the present invention, the wetting agent is one or more selected from Tween 20, Tween 80, and Poloxamer 188, and preferably Poloxamer 188.

[0088] According to an embodiment of the present invention, the concentration range of the osmotic pressure adjusting agent is 20 to 30 mg / mL, preferably 23 mg / mL to 26 mg / mL, for example 23 mg / mL, 24.7 mg / mL or 26 mg / mL.

[0089] According to an embodiment of the present invention, the osmotic pressure adjusting agent is one or more selected from sodium chloride, mannitol and sucrose.

[0090] According to an embodiment of the present invention, the concentration range of the stabilizer is 0 to 30 mg / mL, preferably 1 mg / mL to 10 mg / mL, for example, 1 mg / mL, 3 mg / mL, 5 mg / mL or 7.0 mg / mL.

[0091] According to an embodiment of the present invention, the buffer is one or more selected from phosphoric acid, phosphates, citric acid, sodium citric acid, hydrochloric acid and sodium hydroxide.

[0092] According to an embodiment of the present invention, the solvent is water, for example water for injection.

[0093] By way of example, the pharmaceutical composition of cariprazine may comprise the following ingredients: (a) cariprazine 1-hydroxy-2-naphthoate, (b) sodium carboxymethylcellulose or PVP K30; (c) Tween 20 or poloxamer 188, (d) disodium hydrogen phosphate, (e) Sodium dihydrogen phosphate, and (f) Mannitol.

[0094] And optionally, the pharmaceutical composition of cariprazine may contain a pH adjusting agent, such as sodium hydroxide or hydrochloric acid.

[0095] According to an embodiment of the present invention, the pH of the pharmaceutical composition of cariprazine may be 4.0 to 9.0, for example, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, or 9.0.

[0096] According to an embodiment of the present invention, the pharmaceutical composition of cariprazine is an injectable formulation, for example a long-acting injectable formulation.

[0097] According to an embodiment of the present invention, the pharmaceutical composition of cariprazine is a suspension or a suspension float, preferably a water suspension or a water suspension float.

[0098] According to an embodiment of the present invention, in the pharmaceutical composition or injectable preparation of cariprazine, the mass volume concentration of the cariprazine solid particles is 30 mg / mL or more, for example, 30 to 120 mg / mL, preferably 90 mg / mL.

[0099] According to an embodiment of the present invention, the process for preparing a pharmaceutical composition of cariprazine comprises mixing the ingredients.

[0100] Preferably, the method for preparing the pharmaceutical composition of cariprazine comprises the steps of: (1) Optionally, a suspending agent, a wetting agent, a buffer, and an osmotic pressure adjusting agent are dissolved in the solvent. (2) Solid cariprazine particles are added to obtain a suspension of coarse particles. (3) Optionally, the aqueous suspension of the coarse particles is ground in a ball mill to obtain a suspension of fine particles. (4) Optionally, a suspending agent is added to the above suspension of fine particles, and mixed uniformly. The pH is adjusted to 4.0 to 9.0 using optional sodium hydroxide or hydrochloric acid, and the volume is adjusted to constant to obtain an aqueous suspension. According to an embodiment of the manufacturing method of the present invention, in step (1), a suspending agent, a wetting agent, a buffering agent and an osmotic pressure adjusting agent can be dissolved in a solvent such as water for injection in sequence.

[0101] According to an embodiment of the production method of the present invention, in step (4), the pH after adjustment may be 4.0 to 9.0, for example, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, or 9.0.

[0102] The present invention provides the use of one of the above-mentioned cariprazine mono 1-hydroxy-2-naphthoate, cariprazine bis 1-hydroxy-2-naphthoate, cariprazine pamoate or a crystalline form thereof, a combination of pharma- ceutically acceptable salts of cariprazine, or the above-mentioned pharmaceutical composition of cariprazine, in the manufacture of a medicament for treating and / or preventing a cognitive or psychiatric disorder, such as psychosis, bipolar disorder, acute mania, etc.

[0103] The present invention further provides a method for treating and / or preventing a cognitive or psychiatric disorder, such as psychosis, bipolar disorder or acute mania, comprising administering to a patient in need thereof cariprazine mono 1-hydroxy-2-naphthoate, cariprazine bis 1-hydroxy-2-naphthoate, cariprazine pamoate or one of its crystalline forms, or a pharmaceutical composition of cariprazine as described above.

[0104] According to an embodiment of the present invention, the above "Dv(10)", "Dv(50)", "Dv(90)" and "Dv(100)" are volume weighted particle diameters of which 10 v / v%, 50 v / v%, 90 v / v% or 100 v / v% of the cumulative particles have equal or smaller diameters when measured. For example, if the Dv(50) of a particle population is about 25 microns, then 50% of the volume of particles have a diameter of about 25 microns or less.

[0105] Without departing from the spirit of the present invention, those skilled in the art can combine each of the above preferred conditions to obtain each of the relatively preferred embodiments of the present invention.

[0106] All of the reagents and raw materials used in the present invention are commercially available.

[0107] According to an embodiment of the present invention, the room temperature refers to an environmental temperature of 10°C to 35°C.

[0108] Beneficial effects As a result of extensive research, screening and trials, the inventors have found that the salts of cariprazine and solid forms thereof provided by the present invention, particularly cariprazine 1-hydroxy-2-naphthoate in the poorly soluble cariprazine salt, have the characteristics of a long-acting sustained-release preparation and can be developed into a suspension injection, while at the same time overcoming the problems of the conventional salt-type dissociation risk or lack of sustained release effect such as cariprazine hydrochloride, can achieve the effect of long-acting administration, and greatly improve patient compliance and drug bioavailability and administration safety.

[0109] The cariprazine salt and pharmaceutical composition thereof of the present invention have characteristics such as sustained release effect, high bioavailability, good solution stability, and small dosage volume, and can provide sustained release of cariprazine for more than 3 weeks with a single administration, so the market prospects are good.

[0110] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is an XRPD pattern of crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate.

[0111] FIG. 2 is a DSC / TGA pattern of crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate.

[0112] [Figure 3] 1H-NMR pattern of crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate.

[0113] FIG. 4 is an XRPD pattern of crystalline form B of cariprazine mono-1-hydroxy-2-naphthoate.

[0114] FIG. 5 is a DSC pattern of crystalline form B of cariprazine mono-1-hydroxy-2-naphthoate.

[0115] FIG. 6 is a 1H-NMR pattern of crystalline form B of cariprazine mono 1-hydroxy-2-naphthoate.

[0116] FIG. 7 is an XRPD pattern of crystalline form C of cariprazine mono-1-hydroxy-2-naphthoate.

[0117] FIG. 8 is a DSC pattern of crystalline form C of cariprazine mono-1-hydroxy-2-naphthoate.

[0118] FIG. 9 is a 1H-NMR pattern of crystalline form C of cariprazine bis(1-hydroxy-2-naphthoate).

[0119] FIG. 10 is an XRPD pattern of crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate hydrate.

[0120] FIG. 11 is a DSC / TGA pattern of crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate hydrate.

[0121] FIG. 12 is a 1H-NMR pattern of crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate hydrate.

[0122] FIG. 13 is an XRPD pattern of crystalline form H of cariprazine pamoate.

[0123] FIG. 14 is an amorphous XRPD pattern of cariprazine pamoate.

[0124] FIG. 15 is an XRPD pattern of crystalline form I of cariprazine hydrochloride.

[0125] FIG. 16 is an XRPD pattern overlay of the cariprazine hydrochloride dissociation study at pH 7.4 in Example 44, where A is cariprazine free base, B is cariprazine hydrochloride form I, and C is a sample of cariprazine hydrochloride form I after shaking in pH 7.4 medium.

[0126] FIG. 17 is a graph showing the relationship between the average blood drug concentration of cariprazine in the oral liquid sample of the formulation of Example 48 of the present invention and time in a rat.

[0127] [Figure 18] This is a graph showing the relationship between the average blood drug concentration of cariprazine and time in the injected samples of the formulations of Examples 45 to 47 of the present invention in the rat body, in which ■ is crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate, ▲ is crystalline form A of cariprazine bis 1-hydroxy-2-naphthoate hydrate, and ◆ is amorphous cariprazine pamoate.

[0128] [Figure 19] A local enlargement of Figure 18 (a graph showing the relationship between the average blood drug concentration of cariprazine over a period of 0 to 24 hours and time, in which ■ represents crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, ▲ represents crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate hydrate, and ◆ represents amorphous cariprazine pamoate.

[0129] [Figure 20] This is a graph showing the relationship between the average blood drug concentration of cariprazine and time in the injection sample of the formulation of Example 42 of the present invention in rats of different genders, where ■ is a graph showing the relationship between crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate in the male rat, and ▲ is a graph showing the relationship between crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate in the female rat.

[0130] [Figure 21] Local release diagram of Figure 18 (relationship between average blood drug concentration of cariprazine over 0 to 24 hours and time, in which ■ is a relationship diagram of crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate in the body of a male rat, and ▲ is a relationship diagram of crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate in the body of a female rat.

[0131] FIG. 22 is an X-ray diffraction pattern of a single crystal of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, crystalline form A.

[0132] FIG. 23 is an ellipsoidal diagram of the single crystal molecular conformation of cariprazine mono 1-hydroxy-2-naphthoate dihydrate.

[0133] FIG. 24 is a projection of unit cell stacking along the b-axis direction of a single crystal of cariprazine mono 1-hydroxy-2-naphthoate dihydrate.

[0134] [Mode for carrying out the invention] The present invention will be further described below with reference to examples, but the present invention is not limited to the scope of the described examples. In the following examples, the experimental methods without specific conditions are selected according to conventional methods, conditions, or product instructions.

[0135] The salt compounds of the examples were subjected to nuclear magnetic resonance ( 1 Measurements were performed using H-NMR, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and high performance liquid chromatography (HPLC), and the measurement parameters were as follows:

[0136] (1) 1 H-NMR measurements were performed on a Bruker Advance III 500M nuclear magnetic resonance spectrometer, the measurement frequency was 400 MHz, and the solvent used was deuterated DMSO.

[0137] (2) DSC measurements were performed using a TA Instruments Model 25 closed pan apparatus. Samples (approximately 1-2 mg) were weighed into aluminum pans and transferred to the instrument for measurement. The measurement parameters were equilibrated at 40°C, heated to 230-300°C at a rate of 10-20°C / min, and data were collected under nitrogen gas as the experimental atmosphere.

[0138] (3) TGA measurements were performed using a TA Instruments Model 55 instrument. Samples (approximately 2-5 mg) were weighed into aluminum pans and transferred to the instrument for measurement. Measurement parameters included heating the instrument to 300°C at a rate of 10°C / min, data collection, and nitrogen gas as the experimental atmosphere.

[0139] (4) XRPD measurements were performed on a Bruker D8 Advance X-ray powder diffractometer using a circular zero-background single crystal silicon sample stage with CuKα radiation as the light source, scanning parameters were 40 kV voltage, 40 mA current, 3°-45° scan range, 0.02° scan step, and continuous scan mode.

[0140] (5) Single crystal detection method: Referring to Method 1 of Part 0451 of the Four General Rules of the Chinese Pharmacopoeia 2020, single crystal X-ray diffraction analysis was performed using a Bruker single crystal X-ray diffractometer of SMART APEX-II model. The measurement conditions were CuKα radiation, voltage 40 kV, current 30 mA, scan range 4.31~66.50°, scanning mode φ / ω, and scanning step 0.5°.

[0141] (6) HPLC content and related substances determination method:

[0142] [Table 1]

[0143] Unless otherwise specified, the detection conditions for the particle size detector for the aqueous suspension of the cariprazine pharmaceutical composition of the present invention are as follows.

[0144] [Table 2]

[0145] Example 1A: Preparation of crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate 0.5 g of cariprazine free base was placed in a 10 mL centrifuge tube, 4 mL of pure water was added, 1 mL of phosphoric acid solution with a concentration of 100 mL / mL was further added, and the solution was dissolved by ultrasonication and filtered into a 30 mL vial to obtain solution A. 0.22 g of 1-hydroxy-2-naphthoic acid was placed in a 5 mL centrifuge tube, 4 mL of pure water was added, 0.936 mL of 50 mg / mL sodium hydroxide solution was further added, and the solution was dissolved by ultrasonication to obtain solution B. Solution B was gradually filtered into solution A under stirring conditions to precipitate a gray-brown solid, which was stirred at room temperature overnight, suction filtered, and dried under reduced pressure at 40°C overnight to obtain 0.7 g of cariprazine mono 1-hydroxy-2-naphthoate crystal form A, with a yield of 97% and an HPLC purity of 99.19%.

[0146] Its X-ray powder diffraction pattern is shown in FIG.

[0147] Its differential scanning calorimetry pattern is shown in FIG. 2 and indicated a melting point of about 101.3°C.

[0148] Its thermogravimetric analysis pattern is shown in FIG. 2, which showed a weight loss of about 4.82% before 100° C., which was attributed to the loss of crystal water and adsorbed water, and the crystalline form A was a dihydrate of cariprazine mono 1-hydroxy-2-naphthoate.

[0149] The nuclear magnetic resonance spectrum is shown in FIG. 3 and indicates that a salt is formed between cariprazine and 1-hydroxy-2-naphthoic acid in a molar ratio of 1:1.

[0150] Example 1B: Preparation of single crystals of crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate 0.25 g of cariprazine free base and 0.1075 g of 1-hydroxy-2-naphthoic acid were taken, and 2.5 mL of a mixture of acetone:water=6:4 was added, stirred at 70°C for 0.5 hours, dissolved, filtered, and the heating was stopped and the mixture was left to stand overnight, and the sample was sent for single crystal detection.

[0151] Single crystal X-ray diffraction analysis was performed using a Bruker single crystal X-ray diffractometer, model SMART APEX-II, referring to Method 1 of the 2020 edition of the Chinese Pharmacopoeia, with the measurement conditions being CuKα radiation, voltage 40 kV, current 30 mA, scan range 4.31~66.50°, scanning mode φ / ω, and scanning step 0.5°.

[0152] The single crystal X-ray diffraction pattern of the obtained sample is shown in FIG. 22, the single crystal molecular conformation ellipsoid diagram is shown in FIG. 23, and the stacked projection diagram of the unit cell of the single crystal along the b-axis direction is shown in FIG. 24.

[0153] Example 2: Preparation of crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate 100 g of cariprazine free base and 43 g of 1-hydroxy-2-naphthoic acid were added to 1000 mL of a mixed reagent of ethanol:water=1:1, and dissolved under stirring at 70°C. Heating was stopped and the temperature was lowered to cause precipitation. The mixture was stirred for 5 hours, suction filtered, and dried under reduced pressure at 40°C overnight to obtain 13.6 g of cariprazine mono-1-hydroxy-2-naphthoic acid salt dihydrate crystalline form A, with a yield of 95% and an HPLC purity of 99.59%.

[0154] Proton nuclear magnetic resonance, X-ray powder diffraction, differential scanning calorimetry and thermogravimetry showed it to be consistent with the chemical and crystalline structure of Example 1A, with a melting point of about 103.7°C and a weight loss of about 4.45% before 100°C.

[0155] Example 3: Preparation of cariprazine mono 1-hydroxy-2-naphthoate crystalline form B 1 g of cariprazine free base and 0.43 g of 1-hydroxy-2-naphthoic acid were added to 1 mL of a mixed reagent of acetone:water=6:4, and dissolved under stirring at 70°C. The mixture was filtered, the heating was stopped, and the mixture was allowed to stand at room temperature overnight, suction filtered, and dried under reduced pressure at 60°C for 1 hour to obtain 1.27 g of cariprazine mono-1-hydroxy-2-naphthoic acid salt crystal form B, with a yield of 89%.

[0156] The X-ray powder diffraction pattern is shown in FIG.

[0157] Its differential scanning calorimetry pattern is shown in FIG. 5 and indicated a melting point of about 106.8°C.

[0158] The nuclear magnetic resonance spectrum is shown in FIG. 6 and indicates that a salt is formed between cariprazine and 1-hydroxy-2-naphthoic acid in a molar ratio of 1:1.

[0159] Example 4: Preparation of cariprazine mono 1-hydroxy-2-naphthoate crystalline form C 10 g of cariprazine free base and 4.3 g of 1-hydroxy-2-naphthoic acid were added to 100 mL of a mixed reagent of acetone:water=6:4, and dissolved under stirring at 70°C. The mixture was filtered, the heating was stopped, and the mixture was allowed to stand at room temperature overnight, suction filtered, and dried under reduced pressure at 60°C for 5 hours to obtain 10.8 g of cariprazine mono-1-hydroxy-2-naphthoic acid salt crystal form C, with a yield of 76%.

[0160] The X-ray powder diffraction pattern is shown in FIG.

[0161] Its differential scanning calorimetry pattern is shown in FIG. 8 and indicated a melting point of about 103.4°C.

[0162] The nuclear magnetic resonance spectrum is shown in FIG. 9 and indicates that a salt is formed between cariprazine and 1-hydroxy-2-naphthoic acid in a molar ratio of 1:1.

[0163] Example 5: Preparation of crystalline form A of cariprazine bis 1-hydroxy-2-naphthoate hydrate Taking 1 g of cariprazine free base and 0.85 g of 1-hydroxy-2-naphthoic acid, adding 20 mL of a mixture of ethanol:water=1:1, stirring at 70°C for 2 hours, stopping heating and continuing to stir for 3 hours, suction filtering, and drying under reduced pressure at 40°C overnight to obtain 1.63 g of cariprazine bis-1-hydroxy-2-naphthoate crystalline form A, with a yield of 88% and an HPLC purity of 99.44%.

[0164] The X-ray powder diffraction pattern is shown in FIG.

[0165] Its differential scanning calorimetry pattern is shown in FIG. 11 and showed a melting point of about 86.3°C.

[0166] Its thermogravimetric analysis pattern is shown in FIG. 11, which showed a weight loss of about 1.31% before 100° C., which was attributed to the loss of crystal water and adsorbed water, and therefore the crystalline form A was cariprazine bis-1-hydroxy-2-naphthoate hydrate.

[0167] The nuclear magnetic resonance spectrum is shown in FIG. 12, which indicates that a salt is formed between cariprazine and 1-hydroxy-2-naphthoic acid in a molar ratio of 1:2.

[0168] Example 6: Preparation of cariprazine pamoate crystalline form H 2 g of commercially available cariprazine free base and 1.62 g of pamoic acid were taken, and 80 mL of tetrahydrofuran:methanol (2:1) was added, dissolved at 60°C, filtered, and rotary distilled to remove the solvent, to obtain a yellow solid, 30 mL of methanol was added, dissolved at 60°C, rotary distilled to remove the solvent, and dried to obtain a pale yellow solid. 0.1 g of the above pale yellow solid was taken, and 2.5 mL of dibutanone was added, dissolved at 60°C, filtered, and 5 volumes of n-heptane were gradually added with stirring at room temperature, stirred for 1 month, and filtered to obtain 0.08 g of cariprazine pamoate crystal form H, with a yield of 80%.

[0169] Its X-ray powder diffraction pattern is shown in FIG. 13 and was shown to be cariprazine pamoate crystalline form H.

[0170] Example 7: Preparation of amorphous cariprazine pamoate 4000 mg (9.36 mmol) of cariprazine was dissolved in 200 mL (5.4 mg / mL) of phosphoric acid solution to obtain solution A, and 3634 mg (9.36 mmol) of pamoic acid was dissolved in 100 mL (7.5 mg / mL) of sodium hydroxide solution to obtain solution B. 100 mL of solution B was added to 200 mL of solution A within 30 min under stirring, and the product was separated by filtration, washed with water and dried in vacuum at 40 °C for 12 h to obtain 5840 mg of a pale yellow solid with a yield of 76% (calculated on the free base).

[0171] The structure and molar ratio of cariprazine pamoate salt described in this invention were confirmed by proton nuclear magnetic resonance.

[0172] 1 H-NMR (400MHz, DMSO-d6): δ8.38(s, 2H),8.16(d, 2H),8.80(d, 2H),7.39-7.13(m, 7H),5.86(d, 1H),4.76(s, 2H),3.40-3.32(m, 3H),3.22-3.18(m, 4H),2.75(s, 6H),1.76(t, 4H),1.63-1.57(m, 2H),1.25-1.16(m, 3H),1.04-0.96(m, 2H).

[0173] Nuclear magnetic results showed that cariprazine and pamoic acid formed a salt in a molar ratio of 1:1.

[0174] The above sample was subjected to solid phase characterization detection, and the XRPD pattern is shown in FIG. 14, which indicated that it was an amorphous form of cariprazine pamoate.

[0175] Example 8: Preparation of cariprazine hydrochloride crystalline form I According to the prior research patent of cariprazine hydrochloride, a sample of cariprazine hydrochloride crystalline form I was prepared.

[0176] 1 g of commercially available cariprazine free base was taken and added to a 25 mL round-bottom flask, 2 mL of methanol and 8 mL of water were added, and the mixture was stirred in an oil bath at 70°C for 0.5 h. A mixed solution of 0.226 mL of concentrated hydrochloric acid and 0.35 mL of water was added, and after dissolution and clarification, the mixture was filtered while still hot. Heating was stopped and the mixture was allowed to cool naturally overnight to obtain 0.8 g of an off-white solid.

[0177] The X-ray powder diffraction pattern is shown in FIG. 15 and indicates that it is cariprazine hydrochloride crystalline form I.

[0178] Example 9: Comparison of stability of related substances and crystalline forms Crystal form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate prepared in Example 2, crystal form A of hydrate of cariprazine bis-1-hydroxy-2-naphthoate prepared in Example 5, amorphous cariprazine pamoate prepared in Example 7, and crystal form I of cariprazine hydrochloride prepared in Example 8 were respectively subjected to high temperature (60° C.), high humidity (25° C. / 90% RH), accelerated (40° C. / 75% RH), light irradiation (1.2×10 6 The samples were left at room temperature for 10 min at 25 °C (Lux·hr), and samples were taken on the 0th and 10th days for HPLC or XRPD detection.

[0179] The results of detection of related substances are shown in Table 1. After the crystal form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate and the crystal form A of cariprazine bis 1-hydroxy-2-naphthoate hydrate of the present invention were left for 10 days under high temperature, high humidity and accelerated conditions, the changes in related substances were all within 0.3%, and the increase was smaller than that of pamoate under high temperature conditions, which was similar to that of pamoate. The impurities increased slightly when exposed to light, and relatively good stability was maintained even when appropriate light-shielding measures were taken. The crystal form stability results are shown in Table 2, which shows that compared with the known cariprazine hydrochloride crystal form I, the cariprazine bis-1-hydroxy-2-naphthoate hydrate crystal form A of the present invention has better crystal form stability, and the crystal form and crystallinity do not change obviously after standing for 10 days under each condition. The cariprazine mono-1-hydroxy-2-naphthoate dihydrate crystal form A of the present invention is relatively stable and does not change in crystal form under high humidity, light exposure and accelerated conditions, but is converted to cariprazine mono-1-hydroxy-2-naphthoate crystal form C under high temperature conditions.

[0180] [Table 3]

[0181] [Table 4]

[0182] Example 10: Comparison of solubility at different pH levels Crystal form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate prepared in Example 1A, crystal form C of cariprazine semi-mono-1-hydroxy-2-naphthoate prepared in Example 4, crystal form A of cariprazine bis-1-hydroxy-2-naphthoate hydrate prepared in Example 5, amorphous cariprazine pamoate prepared in Example 7, crystal form I of cariprazine hydrochloride prepared in Example 8, and cariprazine free base (commercially available) were taken and added to the following media having different pH values, shaken at 37°C for 24 hours, filtered through a 0.45 μm aqueous phase filter membrane, and the filtrates were collected and their solubilities were measured by high performance liquid chromatography. Among them, pH3, pH4, pH5, and pH6 were acetate buffer solutions, and pH7, pH7.4, pH8, and pH9 were phosphate buffer solutions.

[0183] The results of the solubility test are shown in Table 3, which shows that the solubility of cariprazine mono 1-hydroxy-2-naphthoate and its crystalline form and cariprazine bis 1-hydroxy-2-naphthoate prepared in the present invention is relatively low in the range of pH 3-9, and the solubility in the range of pH 3-6 is significantly lower than that of hydrochloride, and the solubility in the range of pH 7-9 is significantly lower than that of pamoate. The relatively low solubility allows the release rate of the salt form and crystalline form to be minimally dependent on pH, thereby avoiding the influence of the pH environment of different regions in the body on the drug release rate, avoiding the occurrence of abrupt release phenomenon or excessive increase in blood drug concentration in local regions in the body, and reducing the difference in drug release between individuals. In addition, the stability of the crystalline form of cariprazine 1-hydroxy-2-naphthoate is relatively good, which is suitable for long-acting preparations, can reduce the number of administrations, and can improve patient compliance, and has a good market prospect.

[0184] [Table 5]

[0185] Examples 11-14: Aqueous suspensions of cariprazine mono 1-hydroxy-2-naphthoate at different doses

[0186] [Table 6]

[0187] Manufacturing process: (1) The formulation amounts of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethylcellulose, and approximately 60% of the total amount of water for injection were weighed out, and the mixture was stirred to dissolve and disperse.

[0188] (2) The prescribed amount of crystalline form C of cariprazine mono 1-hydroxy-2-naphthoate was added, and the pH was adjusted to 4.0 to 9.0 with sodium hydroxide or hydrochloric acid, optionally, followed by volumetric absorption and stirring until completely dispersed to obtain the suspensions of Examples 11 to 14.

[0189] The blended samples prepared in Examples 11 to 14 were taken, and the needle passability, suspendability, sedimentation ratio and redispersibility were examined. It was found that all of the above suspension samples could pass through a 0.45×15 mm injection needle, had good suspendability, and had a sedimentation ratio of greater than 0.9 for at least 10 minutes, and had good redispersibility (when shaken after settling, they could be dispersed quickly).

[0190] Examples 15-19: Aqueous suspensions of cariprazine mono 1-hydroxy-2-naphthoate with different Tween doses

[0191] [Table 7]

[0192] Manufacturing process: (1) The formulation amounts of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethylcellulose, and approximately 60% of the total amount of water for injection were weighed out, and the mixture was stirred to dissolve and disperse.

[0193] (2) The prescribed amount of crystalline form C of cariprazine mono 1-hydroxy-2-naphthoate was added, and the pH was adjusted to 4.0 to 9.0 with sodium hydroxide or hydrochloric acid, optionally, followed by volumetric absorption and stirring until completely dispersed to obtain the suspensions of Examples 15 to 19.

[0194] The blended samples prepared in Examples 15 to 19 were each taken and examined for needle passability, suspendability, wetting ability, sedimentation ratio and redispersibility. It was found that all of the above suspension samples could pass through a 0.45 x 15 mm injection needle and had good suspendability, the sedimentation ratios of the samples in Examples 15 to 19 for at least 10 minutes were greater than 0.9 and had good redispersibility (they could be dispersed quickly when shaken after settling), and the sample drugs in Examples 16 to 19 had little adhesion to the vial wall and had good wetting ability.

[0195] Examples 20-25: Aqueous suspensions of cariprazine 1-hydroxy-2-naphthoate with different poloxamer doses

[0196] [Table 8]

[0197] Manufacturing Process: (1) The formulation amounts of poloxamer 188, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethylcellulose, and approximately 60% of the total amount of water for injection were weighed out, and the mixture was stirred to dissolve and disperse.

[0198] (2) The formulation of crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate or crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate hydrate was added, selectively adjusted to pH 4.0 to 9.0 with sodium hydroxide or hydrochloric acid, made to volume, and stirred until completely dispersed to obtain the suspensions of Examples 20 to 25.

[0199] The blended samples prepared in Examples 20 to 25 were each taken and examined for needle passability, suspendability, wetting ability, sedimentation ratio and redispersibility. It was found that all of the above suspension samples could pass through a 0.45×15 mm injection needle, had good suspendability, little adhesion of the drug to the vial wall, and good wetting ability. The sedimentation ratio of the samples in Examples 20 to 25 for at least 10 minutes was greater than 0.9, and they had good redispersibility (they could be dispersed quickly when shaken after sedimentation).

[0200] Examples 26-31: Aqueous suspensions of cariprazine mono 1-hydroxy-2-naphthoate with different dosages of sodium carboxymethylcellulose

[0201] [Table 9]

[0202] Manufacturing Process: (1) The formulation amounts of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethylcellulose, and approximately 60% of the total amount of water for injection were weighed out, and the mixture was stirred to dissolve and disperse.

[0203] (2) The prescribed amount of crystalline form C of cariprazine mono 1-hydroxy-2-naphthoate was added, and the pH was adjusted to 4.0 to 9.0 with sodium hydroxide or hydrochloric acid, optionally, followed by volumetric absorption and stirring until completely dispersed to obtain the suspensions of Examples 26 to 31.

[0204] The blended samples prepared in Examples 26 to 31 were taken, and the needle passability, suspendability, sedimentation ratio and redispersibility were examined. It was found that all of the above suspension samples could pass through a 0.45×15 mm injection needle, showing good suspendability, and that the sedimentation ratios of the samples in Examples 26 to 31 for at least 10 minutes were greater than 0.9, showing good redispersibility (they could be dispersed quickly when shaken after settling).

[0205] Examples 32 and 33: Aqueous suspensions of cariprazine mono 1-hydroxy-2-naphthoate with different PVP K30 dosages

[0206] [Table 10]

[0207] Manufacturing Process: (1) The formulation amounts of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, PVP K30, and approximately 60% of the total amount of water for injection were weighed out, and the mixture was stirred to dissolve and disperse.

[0208] (2) The prescribed amount of crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate was added, and the pH was adjusted to 4.0 to 9.0 with sodium hydroxide or hydrochloric acid, optionally, followed by volume adjustment and stirring until completely dispersed to obtain the suspensions of Examples 32 and 33.

[0209] The blended samples prepared in Examples 32 and 33 were taken respectively, and the needle passability, suspendability, sedimentation ratio and redispersibility were examined. It was found that all of the above suspension samples could pass through a 0.45×15 mm injection needle, and had good suspendability. The sedimentation ratio of the samples in Examples 32 and 33 for at least 10 minutes was greater than 0.9, and they had good redispersibility (they could be dispersed quickly when shaken after settling).

[0210] Examples 34-37: Aqueous suspensions of cariprazine mono 1-hydroxy-2-naphthoate with different particle sizes

[0211] [Table 11]

[0212] Manufacturing process: (1) The formulation amounts of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, and approximately 60% of the total amount of water for injection were weighed out, and the mixture was stirred to dissolve and disperse.

[0213] (2) The formulated amount of cariprazine mono 1-hydroxy-2-naphthoate crystal form C was added to obtain an aqueous suspension of coarse particles.

[0214] (3) The aqueous suspensions of the coarse particles obtained in the above Examples 34 to 37 were each pulverized and dispersed in a ball mill.

[0215] (4) To the above suspensions, the respective formulations of sodium carboxymethylcellulose were added, stirred until completely dispersed, and then adjusted to a constant volume to obtain suspensions of Examples 34 to 37 having a pH of 7.4±0.2.

[0216] (5) An OMEC LS-909 particle size analyzer was used to measure the particle size distribution of the samples of Examples 34 to 37, and the results are shown in the table below.

[0217] [Table 12]

[0218] From the results in the table above, it can be seen that even with the same formulation, suspensions with particles of different particle sizes (Dv90) can be produced by controlling the grinding parameters.

[0219] Examples 38-40: Aqueous suspensions of cariprazine mono 1-hydroxy-2-naphthoate in different crystalline forms

[0220] [Table 13]

[0221] Manufacturing process: (1) The formulation amounts of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethylcellulose, and approximately 60% of the total amount of water for injection were weighed out, and the mixture was stirred to dissolve and disperse.

[0222] (2) The above-mentioned crystalline form of cariprazine mono 1-hydroxy-2-naphthoate in the formulation amount was added, and the pH was adjusted to 4.0 to 9.0 with sodium hydroxide or hydrochloric acid, optionally, followed by volume adjustment and stirring until completely dispersed to obtain the suspensions of Examples 38 to 40.

[0223] The blended samples prepared in Examples 38 to 40 were taken, and the needle passability, suspendability, sedimentation ratio and redispersibility were examined. It was found that all of the above suspension samples could pass through a 0.45×15 mm injection needle, showing good suspendability, and that the sedimentation ratios of the samples in Examples 38 to 40 for at least 10 minutes were greater than 0.9, showing good redispersibility (they could be dispersed quickly when shaken after settling). From the results shown in the above table, it was found that the same formulation of aqueous suspension was applicable to all of the different crystalline forms of cariprazine mono-1-hydroxy-2-naphthoate, taking into consideration the needle passability, suspension property, sedimentation ratio and wetting property.

[0224] Example 41: Consideration of the stability of cariprazine 1-hydroxy-2-naphthoate aqueous suspension at 60°C The aqueous suspension of cariprazine mono-1-hydroxy-2-naphthoate dihydrate crystalline form A prepared in Example 21 and the aqueous suspension of cariprazine bis-1-hydroxy-2-naphthoate hydrate crystalline form A prepared in Example 24 were subjected to detection of related substances at 60°C on days 0, 5 and 10, and the results are shown in the table below.

[0225] [Table 14]

[0226] The results in the above table show that, in the same formulation, the aqueous suspension of cariprazine mono-1-hydroxy-2-naphthoate dihydrate crystalline form A is more stable than the aqueous suspension of cariprazine bis-1-hydroxy-2-naphthoate hydrate crystalline form A.

[0227] Examples 42-43: Amplification and stability of aqueous suspensions of cariprazine mono 1-hydroxy-2-naphthoate in different formulations

[0228] [Table 15]

[0229] Manufacturing process: (1) The compounded amounts of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethylcellulose / PVPK30, and approximately 60% of the total amount of water for injection were weighed out, stirred to dissolve and disperse, and the volume was adjusted to 200 mL.

[0230] (2) The formulated amount of cariprazine mono 1-hydroxy-2-naphthoate dihydrate crystalline form A was added to obtain an aqueous suspension of coarse particles, and the volume was adjusted to 200 mL.

[0231] (3) The aqueous suspensions of the coarse particles obtained in Examples 42 and 43 were each pulverized and dispersed in a ball mill.

[0232] (4) An OMEC LS-909 particle size analyzer was used to measure the particle size distribution of the samples of Examples 42 and 43, and the results are shown in the table below.

[0233] [Table 16]

[0234] The results in the above table show that by controlling the milling parameters it is possible to produce aqueous suspensions of particles with smaller particle size (Dv90).

[0235] The suspensions prepared in the above examples were subjected to high temperature (60°C), light irradiation, accelerated (40°C / 75% RH), long-term (25°C / 60% RH), and low temperature (2-8°C) conditions to obtain stability samples. Data on content, particle size, etc. are shown in the table below.

[0236] [Table 17]

[0237] From the above data, it can be seen that the abrasive samples with different formulations all have good stability in terms of related substances, content, particle size, etc. under different conditions, and at the same time, the needle passability and redispersibility of the above stability samples are all good, with no abnormalities observed.

[0238] Example 44: Hydrochloride Salt Dissociation Studies The cariprazine hydrochloride crystalline form I prepared in Example 8 was added to corresponding aqueous media such as pH 6, pH 7, pH 7.4, pH 8 and pH 9, respectively, and shaken at 37°C for 4 hours, centrifuged, and the residue was subjected to XRPD detection. The result showed that cariprazine hydrochloride crystalline form I was dissociated into cariprazine free base, and the comparative result of pH 7.4 is shown in FIG. 16 (the rest are not shown), which shows that cariprazine hydrochloride crystalline form I is unstable in solution, and the change of the crystalline form after administration changes the efficacy and reduces the safety of administration.

[0239] Examples 45-47: Pharmacokinetic study of cariprazine 1-hydroxy-2-naphthoate suspension formulation in rats

[0240] [Table 18]

[0241] The manufacturing process of the suspension injection of Example 42 was as described in Example 42 above.

[0242] 1. Preparation process of the suspension injection of Examples 45-46: (1) The formulation amounts of poloxamer 188, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethylcellulose, and approximately 60% of the total amount of water for injection were weighed out, and the mixture was stirred to dissolve and disperse.

[0243] (2) The corresponding sample of crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate or crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate hydrate was added in the prescribed amount, stirred until completely dispersed, and then adjusted to the specified volume to obtain the suspension injections of Examples 45 to 46 having a pH of 7.4±0.2.

[0244] 2. Preparation process of the suspension injection of Example 47: (1) The formulation amounts of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethylcellulose, and approximately 60% of the total amount of water for injection were weighed out, and the mixture was stirred to dissolve and disperse.

[0245] (2) The formulated amount of amorphous cariprazine pamoate was added to each solution, stirred until completely dispersed, and then adjusted to the specified volume to obtain a suspension injection solution of Example 47 having a pH of 7.4±0.2.

[0246] 3. An OMEC LS-909 particle size analyzer was used to measure the particle size distribution of the samples in Examples 45 to 46, and the results are shown in the table below.

[0247] [Table 19]

[0248] Example 48: Preparation of hydrochloride crystalline form I oral liquid (1) An appropriate amount of the sample of cariprazine hydrochloride crystalline form I obtained in Example 8 was taken and added to about 60% of the total amount of water for injection, optionally adding 0.1% Tween 20 and 0.35% sodium carboxymethylcellulose, and dispersed by stirring.

[0249] (2) The pH was adjusted to 5.0 to 5.5 with hydrochloric acid, and the volume was adjusted to constant, thereby obtaining the final clear oral liquid of Example 48.

[0250] Example 49: Pharmacokinetics Experiments Examples 45-48: 12 male SD rats were divided into 4 groups, and 3 of the groups were administered a single dose of 9 mg / kg of cariprazine mono 1-hydroxy-2-naphthoate (Example 45), cariprazine bis 1-hydroxy-2-naphthoate (Example 46) and cariprazine pamoate (Example 47) by intramuscular injection, respectively, and plasma was collected 0 h, 1 h, 3 h, 7 h, 24 h, 4 d, 7 d, 15 d, 20 d, 25 d and 30 d after administration. The 4th group was administered a single dose of 0.3 mg / kg of cariprazine hydrochloride crystalline form I (Example 48) by forced oral administration, and plasma was collected 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h and 24 h after administration. During the study, animals in the intramuscular injection group had free access to food and water, whereas animals in the gavage group were fasted overnight before dosing and resumed eating and drinking 4 hours after dosing.

[0251] Collection of plasma samples: Approximately 150 μL of blood was collected from the jugular vein (whole blood was centrifuged within 30 minutes to separate plasma) and placed in a test tube containing anticoagulant EDTA-K2, and the treated plasma was stored in a refrigerator at -70°C until use. After pretreatment of the plasma samples, 1 μL of the solution was taken for LC-MS / MS analysis.

[0252] The pharmacokinetic parameters in the animals are shown in Tables 4 to 7, and the drug time course curves are shown in Figures 17 to 19.

[0253] The results showed that in the cariprazine hydrochloride oral combination group, the peak blood drug concentration Cmax absorbed within 1 hour after administration reached 20 ng / mL, which decreased to 1 ng / mL at 12 hours, and the mean residence time (MRTlast) was only 2.75 hours, while the three injection groups of Examples 45, 46, and 47 had significantly longer peak arrival times Tmax and mean residence times (MRTlast) compared with the oral group, with Tmax extended from several hours to several days, and MRTlast being 4.5 days, 6.5 days, and 5.4 days, respectively, which were 39, 57, and 47 times that of the oral experimental group, indicating a significant sustained release effect.

[0254] Example 42: Three male SD rats and three female SD rats were divided into two groups, one for each group, and each group was intramuscularly administered with a single dose of 9 mg / kg of cariprazine mono 1-hydroxy-2-naphthoate formulation (Example 42), and plasma samples were collected 1 h, 3 h, 7 h, 24 h, 4 d, 7 d, 10 d, 13 d, 16 d, 19 d, 22 d, 25 d, and 28 d after administration. During the study, the animals were allowed to freely access food and water.

[0255] Collection of plasma samples: After blood samples were collected, they were placed on ice and centrifuged within 1 hour (centrifugation conditions: 6800 g, 6 min, 2-8°C) to separate the plasma, which was placed in a test tube containing the anticoagulant EDTA-K2, and the plasma samples were stored in a refrigerator at -80°C before analysis. After pretreatment of the plasma samples, the solution was taken and subjected to LC-MS / MS analysis.

[0256] The pharmacokinetic parameters in the animals are shown in Tables 8 and 9, and the drug time course curves are shown in Figures 20 and 21.

[0257] The results showed that the two groups of rats of different sexes in Example 42 showed significantly longer peak time Tmax and mean residence time (MRTlast) than the oral group (Example 48, the peak blood drug concentration Cmax absorbed within 1 hour reached 20 ng / ml, decreased to 1 ng / ml at 12 hours, and the mean residence time (MRTlast) was only 2.75 hours), Tmax was extended from several hours to several days, and MRTlast was 5.9 days and 6.5 days, respectively, which was 51 and 57 times that of the oral experimental group, showing a significant sustained release effect.

[0258] The Cmax values ​​of the injection groups of Examples 42, 45 and 46 (26 (male), 29 (female), 13 and 24 ng / mL) were not significantly different from those of the oral group, indicating that the formulations produced in this patent application do not pose safety concerns such as adverse drug reactions due to excessive increases in blood drug concentrations after administration, while the Cmax value of the injection group of Example 47 was relatively high at 50.5 ng / mL, which may raise safety concerns regarding certain adverse reaction events.

[0259] In addition, from the viewpoint of maintaining the blood drug concentration, Examples 42, 45 and 46 were maintained at approximately 1 ng / mL within 15 to 20 days after administration to the injection group, while Example 47 was maintained for only 11 days, indicating that Examples 42, 45 and 46 have a longer period during which they exert their pharmacological effects in the body and have a superior sustained release effect to Example 47.

[0260] Furthermore, the AUClast values ​​of the injected male rats in Examples 42, 45 and 46 were 138, 68 and 168 day×ng / mL, respectively, indicating that Examples 42 and 46 were more advantageous in terms of bioavailability than Example 45.

[0261] [Table 20]

[0262] [Table 21]

[0263] [Table 22]

[0264] [Table 23]

[0265] [Table 24]

[0266] [Table 25]

[0267] The above is an illustrative description of the embodiments of the technical solution of the present invention. It should be understood that the scope of the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made by those skilled in the art within the scope of the spirit and principle of the present invention should be included in the scope of the claims of this application. [Brief description of the drawings]

[0268] [Figure 1] 1 is an XRPD pattern of crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate. [Diagram 2] 1 is a DSC / TGA pattern of crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate. [Diagram 3] 1 is a 1H-NMR pattern of crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate. [Figure 4] 1 is an XRPD pattern of crystalline form B of cariprazine mono 1-hydroxy-2-naphthoate. [Diagram 5] 1 is a DSC pattern of crystalline form B of cariprazine mono 1-hydroxy-2-naphthoate. [Figure 6]1 is a 1H-NMR pattern of crystalline form B of cariprazine mono 1-hydroxy-2-naphthoate. [Figure 7] 1 is an XRPD pattern of crystalline form C of cariprazine mono 1-hydroxy-2-naphthoate. [Figure 8] 1 is a DSC pattern of crystalline form C of cariprazine mono 1-hydroxy-2-naphthoate. [Figure 9] 1 is a 1H-NMR pattern of crystalline form C of cariprazine bis-1-hydroxy-2-naphthoate. [Figure 10] 1 is an XRPD pattern of crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate hydrate. [Figure 11] 1 is a DSC / TGA pattern of crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate hydrate. [Figure 12] 1 is a 1H-NMR pattern of crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate hydrate. [Figure 13] 1 is an XRPD pattern of crystalline form H of cariprazine pamoate. [Figure 14] 1 is an amorphous XRPD pattern of cariprazine pamoate. [Figure 15] 1 is an XRPD pattern of crystalline form I of cariprazine hydrochloride. [Figure 16] 4 is an XRPD pattern overlay of cariprazine hydrochloride dissociation study at pH 7.4 condition in Example 44, where A is cariprazine free base, B is cariprazine hydrochloride crystalline form I, and C is a sample of cariprazine hydrochloride crystalline form I after shaking in pH 7.4 medium. [Figure 17] FIG. 1 shows the relationship between the average blood drug concentration of cariprazine in an oral liquid sample of the formulation of Example 48 of the present invention and time in a rat. [Figure 18]This is a graph showing the relationship between the average blood drug concentration of cariprazine and time in rats for the injection samples of the formulations of Examples 45 to 47 of the present invention, in which ■ is crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate, ▲ is crystalline form A of cariprazine bis 1-hydroxy-2-naphthoate hydrate, and ◆ is amorphous cariprazine pamoate. [Figure 19] A local enlargement of Figure 18 (a relationship between the average blood drug concentration of cariprazine over a period of 0 to 24 hours and time, in which ■ represents crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, ▲ represents crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate hydrate, and ◆ represents amorphous cariprazine pamoate. [Figure 20] This is a graph showing the relationship between the average blood drug concentration of cariprazine and time in the injection sample of the formulation of Example 42 of the present invention in rats of different genders, in which ■ is a graph showing the relationship between crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate in the male rat, and ▲ is a graph showing the relationship between crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate in the female rat. [Figure 21] FIG. 18 shows the local release diagram (a relationship diagram between the average blood drug concentration of cariprazine over a period of 0 to 24 hours and time, in which ■ shows the relationship diagram of crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate in the body of a male rat, and ▲ shows the relationship diagram of crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate in the body of a female rat. [Figure 22] 1 is an X-ray diffraction pattern of a single crystal of crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate. [Figure 23] FIG. 1 is an ellipsoidal diagram of the single crystal molecular conformation of cariprazine mono 1-hydroxy-2-naphthoate dihydrate. [Figure 24] FIG. 2 is a projection of unit cell stacking along the b-axis direction of a single crystal of cariprazine mono 1-hydroxy-2-naphthoate dihydrate.

Claims

1. A pharma- ceutically acceptable salt of cariprazine, selected from cariprazine mono 1-hydroxy-2-naphthoate represented by the following formula (I), cariprazine bis 1-hydroxy-2-naphthoate represented by the following formula (II), or cariprazine pamoate represented by the following formula (III): 【Chemistry 1】 Preferably, the pharma- ceutically acceptable salt is The crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate, of which the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate, preferably the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, has characteristic peaks at 2θ values ​​of 15.6°±0.2°, 19.7°±0.2°, 20.7°±0.2°, etc.; Preferably, the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate is crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate; A single crystal of crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, wherein the X-ray diffraction pattern of the single crystal has characteristic peaks at 2θ values ​​of 17.5°±0.2°, 19.7°±0.2°, 20.8°±0.2°, etc.; The crystalline form B of cariprazine mono-1-hydroxy-2-naphthoate, wherein the X-ray powder diffraction pattern of the crystalline form B of cariprazine mono-1-hydroxy-2-naphthoate has characteristic peaks at 2θ values ​​of 14.6°±0.2°, 18.8°±0.2°, 19.5°±0.2°, etc.; Form C of cariprazine mono-1-hydroxy-2-naphthoate, wherein the X-ray powder diffraction pattern of Form C of cariprazine mono-1-hydroxy-2-naphthoate has characteristic peaks at 2θ values ​​of 17.8°±0.2°, 19.9°±0.2°, 21.1°±0.2°, etc.; It is an amorphous substance of cariprazine bis(1-hydroxy-2-naphthoate). A crystalline form of cariprazine bis-1-hydroxy-2-naphthoate, for example, crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate, wherein the X-ray powder diffraction pattern of crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate has characteristic peaks at 2θ values ​​of 4.7°±0.2°, 9.4°±0.2°, 20.8°±0.2°, etc.; Preferably, the crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate is crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate hydrate; It is an amorphous form of cariprazine pamoate. crystalline form H of cariprazine pamoate, the X-ray powder diffraction pattern of which has characteristic peaks at 2θ values ​​of 7.3°±0.2°, 8.8°±0.2°, 9.4°±0.2°, 14.6°±0.2°, 17.4°±0.2°, 18.1°±0.2°, 18.6°±0.2°, 19.2°±0.2°, 22.9°±0.2°, etc. At least one of the following forms is selected from the above: A pharma- ceutically acceptable salt of cariprazine.

2. The X-ray powder diffraction pattern of the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate, preferably the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, has characteristic peaks at 2θ values ​​of 12.7°±0.2°, 15.6°±0.2°, 17.3°±0.2°, 19.7°±0.2°, 20.2°±0.2°, 20.7°±0.2°, etc. Preferably, the X-ray powder diffraction pattern of the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate, preferably the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, has characteristic peaks at 2θ values ​​of 12.7°±0.2°, 15.6°±0.2°, 17.3°±0.2°, 18.8°±0.2°, 19.7°±0.2°, 20.2°±0.2°, 20.7°±0.2°, 24.3°±0.2°, etc.; More preferably, the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate, preferably the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, has an X-ray powder diffraction pattern with 2θ values ​​of 4.4°±0.2°, 8.6°±0.2°, 9.7°±0.2°, Absorption peaks at 11.4°±0.2°, 12.7°±0.2°, 15.6°±0.2°, 16.5°±0.2°, 16.9°±0.2°, 17.3°±0.2°, 18.8°±0.2°, 19.7°±0.2°, 20.2°±0.2°, 20.7°±0.2°, 23.3°±0.2°, 24.3°±0.2°, 24.9°±0.2°, 29.5°±0.2°, etc. More preferably, the crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate, preferably crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate hydrate, more preferably crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate, has an X-ray powder diffraction pattern essentially as shown in FIG. Preferably, the crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate, preferably the crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate hydrate, more preferably the crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate, has a differential scanning calorimetry pattern essentially as shown in FIG. Preferably, the melting point of the crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate, preferably the crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate hydrate, more preferably the crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate, is about 101.3° C.; Preferably, the crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate, preferably the crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate hydrate, more preferably the crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate, has a thermogravimetric analysis pattern essentially as shown in FIG. Preferably, the X-ray diffraction pattern of the single crystal has characteristic peaks at 2θ values ​​of 17.5°±0.2°, 19.0°±0.2°, 19.7°±0.2°, 20.3°±0.2°, 20.8°±0.2°, 23.4°±0.2°, etc., Preferably, the X-ray diffraction pattern of the single crystal has characteristic peaks at 2θ values ​​of 12.7°±0.2°, 15.7°±0.2°, 17.5°±0.2°, 19.0°±0.2°, 19.7°±0.2°, 20.3°±0.2°, 20.8°±0.2°, 23.4°±0.2°, etc., More preferably, the X-ray diffraction pattern of the single crystal has absorption peaks at 2θ values ​​of 11.5°±0.2°, 12.7°±0.2°, 15.7°±0.2°, 16.6°±0.2°, 16.9°±0.2°, 17.5°±0.2°, 18.1°±0.2°, 19.0°±0.2°, 19.7°±0.2°, 20.0°±0.2°, 20.3°±0.2°, 20.8°±0.2°, 21.3°±0.2°, 23.4°±0.2°, 23.6°±0.2°, 24.4°±0.2°, 24.9°±0.2°, 29.6°±0.2°, etc.

2. A pharma- ceutically acceptable salt according to claim 1.

3. The X-ray powder diffraction pattern of the crystalline form B of the cariprazine mono 1-hydroxy-2-naphthoate salt has characteristic peaks at 2θ values ​​of 14.6°±0.2°, 18.8°±0.2°, 19.5°±0.2°, etc. Preferably, the X-ray powder diffraction pattern of the crystalline form B of cariprazine mono 1-hydroxy-2-naphthoate has characteristic peaks at 2θ values ​​of 5.5°±0.2°, 11.5°±0.2°, 14.6°±0.2°, 18.8°±0.2°, 19.5°±0.2°, 23.7°±0.2°, etc.; More preferably, the X-ray powder diffraction pattern of crystalline form B of cariprazine mono 1-hydroxy-2-naphthoate has characteristic peaks at 2θ values ​​of 5.5°±0.2°, 11.5°±0.2°, 13.0°±0.2°, 14.6°±0.2°, 16.9°±0.2°, 18.8°±0.2°, 19.5°±0.2°, 23.7°±0.2°, etc.; More preferably, the X-ray powder diffraction pattern of crystalline form B of cariprazine mono-1-hydroxy-2-naphthoate has characteristic peaks at 2θ values ​​of 5.5°±0.2°, 9.2°±0.2°, 11.1°±0.2°, 11.5°±0.2°, 13.0°±0.2°, 13.9°±0.2°, 14.6°±0.2°, 16.6°±0.2°, 16.9°±0.2°, 18.5°±0.2°, 18.8°±0.2°, 19.5°±0.2°, 19.9°±0.2°, 20.3°±0.2°, 21.2°±0.2°, 23.7°±0.2°, 24.3°±0.2°, etc. More preferably, the crystalline form B of cariprazine mono 1-hydroxy-2-naphthoate has an X-ray powder diffraction pattern essentially as shown in FIG. Preferably, the crystalline form B of cariprazine mono 1-hydroxy-2-naphthoate has a differential scanning calorimetry pattern essentially as shown in FIG. Preferably, the melting point of the crystalline form B of the cariprazine mono 1-hydroxy-2-naphthoate salt is about 106.8° C. A pharma- ceutically acceptable salt according to claim 1 or 2.

4. The X-ray powder diffraction pattern of the crystalline form C of cariprazine mono-1-hydroxy-2-naphthoate has characteristic peaks at 2θ values ​​of 4.4°±0.2°, 15.6°±0.2°, 17.8°±0.2°, 19.9°±0.2°, 21.1°±0.2°, 23.7°±0.2°, etc. Preferably, the X-ray powder diffraction pattern of crystalline form C of cariprazine mono 1-hydroxy-2-naphthoate has characteristic peaks at 2θ values ​​of 4.4°±0.2°, 12.8°±0.2°, 15.6°±0.2°, 17.8°±0.2°, 19.9°±0.2°, 20.2°±0.2°, 21.1°±0.2°, 23.7°±0.2°, etc.; More preferably, the X-ray powder diffraction pattern of crystalline form C of cariprazine mono 1-hydroxy-2-naphthoate has characteristic peaks at 2θ values ​​of 4.4°±0.2°, 8.6°±0.2°, 9.7°±0.2°, 11.5°±0.2°, 12.8°±0.2°, 13.2°±0.2°, 15.6°±0.2°, 16.6°±0.2°, 17.8°±0.2°, 19.3°±0.2°, 19.9°±0.2°, 20.2°±0.2°, 21.1°±0.2°, 22.4°±0.2°, 23.7°±0.2°, 24.2°±0.2°, 24.9°±0.2°, etc. More preferably, the crystalline form C of cariprazine mono 1-hydroxy-2-naphthoate has an X-ray powder diffraction pattern essentially as shown in FIG. Preferably, the crystalline form C of cariprazine mono 1-hydroxy-2-naphthoate has a differential scanning calorimetry pattern essentially as shown in FIG. Preferably, the melting point of the crystalline form C of the cariprazine mono 1-hydroxy-2-naphthoate salt is about 103.4° C. A pharma- ceutically acceptable salt according to any one of claims 1 to 3.

5. The X-ray powder diffraction pattern of the crystalline form A of the cariprazine bis(1-hydroxy-2-naphthoate) has characteristic peaks at 2θ values ​​of 4.7°±0.2°, 9.4°±0.2°, 12.7°±0.2°, 20.1°±0.2°, 20.8°±0.2°, 27.4°±0.2°, etc. Preferably, the X-ray powder diffraction pattern of the crystalline form A of cariprazine bis(1-hydroxy-2-naphthoate) has characteristic peaks at 2θ values ​​of 4.7°±0.2°, 9.4°±0.2°, 12.7°±0.2°, 17.1°±0.2°, 19.1°±0.2°, 20.1°±0.2°, 20.8°±0.2°, 27.4°±0.2°, etc.; More preferably, the X-ray powder diffraction pattern of the crystalline form A of cariprazine bis(1-hydroxy-2-naphthoate) has characteristic peaks at 2θ values ​​of 4.7°±0.2°, 8.8°±0.2°, 9.4°±0.2°, 12.7°±0.2°, 16.5°±0.2°, 17.1°±0.2°, 18.4°±0.2°, 19.1°±0.2°, 19.9°±0.2°, 20.1°±0.2°, 20.8°±0.2°, 21.1°±0.2°, 21.9°±0.2°, 24.1°±0.2°, 24.8°±0.2°, 25.6°±0.2°, 27.4°±0.2°, etc. More preferably, the crystalline form A of cariprazine bis 1-hydroxy-2-naphthoate has an X-ray powder diffraction pattern essentially as shown in Figure 10; Preferably, the crystalline form A of cariprazine bis 1-hydroxy-2-naphthoate has a differential scanning calorimetry pattern essentially as shown in FIG. Preferably, the melting point of the crystalline form A of the cariprazine bis 1-hydroxy-2-naphthoate is about 86.3°C; Preferably, the thermogravimetric analysis pattern of the crystalline form A of the cariprazine bis-1-hydroxy-2-naphthoate salt is essentially as shown in FIG. A pharma- ceutically acceptable salt according to any one of claims 1 to 4.

6. The crystalline form H of cariprazine pamoate has an X-ray powder diffraction pattern essentially as shown in FIG. Alternatively, the cariprazine pamoate salt is amorphous and preferably has an X-ray powder diffraction pattern essentially as shown in FIG. A pharma- ceutically acceptable salt according to any one of claims 1 to 5.

7. A method for producing a pharma- ceutically acceptable salt according to any one of claims 1 to 5, comprising the steps of: (1) A method for producing crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate, preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, comprising the steps of: (a1) dissolving cariprazine in an aqueous phosphoric acid solution, filtering to obtain solution A, mixing with an aqueous 1-hydroxy-2-naphthoic acid solution and an aqueous sodium hydroxide solution, and filtering to obtain solution B; (a2) adding solution B to solution A in a solute molar ratio of 1:1 and stirring at room temperature to obtain crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate, preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate; (2) A method for producing crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate, preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, comprising the steps of: (a3) mixing cariprazine and 1-hydroxy-2-naphthoic acid in a molar ratio of 1:1 with a solvent; (a4) stirring at 25-70° C. to obtain crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate, preferably crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate hydrate, more preferably crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate; Preferably, the solvent is a mixture of methanol, ethanol or acetone with water; Preferably, the volume ratio of methanol, ethanol or acetone to water may be 2:1 to 1:2, for example 1:1; Preferably, the mass / volume ratio of cariprazine to the total volume of the solvent system is 1 g:5-30 mL, for example 1 g:5-20 mL, for example 1 g:10 mL; (3) A method for producing crystalline form B of cariprazine mono 1-hydroxy-2-naphthoate, comprising the steps of: (b1) mixing cariprazine and 1-hydroxy-2-naphthoic acid in a molar ratio of 1:1 with a solvent; (b2) stirring at 25-70° C. to obtain crystalline form B of cariprazine mono 1-hydroxy-2-naphthoate; Preferably, the solvent is a mixture of methanol, ethanol or acetone with water; Preferably, the volume ratio of methanol, ethanol or acetone to water may be 2:1 to 1:2, for example 1.5:1; Preferably, the mass / volume ratio of cariprazine to the total volume of the solvent system is 1 g:0.5-10 mL, for example 1 g:0.5-1.5 mL, for example 1 g:1 mL; (4) A method for producing crystalline form C of cariprazine mono-1-hydroxy-2-naphthoate, comprising the steps of: (c1) mixing cariprazine and 1-hydroxy-2-naphthoic acid in a molar ratio of 1:1 with a solvent; (c2) stirring at 25-70° C. to obtain crystalline form C of the cariprazine mono 1-hydroxy-2-naphthoate; Preferably, the solvent is a mixture of methanol, ethanol or acetone with water; Preferably, the volume ratio of methanol, ethanol or acetone to water may be 2:1 to 1:2, for example 1.5:1; Preferably, the mass / volume ratio of cariprazine to the total volume of the solvent system is 1 g:5-30 mL, for example 1 g:5-20 mL, for example 1 g:10 mL; (5) A method for producing crystalline form A of cariprazine bis(1-hydroxy-2-naphthoate), comprising the steps of: adding cariprazine and 1-hydroxy-2-naphthoic acid in a molar ratio of 1:2 to a solvent and stirring at 25-70° C. to obtain crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate; Preferably, the solvent is a mixture of methanol, ethanol or acetone with water; Preferably, the volume ratio of methanol, ethanol or acetone to water may be 2:1 to 1:2, for example 1:1; Preferably, the mass / volume ratio of cariprazine to the total volume of the solvent system is 1 g:5-40 mL, for example 1 g:10-30 mL, for example 1 g:20 mL; A manufacturing method comprising one selected from the following:

8. A combination of pharma- ceutically acceptable salts of cariprazine, At least one, for example two or three, of the pharma- ceutically acceptable salts according to any one of claims 1 to 6; and optionally, other pharma- ceutically acceptable salts of cariprazine, or other forms of said cariprazine mono 1-hydroxy-2-naphthoate, cariprazine bis 1-hydroxy-2-naphthoate or cariprazine pamoate, optionally with or without the presence of other pharma- ceutically acceptable salts of cariprazine, Preferably, the weight percentage content of the crystalline form of cariprazine mono 1-hydroxy-2-naphthoate or cariprazine bis 1-hydroxy-2-naphthoate according to any one of claims 1 to 5 in the total weight of the pharma- ceutically acceptable salts of cariprazine in the combination is greater than the content of other salt forms or crystalline forms of cariprazine; For example, the weight percentage content of the crystalline form of cariprazine mono 1-hydroxy-2-naphthoate or cariprazine bis 1-hydroxy-2-naphthoate according to any one of claims 1 to 5 in the total weight of the pharma- ceutically acceptable salt of cariprazine in the combination is 80% or more, preferably 90% or more, more preferably 95% or 99% or more. combination.

9. A pharmaceutical composition comprising a pharma- ceutically acceptable salt according to any one of claims 1 to 6, preferably comprising cariprazine mono 1-hydroxy-2-naphthoate, cariprazine bis 1-hydroxy-2-naphthoate, cariprazine pamoate or one of its crystalline forms, Preferably, the pharmaceutical composition comprises solid particles of cariprazine having a particle size of Dv(10)≦30 microns, Dv(50)≦50 microns and Dv(90)≦100 microns, preferably ≦50 microns, wherein the solid particles of cariprazine may be one selected from cariprazine mono 1-hydroxy-2-naphthoate, cariprazine bis 1-hydroxy-2-naphthoate, cariprazine pamoate or a crystalline form thereof according to any one of claims 1 to 6; Preferably, the pharmaceutical composition of cariprazine comprises: (a) cariprazine 1-hydroxy-2-naphthoate, (b) sodium carboxymethylcellulose or PVP K30; (c) Tween 20 or poloxamer 188, (d) disodium hydrogen phosphate, (e) Sodium dihydrogen phosphate, and (f) may contain the ingredient mannitol; Optionally, the pharmaceutical composition of cariprazine may also include a pH adjusting agent, such as sodium hydroxide or hydrochloric acid; Preferably, the pH of the pharmaceutical composition of cariprazine may be 4.0 to 9.0; More preferably, the pharmaceutical composition of cariprazine is a suspension or suspension float, preferably a water suspension or a water suspension float; More preferably, the pharmaceutical composition of cariprazine is an injectable formulation, e.g., a long-acting injectable formulation; For example, in the pharmaceutical composition or injection of cariprazine, the mass volume concentration of the cariprazine solid particles is 30 mg / mL or more, for example, 30 to 120 mg / mL, preferably 90 mg / mL. Pharmaceutical compositions.

10. 10. Use of a pharma- ceutically acceptable salt according to any one of claims 1 to 6, a combination of a pharma- ceutically acceptable salt of cariprazine according to claim 8 or one of the pharmaceutical compositions according to claim 9 in the manufacture of a medicament for the treatment and / or prevention of cognitive or psychiatric disorders, such as psychosis, bipolar disorder, acute mania.

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