Cariprazine pharmaceutical salt and crystal form, pharmaceutical composition, preparation method and application thereof

Abstract

The present invention provides 1-hydroxy-2-naphthoate or pamoate of cariprazine, and / or a novel solid form thereof, as well as pharmaceutical compositions, methods of preparation and uses thereof. The cariprazine salt and the solid form thereof provided by the invention, especially the cariprazine 1-hydroxy-2-naphthoate in the cariprazine indissolvable salt, conform to the advantages of a long-acting sustained release preparation, and can be developed into a suspension injection; meanwhile, the problem that existing salt forms such as cariprazine hydrochloride have dissociation risks or do not have a sustained release effect can be solved, the effect of long-acting administration can be achieved, and the compliance of patients and the bioavailability and medication safety of the medicine are greatly improved.

Description

[0001] This application claims the benefit of priority to the applicant’s prior application, application number 202210162007.8, filed with the State Intellectual Property Office of China on February 22, 2022, entitled “Cariprazine Pharmaceutical Salts, Crystal Forms, Pharmaceutical Compositions, Preparation Methods, and Uses Thereof.” The entire text of the aforementioned prior application is incorporated herein by reference.

[0002] This application is a divisional application of application number 202310155920.X, filed with the State Intellectual Property Office of China on February 22, 2023, entitled "Cariprazine pharmaceutical salt and its crystal form, pharmaceutical composition, preparation method and use". Technical Field

[0003] The present invention belongs to the field of chemical medicine, and specifically relates to a pharmaceutical salt of cariprazine and its crystal form, a pharmaceutical composition, a preparation method and use. Background Art

[0004] Cariprazine, whose chemical structure is shown below, is a new atypical antipsychotic drug that antagonizes dopamine D3, dopamine D2, and serotonin 2B receptors. It is used to treat schizophrenia and bipolar disorder type 1. Currently available is cariprazine hydrochloride capsules, an oral formulation that requires daily dosing to maintain blood levels. However, this frequent dosing can lead to poor patient compliance.

[0005]

[0006] Patent CN101679315A discloses various salts of cariprazine, including monohydrochloride, dihydrochloride, monohydrobromide, maleate and methanesulfonate.

[0007] Patent CN105218484A discloses cariprazine tartrate and provides the solubility of cariprazine tartrate, cariprazine hydrochloride, cariprazine maleate, cariprazine benzenesulfonate and cariprazine phosphate, all of which are greater than 3 mg / mL.

[0008] Patent WO2020056929A discloses a new crystalline form of cariprazine hydrochloride, which mentions that cariprazine hydrochloride will quickly dissociate into a free base in a pH 6.5 buffer.

[0009] Patent document CN108261394A discloses a cariprazine hydrochloride injection preparation, including a suspension aqueous solution and a lyophilized form, which can obtain a sustained release of at least 1 week or longer. However, the inventors found during the research process that the stability of the cariprazine hydrochloride aqueous solution is not ideal, and dissociation occurs under weakly acidic to alkaline conditions. Therefore, there is a risk of dissociation in the suspension aqueous solution, which easily causes changes in product properties and quality, resulting in changes in drug dissolution and absorption, affecting the efficacy of the drug and the patient's medication safety, and is not suitable for long-acting sustained-release preparations. Moreover, the cariprazine concentration in the cariprazine hydrochloride injection preparation disclosed in patent document CN108261394A is too high in the dosing concentration and blood drug concentration in the animal pK experiment. Combined with the original research data, the elimination of cariprazine varies greatly between species (about 2 to 4 hours in rats and 3 to 9 days in humans). Excessive blood drug concentration may lead to larger toxic side effects and excessive drug accumulation in the human body.

[0010] Currently, there are no reports on injectable preparations of poorly soluble salts of cariprazine with improved properties.

[0011] In view of the shortcomings of the existing technology, finding a pharmaceutical salt of cariprazine and its crystal form that has low solubility, is suitable for long-term administration, has high stability, good clinical effect and / or is suitable for commercialization is a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0012] To improve the above-mentioned problems existing in the prior art, the present invention provides a pharmaceutically acceptable salt of cariprazine, in particular 1-hydroxy-2-naphthoate or cariprazine pamoate, and / or a new solid form thereof, as well as a pharmaceutical composition, preparation method and use thereof.

[0013] 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):

[0014]

[0015] According to an embodiment of the present invention, the cariprazine 1-hydroxy-2-naphthoate is 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; wherein 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 characteristic peak at 2θ values ​​of 15.6°±0.2°, 19.7°±0.2°, 20.7°±0.2°, etc.

[0016] 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, and more preferably the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, has an X-ray powder diffraction pattern with 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.

[0017] 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, and more preferably the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, has an X-ray powder diffraction pattern 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., having characteristic peaks.

[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 at 2θ values ​​of 4.4°±0.2°, 8.6°±0.2°, 9.7°±0.2°, 11.4°±0.2°, 12.7° There are absorption peaks at ±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°.

[0019] 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 substantially the following characteristics: Figure 1 The X-ray powder diffraction pattern is shown.

[0020] 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 substantially the following properties: Figure 2 The differential scanning calorimetry analysis diagram is shown.

[0021] 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 melting point of about 101.3°C.

[0022] 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 substantially the following properties: Figure 2 The thermogravimetric analysis diagram shown shows that there is a weight loss of about 4.82% before 100°C.

[0023] Preferably, the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate is cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably cariprazine mono-1-hydroxy-2-naphthoate dihydrate crystalline form A.

[0024] Furthermore, the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoic acid salt, preferably the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoic acid salt hydrate, more preferably the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoic acid salt dihydrate, cariprazine and 1-hydroxy-2-naphthoic acid are salified in a molar ratio of 1:1, wherein 1 The H-NMR diagram is basically as follows Figure 3 shown.

[0025] The present invention also provides a single crystal of cariprazine mono-1-hydroxy-2-naphthoate dihydrate in form A, 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.

[0026] Furthermore, 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.

[0027] Furthermore, 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.

[0028] Furthermore, 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°, and 29.6°±0.2°.

[0029] According to an embodiment of the present invention, there is also provided a method for preparing 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, comprising the following steps:

[0030] (a1) dissolving cariprazine in a phosphoric acid aqueous solution and filtering to obtain solution A; mixing an aqueous 1-hydroxy-2-naphthoic acid solution and an aqueous sodium hydroxide solution and filtering to obtain solution B;

[0031] (a2) adding solution B to solution A according to a solute molar ratio of 1:1, stirring at room temperature to obtain 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.

[0032] Alternatively, the preparation method 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 comprises the following steps:

[0033] (a3) mixing cariprazine and 1-hydroxy-2-naphthoic acid with a solvent in a molar ratio of 1:1;

[0034] (a4) stirring at 25-70° C. to obtain 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.

[0035] According to an embodiment of the present invention, the solvent is a mixture of methanol, ethanol or acetone and water. Preferably, the volume ratio of methanol, ethanol or acetone to water can be 2:1 to 1:2, such as 1:1.

[0036] Preferably, the mass volume ratio of cariprazine to the total volume of the solvent system is 1 g:5 to 30 mL, such as 1 g:5 to 20 mL, for example 1 g:10 mL.

[0037] According to an embodiment of the present invention, the cariprazine 1-hydroxy-2-naphthoate is 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.

[0038] Furthermore, the X-ray powder diffraction pattern of the crystalline form B of the 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.

[0039] Furthermore, the X-ray powder diffraction pattern of the crystalline form B of the 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.

[0040] Further, according to an embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form B of the 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°, and 24.3°±0.2°.

[0041] Furthermore, the crystalline form B of the cariprazine mono-1-hydroxy-2-naphthoate has substantially Figure 4 The X-ray powder diffraction pattern is shown.

[0042] Preferably, the crystalline form B of cariprazine mono-1-hydroxy-2-naphthoate has substantially Figure 5 The differential scanning calorimetry analysis diagram is shown.

[0043] Preferably, the melting point of the crystalline form B of cariprazine mono-1-hydroxy-2-naphthoate is about 106.8°C.

[0044] Furthermore, in the crystalline form B of the cariprazine mono-1-hydroxy-2-naphthoic acid salt, cariprazine and 1-hydroxy-2-naphthoic acid are salified in a molar ratio of 1:1. 1 The H-NMR diagram is basically as follows Figure 6 shown.

[0045] According to an embodiment of the present invention, the preparation method of the crystalline form B of cariprazine mono-1-hydroxy-2-naphthoate comprises the following steps:

[0046] (b1) mixing cariprazine and 1-hydroxy-2-naphthoic acid with a solvent in a molar ratio of 1:1;

[0047] (b2) stirring at 25-70° C. to obtain the crystal form B of the cariprazine mono-1-hydroxy-2-naphthoate.

[0048] According to an embodiment of the present invention, the solvent is a mixture of methanol, ethanol or acetone and water. Preferably, the volume ratio of methanol, ethanol or acetone to water can be 2:1 to 1:2, such as 1.5:1.

[0049] Preferably, the mass volume ratio of cariprazine to the total volume of the solvent system is 1 g:0.5-10 mL, such as 1 g:0.5-1.5 mL, for example 1 g:1 mL.

[0050] According to an embodiment of the present invention, the cariprazine 1-hydroxy-2-naphthoate is the crystalline form C of cariprazine mono-1-hydroxy-2-naphthoate, wherein 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 17.8°±0.2°, 19.9°±0.2°, 21.1°±0.2°, etc.

[0051] Furthermore, the X-ray powder diffraction pattern of the crystalline form C of the 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.

[0052] Furthermore, the X-ray powder diffraction pattern of the crystalline form C of the 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°, and 23.7°±0.2°.

[0053] Further, according to an embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form C of the 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.

[0054] Furthermore, the crystalline form C of cariprazine mono-1-hydroxy-2-naphthoate has substantially Figure 7 The X-ray powder diffraction pattern is shown.

[0055] Preferably, the crystalline form C of cariprazine mono-1-hydroxy-2-naphthoate has substantially Figure 8 The differential scanning calorimetry analysis diagram is shown.

[0056] Preferably, the melting point of the crystalline form C of cariprazine mono-1-hydroxy-2-naphthoate is about 103.4°C.

[0057] According to an embodiment of the present invention, in the crystalline form C of the cariprazine mono-1-hydroxy-2-naphthoic acid salt, cariprazine and 1-hydroxy-2-naphthoic acid are salted in a molar ratio of 1:1. 1 The H-NMR diagram is basically as follows Figure 9 shown.

[0058] According to an embodiment of the present invention, the preparation method of the crystalline form C of cariprazine mono-1-hydroxy-2-naphthoate comprises the following steps:

[0059] (c1) mixing cariprazine and 1-hydroxy-2-naphthoic acid with a solvent in a molar ratio of 1:1;

[0060] (c2) stirring at 25-70° C. to obtain the crystal form C of the cariprazine mono-1-hydroxy-2-naphthoate.

[0061] According to an embodiment of the present invention, the solvent is a mixture of methanol, ethanol or acetone and water. Preferably, the volume ratio of methanol, ethanol or acetone to water can be 2:1 to 1:2, such as 1.5:1.

[0062] Preferably, the mass volume ratio of cariprazine to the total volume of the solvent system is 1 g:5 to 30 mL, such as 1 g:5 to 20 mL, for example 1 g:10 mL.

[0063] According to an embodiment of the present invention, the cariprazine 1-hydroxy-2-naphthoic acid salt is the cariprazine bis-1-hydroxy-2-naphthoic acid salt represented by the above formula (II), wherein the molar ratio of cariprazine to 1-hydroxy-2-naphthoic acid is 1:2.

[0064] According to an embodiment of the present invention, the cariprazine bis-1-hydroxy-2-naphthoate salt may be in a solid form, such as an amorphous or crystalline form.

[0065] According to an embodiment of the present invention, the cariprazine bis 1-hydroxy-2-naphthoate is the crystalline form A of cariprazine bis 1-hydroxy-2-naphthoate, wherein 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°, 20.8°±0.2°, etc.

[0066] Furthermore, 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.

[0067] Furthermore, 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°, 17.1°±0.2°, 19.1°±0.2°, 20.1°±0.2°, 20.8°±0.2°, 27.4°±0.2°, etc.

[0068] Further, according to an embodiment of the present invention, 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°, 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.

[0069] Furthermore, the crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate has substantially Figure 10 The X-ray powder diffraction pattern is shown.

[0070] Preferably, the crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate has substantially Figure 11 The differential scanning calorimetry analysis diagram is shown.

[0071] Preferably, the melting point of the crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate is about 86.3°C.

[0072] Preferably, the thermogravimetric analysis diagram of the crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate is substantially as follows Figure 11 As shown, there is a weight loss of about 1.31% before 100°C.

[0073] Preferably, the crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate is a hydrate of cariprazine bis-1-hydroxy-2-naphthoate.

[0074] Preferably, the crystalline form A of the cariprazine bis-1-hydroxy-2-naphthoate 1 The H-NMR diagram is basically as follows Figure 12 As shown, cariprazine and 1-hydroxy-2-naphthoic acid are salted at a molar ratio of 1:2.

[0075] According to an embodiment of the present invention, the preparation method of the crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate comprises the following steps:

[0076] Cariprazine and 1-hydroxy-2-naphthoic acid are added to a solvent in a molar ratio of 1:2, and stirred at 25-70° C. to obtain the crystalline form A of cariprazine bis-1-hydroxy-2-naphthoic acid salt.

[0077] The solvent is a mixture of methanol, ethanol or acetone and water. Preferably, the volume ratio of methanol, ethanol or acetone to water can be 2:1 to 1:2, such as 1:1.

[0078] Preferably, the mass volume ratio of cariprazine to the total volume of the solvent system is 1 g:5-40 mL, such as 1 g:10-30 mL, for example 1 g:20 mL.

[0079] According to an embodiment of the present invention, the cariprazine pamoate has a structure shown in the following formula (III):

[0080]

[0081] According to an embodiment of the present invention, in the cariprazine pamoate, the molar ratio of cariprazine to pamoic acid is 1:1.

[0082] According to an embodiment of the present invention, the cariprazine pamoate is the crystalline form H of cariprazine pamoate, and the X-ray powder diffraction pattern of the cariprazine pamoate crystalline form H 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.

[0083] Furthermore, the crystalline form H of cariprazine pamoate has substantially Figure 13 The X-ray powder diffraction pattern is shown.

[0084] According to an embodiment of the present invention, the cariprazine pamoate is an amorphous substance, which preferably has a substantially Figure 14 The X-ray powder diffraction pattern is shown.

[0085] According to an embodiment of the present invention, the solid form includes a crystalline or non-crystalline (amorphous) form of a pharmaceutically acceptable salt of cariprazine, which may be an anhydrate, a hydrate or a solvate. When present, the molar ratio of the water molecules or solvent molecules in the salt and its 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 also be obtained by detection methods known to those skilled in the art.

[0086] The present invention also provides a combination of pharmaceutically acceptable salts of cariprazine, comprising at least one, for example, two or three, of the pharmaceutically acceptable salts of cariprazine or their solid forms described above, and optionally other pharmaceutically acceptable salts of cariprazine, or other forms of the cariprazine mono-1-hydroxy-2-naphthoate, cariprazine bis-1-hydroxy-2-naphthoate or cariprazine pamoate.

[0087] According to an embodiment of the present invention, based on the total weight of the pharmaceutically acceptable salt of cariprazine in the 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.

[0088] For example, based on the total weight of the pharmaceutically acceptable salt of cariprazine in the combination, the weight percentage content of the crystalline form of cariprazine mono-1-hydroxy-2-naphthoate or cariprazine bis-1-hydroxy-2-naphthoate is above 80%, preferably above 90%, more preferably above 95% or 99%.

[0089] The present invention also provides a pharmaceutical composition comprising a pharmaceutically 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 their crystalline forms.

[0090] The present invention also provides a pharmaceutical composition of cariprazine, comprising cariprazine solid particles, wherein the particle size of the cariprazine solid particles is Dv(10)≤30 microns, Dv(50)≤50 microns, and Dv(90)≤100 microns, preferably ≤50 microns;

[0091] The cariprazine solid particles can be selected from the cariprazine mono-1-hydroxy-2-naphthoate, cariprazine bis-1-hydroxy-2-naphthoate, cariprazine pamoate or one of their crystalline forms as described above.

[0092] According to an embodiment of the present invention, the pharmaceutically 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.

[0093] According to an embodiment of the present invention, the cariprazine solid particles may be in an amorphous or crystalline form.

[0094] According to an embodiment of the present invention, the pharmaceutical composition of cariprazine may further include an excipient, and the excipient may be selected from one or more of a suspending agent, a wetting agent, an osmotic pressure regulator, a solvent, and a buffer.

[0095] According to an embodiment of the present invention, the concentration of the suspending agent ranges from 0 to 10 mg / mL, preferably from 3.5 mg / mL to 7.5 mg / mL, such as 5.0 mg / mL or 7.5 mg / mL.

[0096] According to an embodiment of the present invention, the suspending agent is selected from one or more of sodium carboxymethyl cellulose, methyl cellulose and polyvinyl pyrrolidone, preferably sodium carboxymethyl cellulose.

[0097] 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, such as 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.

[0098] According to an embodiment of the present invention, the wetting agent is selected from one or more of Tween 20, Tween 80, and Poloxamer 188, preferably Poloxamer 188.

[0099] According to an embodiment of the present invention, the concentration range of the osmotic pressure regulator is 20-30 mg / mL, preferably 23 mg / mL-26 mg / mL, such as 23 mg / mL, 24.7 mg / mL or 26 mg / mL.

[0100] According to an embodiment of the present invention, the osmotic pressure regulator is selected from one or more of sodium chloride, mannitol and sucrose.

[0101] According to an embodiment of the present invention, the concentration of the stabilizer ranges from 0 to 30 mg / mL, preferably from 1 mg / mL to 10 mg / mL, such as 1 mg / mL, 3 mg / mL, 5 mg / mL or 7.0 mg / mL.

[0102] According to an embodiment of the present invention, the buffer is selected from one or more of phosphoric acid, phosphate, citric acid, sodium citrate, hydrochloric acid and sodium hydroxide.

[0103] According to an embodiment of the present invention, the solvent is water, such as water for injection.

[0104] As an example, the pharmaceutical composition of cariprazine may comprise the following components:

[0105] (a) Cariprazine 1-hydroxy-2-naphthoate;

[0106] (b) sodium carboxymethylcellulose or PVP K30;

[0107] (c) Tween 20 or Poloxamer 188;

[0108] (d) disodium hydrogen phosphate;

[0109] (e) sodium dihydrogen phosphate;

[0110] (f) mannitol;

[0111] Also, optionally, the pharmaceutical composition of cariprazine may comprise a pH adjuster, such as sodium hydroxide or hydrochloric acid.

[0112] 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.

[0113] According to an embodiment of the present invention, the pharmaceutical composition of cariprazine is an injection, such as a long-acting injection.

[0114] According to an embodiment of the present invention, the pharmaceutical composition of cariprazine is a suspension or a suspending agent, preferably an aqueous suspension or an aqueous suspending agent.

[0115] According to an embodiment of the present invention, in the pharmaceutical composition or injection of cariprazine, the mass volume concentration of the cariprazine solid particles is not less than 30 mg / mL, such as 30 to 120 mg / mL, preferably 90 mg / mL.

[0116] According to an embodiment of the present invention, the method for preparing the pharmaceutical composition of cariprazine comprises mixing the components.

[0117] Preferably, the preparation method of the cariprazine pharmaceutical composition comprises the following steps:

[0118] (1) Optionally, dissolving a suspending agent, a wetting agent, a buffer, and an osmotic pressure regulator in a solvent;

[0119] (2) adding cariprazine solid particles to obtain a suspension aqueous solution of coarse particles;

[0120] (3) Optionally, the coarse particle suspension aqueous solution is ground using a ball mill to obtain a fine particle suspension;

[0121] (4) Optionally, a suspending agent is added to the above-mentioned fine particle suspension, mixed evenly, and optionally, the pH is adjusted to 4.0-9.0 with sodium hydroxide or hydrochloric acid, and the volume is constant to obtain a suspension aqueous solution.

[0122] According to an embodiment of the preparation method of the present invention, in step (1), the suspending agent, wetting agent, buffer and osmotic pressure regulator can be dissolved in a solvent in sequence, for example, in water for injection.

[0123] According to an embodiment of the preparation method of the present invention, in step (4), the adjusted pH 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.

[0124] 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 their crystalline forms, a combination of cariprazine pharmaceutically acceptable salts, or a pharmaceutical composition of cariprazine in preparing a medicament, wherein the medicament is used to treat and / or prevent cognitive impairment or mental disorders, such as psychosis, bipolar disorder, and acute mania.

[0125] The present invention also provides a method for treating and / or preventing cognitive impairment or mental disorders, such as psychosis, bipolar disorder or acute mania, comprising administering the above-mentioned cariprazine mono-1-hydroxy-2-naphthoate, cariprazine bis-1-hydroxy-2-naphthoate, cariprazine pamoate or one of their crystalline forms, or a pharmaceutical composition of the cariprazine to a patient in need.

[0126] According to an embodiment of the present invention, "Dv(10)", "Dv(50)", "Dv(90)", and "Dv(100)" refer to the volume-weighted particle diameters, wherein a cumulative 10 v / v%, 50 v / v%, 90 v / v%, or 100 v / v% of the particles, respectively, have an equal or smaller diameter when measured. For example, if the Dv(50) of a population of particles is about 25 microns, then 50% by volume of the particles have a diameter less than or equal to about 25 microns.

[0127] Without violating the spirit of the present invention, those skilled in the art can combine the above-mentioned preferred conditions to obtain preferred embodiments of the present invention.

[0128] The reagents and raw materials used in the present invention are commercially available.

[0129] According to an embodiment of the present invention, the room temperature refers to an ambient temperature of 10°C to 35°C.

[0130] Beneficial effects

[0131] Through extensive research, screening, and experimentation, the inventors have discovered that the salts of cariprazine and their solid forms provided by the present invention, especially the cariprazine 1-hydroxy-2-naphthoate salt among the poorly soluble salts of cariprazine, have the advantages of a long-acting sustained-release preparation and can be developed into a suspension injection. At the same time, they can overcome the risk of dissociation or the problem of lack of sustained-release effect of existing salt forms such as cariprazine hydrochloride, thereby achieving the effect of long-acting drug administration and greatly improving patient compliance as well as the bioavailability and safety of the drug.

[0132] The salt of cariprazine and the pharmaceutical composition thereof of the present invention have the characteristics of sustained release, high bioavailability, good solution stability, small administration volume, etc. A single administration can continuously release cariprazine for at least three weeks or longer, and therefore has good market prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0133] Figure 1 The XRPD pattern of Form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate;

[0134] Figure 2 The DSC / TGA spectrum of Form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate;

[0135] Figure 3 It is the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate 1 H-NMR spectrum;

[0136] Figure 4 This is the XRPD pattern of cariprazine mono-1-hydroxy-2-naphthoate salt Form B;

[0137] Figure 5 This is the DSC spectrum of cariprazine mono-1-hydroxy-2-naphthoate crystalline form B;

[0138] Figure 6 It is cariprazine mono 1-hydroxy-2-naphthoate crystal form B 1 H-NMR spectrum;

[0139] Figure 7 This is the XRPD pattern of cariprazine mono-1-hydroxy-2-naphthoate salt Form C;

[0140] Figure 8 This is the DSC spectrum of cariprazine mono-1-hydroxy-2-naphthoate crystal form C;

[0141] Figure 9Cariprazine bis-1-hydroxy-2-naphthoate crystal form C 1 H-NMR spectrum;

[0142] Figure 10 This is the XRPD pattern of Form A of cariprazine bis-1-hydroxy-2-naphthoate hydrate;

[0143] Figure 11 This is the DSC / TGA spectrum of Form A of cariprazine bis-1-hydroxy-2-naphthoate hydrate;

[0144] Figure 12 It is the crystalline form A of cariprazine bis 1-hydroxy-2-naphthoate hydrate 1 H-NMR spectrum;

[0145] Figure 13 is the XRPD pattern of cariprazine pamoate Form H;

[0146] Figure 14 This is the XRPD pattern of cariprazine pamoate amorphous form;

[0147] Figure 15 is the XRPD pattern of cariprazine hydrochloride form I;

[0148] Figure 16 This is an overlay of XRPD patterns of the dissociation study of cariprazine hydrochloride at pH 7.4 in Example 44, wherein A is cariprazine free base; B is cariprazine hydrochloride Form I; and C is a sample of cariprazine hydrochloride Form I after shaking in a pH 7.4 medium.

[0149] Figure 17 This is a graph depicting the relationship between the average blood concentration of cariprazine and time in the oral solution samples of Example 48 of the present invention in rats;

[0150] Figure 18 The figure depicts the relationship between the average blood concentration of cariprazine and time in rats injected with the formulations of Examples 45-47 of the present invention, wherein ■ represents the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate; ▲ represents the crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate hydrate; and ◆ represents the amorphous form of cariprazine pamoate.

[0151] Figure 19 : Figure 18 A partial enlarged view (the relationship between the average blood concentration of cariprazine and time from 0 to 24 hours, wherein ■ is the crystal form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate; ▲ is the crystal form A of cariprazine di-1-hydroxy-2-naphthoate hydrate; ◆ is the amorphous form of cariprazine pamoate;

[0152] Figure 20 : A graph depicting the relationship between the average blood concentration of cariprazine and time in rats of different genders after injection of the preparation of Example 42 of the present invention, wherein ■ represents the relationship between the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate in male rats; ▲ represents the relationship between the crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate in female rats;

[0153] Figure 21 : Figure 18 A partial enlarged view (a graph showing the relationship between the average blood concentration of cariprazine and time from 0 to 24 hours, wherein ■ is a graph showing the relationship between the crystal form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate in male rats; ▲ is a graph showing the relationship between the crystal form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate in female rats;

[0154] Figure 22 is the X-ray diffraction pattern of a single crystal of Form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate;

[0155] Figure 23 This is an ellipsoid diagram of the single crystal molecular stereostructure of cariprazine mono-1-hydroxy-2-naphthoate dihydrate;

[0156] Figure 24 This is a unit cell stacking projection of a single crystal of cariprazine mono-1-hydroxy-2-naphthoate dihydrate along the b-axis. DETAILED DESCRIPTION

[0157] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0158] Nuclear magnetic resonance ( 1 H-NMR), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and high performance liquid chromatography (HPLC) were used to test the salt compounds of the examples. The test parameters were as follows:

[0159] (1) 1 The H-NMR measurements were performed on a Bruker Advance III 500M nuclear magnetic resonance spectrometer at a measurement frequency of 400 MHz using deuterated DMSO as the solvent.

[0160] (2) DSC measurements were performed using a TA Instruments Model 25 sealed pan apparatus. Samples (approximately 1–2 mg) were weighed in an aluminum pan and transferred to the instrument for measurement. The test parameters were as follows: the instrument was equilibrated at 40°C and the temperature was raised to 230–300°C at a rate of 10–20°C / min. Data were collected under a nitrogen atmosphere.

[0161] (3) TGA measurements were performed in a TA Instruments Model 55. Samples (approximately 2–5 mg) were weighed in an aluminum pan and transferred to the instrument for measurement. The test parameters were as follows: the instrument was heated to 300°C at a rate of 10°C / min, and data were collected. The experimental atmosphere was nitrogen.

[0162] (4) XRPD measurements were performed on a Bruker D8 Advance X-ray powder diffractometer using a circular zero-background single-crystal silicon sample stage. The test used CuKα radiation as the light source, and the scanning parameters were as follows: voltage 40 kV, current 40 mA, scanning range 3° to 45°, scanning step size 0.02°, and continuous scanning mode.

[0163] (5) Single crystal detection method: Referring to the first method of Part IV of the 2020 edition of the Chinese Pharmacopoeia, a single crystal X-ray diffraction analysis was performed using a Bruker SMART APEX-II single crystal X-ray diffractometer. The test conditions were: CuKα radiation, voltage 40 kV, current 30 mA, scanning range 4.31-66.50°, scanning mode The scanning step size is 0.5°.

[0164] (6) HPLC content and related substance detection methods:

[0165] Assay method:

[0166]

[0167]

[0168] Content gradient elution program table:

[0169] Time (min) Mobile phase A (%) Mobile phase B (%) 0 60 40 2 40 60 5 15 85 5.1 60 40 10 60 40

[0170] Related material methods:

[0171]

[0172] Gradient elution program table:

[0173] Time (min) Mobile phase A (%) Mobile phase B (%) 0 80 20 7 45 55 17 37 63 25 20 80 25.1 80 20 35 80 20

[0174] Unless otherwise stated, the particle size test conditions of the suspension aqueous solution of the pharmaceutical composition of cariprazine in the context of the present invention are as follows:

[0175]

[0176]

[0177] The measurements were repeated three times and an average value was created.

[0178] Example 1A: Preparation of Form A of Cariprazine Mono-1-Hydroxy-2-Naphthoate Dihydrate

[0179] 0.5g of cariprazine free base was placed in a 10mL centrifuge tube, 4mL of pure water was added, followed by 1mL of 100mL / mL phosphoric acid solution, and ultrasonically dissolved. The solution was then filtered into a 30mL vial to obtain Solution A. 0.22g of 1-hydroxy-2-naphthoic acid was placed in a 5mL centrifuge tube, 4mL of pure water was added, followed by 0.936mL of 50mg / mL sodium hydroxide solution, and ultrasonically dissolved to obtain Solution B. Solution B was slowly filtered into Solution A under stirring, precipitating a gray-brown solid. The solid was stirred at room temperature overnight, filtered, and dried under reduced pressure at 40°C overnight to obtain 0.7g of cariprazine mono-1-hydroxy-2-naphthoate crystalline Form A, with a yield of 97% and an HPLC purity of 99.19%.

[0180] Its X-ray powder diffraction pattern is as follows Figure 1 shown.

[0181] Its differential scanning calorimetry analysis diagram is as follows Figure 2 As shown, the melting point is shown to be about 101.3°C.

[0182] Its thermogravimetric analysis diagram is as follows Figure 2 As shown, there is a weight loss of about 4.82% before 100° C., which is attributed to the loss of crystal water and adsorbed water. The crystalline form A is the dihydrate of cariprazine mono-1-hydroxy-2-naphthoate.

[0183] Its NMR images are as follows Figure 3 As shown, cariprazine and 1-hydroxy-2-naphthoic acid are salted at a molar ratio of 1:1.

[0184] Example 1B: Preparation of Form A Single Crystal of Cariprazine Mono-1-Hydroxy-2-Naphthoate Dihydrate

[0185] Take 0.25g of cariprazine free base and 0.1075g of 1-hydroxy-2-naphthoic acid, add 2.5mL of acetone: water = 6:4 mixed reagent, stir at 70℃ for 0.5 hour, dissolve, filter, turn off the heat and let it stand overnight, and send the sample for single crystal inspection.

[0186] According to the first method of Part 4 of the 2020 edition of the Chinese Pharmacopoeia, a single crystal X-ray diffraction analysis was performed using a Bruker SMART APEX-II single crystal X-ray diffractometer. The test conditions were: CuKα radiation, voltage 40kV, current 30mA, scanning range 4.31-66.50°, scanning mode The scanning step size is 0.5°.

[0187] The single crystal X-ray diffraction pattern of the obtained sample is as follows Figure 22 As shown, the ellipsoidal diagram of the single crystal molecular structure is as follows Figure 23 As shown, the unit cell stacking projection diagram of the single crystal along the b axis is as follows Figure 24 shown.

[0188] Example 2: Preparation of Form A of Cariprazine Mono-1-Hydroxy-2-Naphthoate Dihydrate

[0189] Take 100g of cariprazine free base and 43g of 1-hydroxy-2-naphthoic acid, add 1000mL of ethanol: water = 1:1 mixed reagent, stir and dissolve at 70°C, turn off the heating and cool to precipitate, continue stirring for 5 hours, filter, and dry under reduced pressure at 40°C overnight to obtain 13.6g of cariprazine mono-1-hydroxy-2-naphthoic acid salt dihydrate Form A, with a yield of 95% and an HPLC purity of 99.59%.

[0190] H NMR, X-ray powder diffraction, differential scanning calorimetry, and thermogravimetric analysis showed that the chemical structure and crystal structure of the compound were consistent with those of Example 1A, with a melting point of approximately 103.7°C and a weight loss of approximately 4.45% before 100°C.

[0191] Example 3: Preparation of Cariprazine Mono-1-Hydroxy-2-Naphthoate Crystalline Form B

[0192] Take 1 g of cariprazine free base and 0.43 g of 1-hydroxy-2-naphthoic acid, add 1 mL of acetone: water = 6:4 mixed reagent, stir and dissolve at 70 ° C, filter, turn off the heating and let it stand at room temperature overnight, filter, and dry under reduced pressure at 60 ° C for 1 hour to obtain 1.27 g of cariprazine mono-1-hydroxy-2-naphthoic acid salt Form B, with a yield of 89%.

[0193] Its X-ray powder diffraction pattern is as follows Figure 4 shown.

[0194] Its differential scanning calorimetry analysis diagram is as follows Figure 5 As shown, the melting point is shown to be about 106.8°C.

[0195] Its NMR images are as follows Figure 6 As shown, cariprazine and 1-hydroxy-2-naphthoic acid are salted at a molar ratio of 1:1.

[0196] Example 4: Preparation of Cariprazine Mono-1-Hydroxy-2-Naphthoate Crystalline Form C

[0197] Take 10 g of cariprazine free base and 4.3 g of 1-hydroxy-2-naphthoic acid, add 100 mL of acetone: water = 6:4 mixed reagent, stir and dissolve at 70 ° C, filter, turn off the heating and let it stand at room temperature overnight, filter, and dry under reduced pressure at 60 ° C for 5 hours to obtain 10.8 g of cariprazine mono-1-hydroxy-2-naphthoic acid salt Form C, with a yield of 76%.

[0198] Its X-ray powder diffraction pattern is as follows Figure 7 shown.

[0199] Its differential scanning calorimetry analysis diagram is as follows Figure 8 As shown, the melting point is shown to be about 103.4°C.

[0200] Its NMR images are as follows Figure 9 As shown, cariprazine and 1-hydroxy-2-naphthoic acid are salted at a molar ratio of 1:1.

[0201] Example 5: Preparation of Form A of Cariprazine Bis-1-Hydroxy-2-Naphthoate Hydrate

[0202] Take 1 g of cariprazine free base and 0.85 g of 1-hydroxy-2-naphthoic acid, add 20 mL of ethanol: water = 1:1 mixed reagent, stir at 70 ° C for 2 hours, turn off the heat and continue stirring for 3 hours, filter, and dry under reduced pressure at 40 ° C overnight to obtain 1.63 g of cariprazine bis 1-hydroxy-2-naphthoate salt Form A, with a yield of 88% and an HPLC purity of 99.44%.

[0203] Its X-ray powder diffraction pattern is as follows Figure 10 shown.

[0204] Its differential scanning calorimetry analysis diagram is as follows Figure 11 As shown, the melting point is shown to be about 86.3°C.

[0205] Its thermogravimetric analysis diagram is as follows Figure 11 As shown, there is a weight loss of about 1.31% before 100° C., which is attributed to the loss of crystal water and adsorbed water. Therefore, the crystal form A is cariprazine bis-1-hydroxy-2-naphthoate hydrate.

[0206] Its NMR images are as follows Figure 12 As shown, cariprazine and 1-hydroxy-2-naphthoic acid are salted at a molar ratio of 1:2.

[0207] Example 6: Preparation of Cariprazine Pamoate Form H

[0208] 2g of commercially available cariprazine free base and 1.62g of pamoic acid were added to 80mL of tetrahydrofuran:methanol (2:1) solvent and dissolved at 60°C. Filtered and the solvent was removed by rotary evaporation to obtain a yellow solid. 30mL of methanol was added to dissolve at 60°C, the solvent was removed by rotary evaporation, and dried to obtain a light yellow solid. 0.1g of the above light yellow solid was added to 2.5mL of dibutyl ketone and dissolved at 60°C. Filtered, 5 times the volume of n-heptane was slowly added with stirring at room temperature, stirred for 1 month, and filtered to obtain 0.08g of cariprazine pamoate Form H, with a yield of 80%.

[0209] Its X-ray powder diffraction pattern is as follows Figure 13 As shown, it is cariprazine pamoate crystalline form H.

[0210] Example 7: Preparation of Cariprazine Pamoate Amorphous Form

[0211] 4000 mg (9.36 mmol) of cariprazine was dissolved in 200 mL (5.4 mg / mL) of phosphoric acid solution to obtain solution A. 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 over 30 minutes with stirring. The product was separated by filtration and rinsed with water. It was then dried under vacuum at 40°C for 12 hours to obtain 5840 mg of a light yellow solid, with a yield of 76% (based on the free base).

[0212] The structure and molar ratio of the cariprazine pamoate of the present invention were confirmed by hydrogen nuclear magnetic resonance spectroscopy.

[0213] 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).

[0214] The nuclear magnetic resonance results showed that cariprazine and pamoic acid formed a salt with a molar ratio of 1:1.

[0215] The above samples were subjected to solid phase characterization and the XRPD patterns were shown in Figure 14 , the test results showed it to be cariprazine pamoate amorphous form.

[0216] Example 8: Preparation of Cariprazine Hydrochloride Form I

[0217] Prepare cariprazine hydrochloride crystal form I sample according to the original patent of cariprazine hydrochloride:

[0218] 1 g of commercially available cariprazine free base was added to a 25 mL round-bottom flask, followed by 2 mL of methanol and 8 mL of water. 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. After the solution was clear, it was filtered while hot. The heating was turned off and the mixture was allowed to cool naturally overnight to obtain 0.8 g of an off-white solid.

[0219] Its X-ray powder diffraction pattern is as follows Figure 15 As shown, it is cariprazine hydrochloride form I.

[0220] Example 9: Comparison of stability of related substances and crystal forms

[0221] The cariprazine mono-1-hydroxy-2-naphthoate dihydrate crystal form A prepared in Example 2, the cariprazine bis-1-hydroxy-2-naphthoate hydrate crystal form A prepared in Example 5, the cariprazine pamoate amorphous form prepared in Example 7, and the cariprazine hydrochloride crystal form I prepared in Example 8 were respectively subjected to high temperature (60°C), high humidity (25°C / 90%RH), accelerated (40°C / 75%RH), light (1.2×10 6 Lux·hr) and samples were taken on day 0 and day 10 for HPLC or XRPD analysis.

[0222] The results of related substance detection are shown in Table 1, which show that the changes in related substances of the cariprazine mono-1-hydroxy-2-naphthoate dihydrate crystal form A and the cariprazine bis-1-hydroxy-2-naphthoate hydrate crystal form A of the present invention were within 0.3% after being placed under high temperature, high humidity and accelerated conditions for 10 days, and the increase was less than that of the pamoate under high temperature conditions; similar to the pamoate, the impurities increased slightly under light irradiation, indicating that good stability can still be maintained by taking appropriate light protection measures.

[0223] The results of crystal stability 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 superior crystal stability. After 10 days of storage under various conditions, the crystal form and crystallinity did not change significantly. The cariprazine mono-1-hydroxy-2-naphthoate dihydrate crystal form A of the present invention is relatively stable under high humidity, light, and accelerated conditions, and the crystal form does not change. However, it will transform into the cariprazine mono-1-hydroxy-2-naphthoate crystal form C under high temperature conditions.

[0224] Table 1 Results of related substances

[0225]

[0226]

[0227] Table 2 Crystal stability results

[0228]

[0229] Example 10: Comparison of solubility at different pH values

[0230] The cariprazine mono-1-hydroxy-2-naphthoate dihydrate crystal form A prepared in Example 1A, the cariprazine semi-mono-1-hydroxy-2-naphthoate crystal form C prepared in Example 4, the cariprazine di-1-hydroxy-2-naphthoate hydrate crystal form A prepared in Example 5, the cariprazine pamoate amorphous form prepared in Example 7, the cariprazine hydrochloride crystal form I prepared in Example 8, and cariprazine free base (commercially available) were added to the following media with different pH values, shaken at 37° C. for 24 hours, filtered through a 0.45 μm aqueous filter membrane, and the filtrate collected for solubility determination using high-performance liquid chromatography. Wherein, pH 3, pH 4, pH 5, and pH 6 are acetate buffer solutions, and pH 7, pH 7.4, pH 8, and pH 9 are phosphate buffer solutions.

[0231] The solubility test results are shown in Table 3, which show that the solubility of the cariprazine mono-1-hydroxy-2-naphthoate salt and its crystal form and the cariprazine bis-1-hydroxy-2-naphthoate salt prepared by the present invention is low in the pH range of 3 to 9, and the solubility is significantly lower than that of the hydrochloride salt in the pH range of 3 to 6, and the solubility is significantly lower than that of the pamoate salt in the pH range of 7 to 9. The low solubility allows the release rate of the salt form and crystal form to be minimally dependent on pH, thereby avoiding the influence of the pH environment in different regions of the body on its release rate, avoiding the occurrence of burst release or excessively high blood drug concentration in local areas of the body, and reducing inter-individual drug release variability. In addition, the crystal form of cariprazine 1-hydroxy-2-naphthoate salt has good stability and is suitable for use in long-acting preparations, which can reduce the number of medications and improve patient compliance, and has good market prospects.

[0232] Table 3 Solubility results at different pH

[0233]

[0234]

[0235] Examples 11-14: Suspensions of Cariprazine Mono-1-Hydroxy-2-Naphthoate in Different Doses

[0236]

[0237] Preparation process:

[0238] (1) Weigh the prescribed amount of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, and sodium carboxymethyl cellulose and add approximately 60% of the total amount of water for injection, stir and dissolve;

[0239] (2) Add the prescribed amount of cariprazine mono-1-hydroxy-2-naphthoate crystal form C, optionally adjust the pH to 4.0-9.0 with sodium hydroxide or hydrochloric acid, make up to volume, and stir until completely dispersed to obtain the suspension of Examples 11-14.

[0240] The prescription samples prepared in Examples 11-14 were taken separately for needle permeability, suspensibility, sedimentation ratio and redispersibility. It was found that the above suspension samples could pass through a 0.45*15mm syringe needle, had good suspensibility, a sedimentation ratio greater than 0.9 for at least ten minutes, and good redispersibility (shaking after sedimentation could quickly disperse).

[0241] Examples 15-19: Aqueous suspensions of cariprazine mono-1-hydroxy-2-naphthoate with different Tween dosages

[0242]

[0243] Preparation process:

[0244] (1) Weigh the prescribed amount of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, and sodium carboxymethyl cellulose and add approximately 60% of the total amount of water for injection, stir and dissolve;

[0245] (2) Add the prescribed amount of cariprazine mono-1-hydroxy-2-naphthoate crystal form C, optionally adjust the pH to 4.0-9.0 with sodium hydroxide or hydrochloric acid, make up to volume, and stir until completely dispersed to obtain the suspensions of Examples 15-19.

[0246] The prescription samples prepared in Examples 15-19 were taken respectively for examination of needle permeability, suspensibility, wettability, sedimentation ratio and redispersibility. It was found that the above suspension samples could all pass through a 0.45*15mm syringe needle and had good suspensibility. The samples in Examples 15-19 had a sedimentation ratio greater than 0.9 for at least ten minutes and good redispersibility (shaking after sedimentation could quickly disperse them). The sample drugs in Examples 16-19 had little adhesion to the wall of the vial and had good wettability.

[0247] Examples 20-25: Aqueous Suspensions of Cariprazine 1-Hydroxy-2-Naphthoate with Different Poloxamer Doses

[0248]

[0249] Preparation process:

[0250] (1) Weigh the prescribed amount of poloxamer 188, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, and sodium carboxymethyl cellulose and add approximately 60% of the total amount of water for injection, stirring to dissolve and disperse;

[0251] (2) Add the prescribed amount of cariprazine mono-1-hydroxy-2-naphthoate dihydrate crystal form A or cariprazine bis-1-hydroxy-2-naphthoate hydrate crystal form A, optionally adjust the pH to 4.0-9.0 with sodium hydroxide or hydrochloric acid, fix the volume, and stir until completely dispersed to obtain the suspension of Examples 20-25.

[0252] The prescription samples prepared in Examples 20-25 were taken respectively for needle permeability, suspensibility, wettability, sedimentation ratio and redispersibility. It was found that the above suspension samples could pass through a 0.45*15mm syringe needle, had good suspensibility, little drug adhesion to the wall of the vial, and good wettability. The samples of Examples 20-25 had a sedimentation ratio greater than 0.9 for at least ten minutes and good redispersibility (shaking after sedimentation allowed for rapid dispersion).

[0253] Examples 26-31: Suspensions of Cariprazine Mono-1-Hydroxy-2-Naphthoate with Different Doses of Sodium Carboxymethylcellulose

[0254]

[0255]

[0256] Preparation process:

[0257] (1) Weigh the prescribed amount of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, and sodium carboxymethyl cellulose and add approximately 60% of the total amount of water for injection, stir and dissolve;

[0258] (2) Add the prescribed amount of cariprazine mono-1-hydroxy-2-naphthoate crystal form C, optionally adjust the pH to 4.0-9.0 with sodium hydroxide or hydrochloric acid, make up to volume, and stir until completely dispersed to obtain the suspension of Examples 26-31.

[0259] The prescription samples prepared in Examples 26-31 were taken separately for needle permeability, suspensibility, sedimentation ratio and redispersibility. It was found that the above suspension samples could pass through a 0.45*15mm syringe needle and had good suspensibility. The samples of Examples 26-31 had a sedimentation ratio greater than 0.9 for at least ten minutes and good redispersibility (shaking after sedimentation could quickly disperse them).

[0260] Examples 32 and 33: Suspensions of cariprazine mono-1-hydroxy-2-naphthoate with different PVP K30 dosages

[0261]

[0262] Preparation process:

[0263] (1) Weigh the prescribed amount of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, and PVP K30 and add approximately 60% of the total amount of water for injection, stir and dissolve;

[0264] (2) Add the prescribed amount of cariprazine mono-1-hydroxy-2-naphthoate dihydrate Form A, optionally adjust the pH to 4.0-9.0 with sodium hydroxide or hydrochloric acid, fix the volume, and stir until completely dispersed to obtain the suspensions of Examples 32 and 33.

[0265] The prescription samples prepared in Examples 32 and 33 were taken respectively for examination of needle permeability, suspensibility, sedimentation ratio and redispersibility. It was found that the above suspension samples could all pass through a 0.45*15mm syringe needle and had good suspensibility. The samples of Examples 32 and 33 had a sedimentation ratio greater than 0.9 for at least ten minutes and good redispersibility (shaking after sedimentation could quickly disperse them).

[0266] Examples 34-37: Aqueous suspensions of cariprazine mono-1-hydroxy-2-naphthoate with different particle sizes

[0267]

[0268] Preparation process:

[0269] (1) Weigh the prescribed amount of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, and mannitol and add them to approximately 60% of the total amount of water for injection, stir and dissolve;

[0270] (2) adding a prescribed amount of cariprazine mono-1-hydroxy-2-naphthoate crystal form C to obtain a coarse particle suspension aqueous solution;

[0271] (3) Grinding and dispersing the coarse particle suspension aqueous solutions obtained in Examples 34-37 above respectively using a ball mill;

[0272] (4) Add the prescribed amount of sodium carboxymethyl cellulose to the above suspension, stir until completely dispersed, and adjust the volume to obtain the suspensions of Examples 34-37 with a pH of 7.4±0.2;

[0273] (5) The particle size distribution of the samples of Examples 34-37 was measured using an OMEC LS-909 particle size analyzer. The results are shown in the following table:

[0274] Example Dv10(μm) Dv50(μm) Dv90(μm) Example 34 6.107 16.977 36.631 Example 35 4.502 9.977 18.639 Example 36 0.755 2.193 9.973 Example 37 0.683 1.531 7.104

[0275] According to the results in the table above, it can be seen that in the suspension aqueous solution with the same prescription, by controlling the grinding parameters, suspension aqueous solutions with particles of different particle sizes (Dv90) can be prepared.

[0276] Examples 38-40: Aqueous suspensions of different crystalline forms of cariprazine mono-1-hydroxy-2-naphthoate

[0277]

[0278] Preparation process:

[0279] (1) Weigh the prescribed amount of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, and sodium carboxymethyl cellulose and add approximately 60% of the total amount of water for injection, stir and dissolve;

[0280] (2) Add the prescribed amount of the above-mentioned crystalline form of cariprazine mono-1-hydroxy-2-naphthoate, optionally adjust the pH to 4.0-9.0 with sodium hydroxide or hydrochloric acid, make up to volume, and stir until completely dispersed to obtain the suspension of Examples 38-40.

[0281] The prescription samples prepared in Examples 38-40 were taken separately for needle permeability, suspensibility, sedimentation ratio and redispersibility. It was found that the above suspension samples could pass through a 0.45*15mm syringe needle and had good suspensibility. The samples of Examples 38-40 had a sedimentation ratio greater than 0.9 for at least ten minutes and good redispersibility (shaking after sedimentation could quickly disperse them).

[0282] According to the results in the above table and the investigation of needle permeability, suspensibility, sedimentation ratio and wettability, the mixed aqueous solution with the same prescription is applicable to different crystalline forms of cariprazine mono-1-hydroxy-2-naphthoate.

[0283] Example 41: Stability Study of Cariprazine 1-Hydroxy-2-Naphthoate Aqueous Suspension at 60°C

[0284] 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 taken and tested for related substances at 60° C. on days 0, 5, and 10. The results are shown in the following table:

[0285]

[0286] According to the results in the above table, among the suspension aqueous solutions with the same prescription, the suspension aqueous solution of cariprazine mono-1-hydroxy-2-naphthoate dihydrate crystalline form A is more stable than the suspension aqueous solution of cariprazine bis-1-hydroxy-2-naphthoate hydrate crystalline form A.

[0287] Examples 42-43: Scale-up and stability of aqueous suspensions of cariprazine mono-1-hydroxy-2-naphthoate with different formulations

[0288]

[0289] Preparation process:

[0290] (1) Weigh the prescribed amount of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethyl cellulose /

[0291] PVPK30 is dissolved and dispersed in about 60% of the total amount of injection water, and the volume is adjusted to 200 mL;

[0292] (2) adding the prescribed amount of cariprazine mono-1-hydroxy-2-naphthoate dihydrate crystal form A to obtain a suspension of coarse particles in aqueous solution, and adjusting the volume to 200 mL;

[0293] (3) Grinding and dispersing the coarse particle suspension aqueous solutions obtained in Examples 42 and 43 above respectively using a sand mill;

[0294] (4) The particle size distribution of the samples of Examples 42 and 43 was measured using an OMEC LS-909 particle size analyzer. The results are shown in the following table:

[0295] Example Dv10(μm) Dv50(μm) Dv90(μm) Dv100(μm) Example 42 0.686 0.936 1.618 3.664 Example 43 0.675 0.986 2.166 4.552

[0296] According to the results in the table above, by controlling the grinding parameters, a suspension aqueous solution of particles with a smaller particle size (Dv90) can be prepared.

[0297] The suspension prepared in the above example was subjected to stability tests under conditions such as high temperature (60°C), light, accelerated (40°C / 75%RH), long-term (25°C / 60%RH), and low temperature (2-8°C). The data on the content and particle size are shown in the following table:

[0298]

[0299] The above data show that the sand-grinding samples with different prescriptions have good stability in terms of relevant substances, content and particle size under different conditions. At the same time, the needle-penetrating properties and redispersibility of the above stability samples are good, and no abnormalities are found.

[0300] Example 44: Hydrochloride Dissociation Studies

[0301] The cariprazine hydrochloride crystal form I prepared in Example 8 was added to the corresponding aqueous media at pH 6, pH 7, pH 7.4, pH 8, pH 9, etc., and shaken at 37° C. for 4 hours. The mixture was centrifuged and the residue was subjected to XRPD detection. The results showed that the cariprazine hydrochloride crystal form I dissociated into cariprazine free base. The comparative results of pH 7.4 are shown in FIG. Figure 16 (The rest are not shown). It can be seen that the cariprazine hydrochloride crystal form I is unstable in the solution, and there is a change in the efficacy caused by the change of the crystal form after administration, which reduces the safety of the medication.

[0302] Examples 45-47: Pharmacokinetic Study of Cariprazine 1-Hydroxy-2-Naphthoate Suspension in Rats

[0303]

[0304] The preparation process of Example 42 suspension injection is obtained by referring to Example 42 above.

[0305] 1. Preparation process of suspension injection of Examples 45-46:

[0306] (1) Weigh the prescribed amount of poloxamer 188, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, and sodium carboxymethyl cellulose and add approximately 60% of the total amount of water for injection, stirring to dissolve and disperse;

[0307] (2) adding the corresponding sample of cariprazine mono-1-hydroxy-2-naphthoate dihydrate crystalline form A or cariprazine bis-1-hydroxy-2-naphthoate hydrate crystalline form A in the prescribed amount, stirring until completely dispersed, and adjusting the volume to obtain the suspension injection of Examples 45-46 with a pH of 7.4±0.2;

[0308] 2. Preparation process of suspension injection in Example 47:

[0309] (1) Weigh the prescribed amount of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, and sodium carboxymethyl cellulose and add approximately 60% of the total amount of water for injection, stir and dissolve;

[0310] (2) Add the prescribed amount of cariprazine pamoate amorphous form, stir until completely dispersed, and adjust the volume to obtain the suspension injection of Example 47 with a pH of 7.4±0.2;

[0311] 3. The particle size distribution of the samples of Examples 45-46 was measured using an OMEC LS-909 particle size analyzer. The results are shown in the table below:

[0312] Example Dv10(μm) Dv50(μm) Dv90(μm) Example 45 7.625 15.837 38.015 Example 46 5.847 14.654 32.237

[0313] Example 48: Preparation of Hydrochloride Form I Oral Solution

[0314] (1) Take an appropriate amount of the cariprazine hydrochloride crystal form I sample obtained in Example 8, add it to about 60% of the total amount of water for injection, optionally add 0.1% Tween 20 and 0.35% sodium carboxymethyl cellulose, and stir to disperse;

[0315] (2) Adjust the pH to 5.0 to 5.5 with hydrochloric acid, and make up the volume to obtain the clear oral solution of Example 48.

[0316] Example 49: Pharmacokinetic Experiment

[0317] Examples 45-48: Twelve male SD rats were divided into four groups. Three groups were given a single dose of 9 mg / kg cariprazine mono-1-hydroxy-2-naphthoate (Example 45), cariprazine bis-1-hydroxy-2-naphthoate (Example 46), and cariprazine pamoate (Example 47) by intramuscular injection, and plasma was collected at 0, 1 hour, 3 hours, 7 hours, 24 hours, 4 days, 7 days, 15 days, 20 days, 25 days, and 30 days after administration. The fourth group was given a single dose of 0.3 mg / kg cariprazine hydrochloride Form I (Example 48) by oral gavage, and plasma was collected at 5 minutes, 15 minutes, 30 minutes, 1, 2, 3, 4, 6, 8, 12, and 24 hours after administration. Throughout the experiment, the animals in the intramuscular injection group had free access to food and water, while the animals in the oral gavage group fasted overnight before administration and resumed eating 4 hours after administration.

[0318] Plasma Sample Collection: Approximately 150 μL of blood was collected from the jugular vein (whole blood was centrifuged within 30 minutes to separate the plasma) and placed in a tube containing the anticoagulant EDTA-K2. After processing, the plasma was stored at -70°C until use. After pretreatment, 1 μL of the plasma sample was collected for LC-MS / MS analysis.

[0319] The pharmacokinetic parameters in animals are shown in Tables 4 to 7, and the drug-time curves are shown in Figures 17 to 19 .

[0320] The results showed that the cariprazine hydrochloride oral prescription group absorbed a peak blood concentration of 20 ng / ml within 1 hour after administration, which dropped to 1 ng / ml after 12 hours, and the mean residence time (MRTlast) was only 2.75 hours; the three injection groups of Examples 45, 46, and 47 showed significantly prolonged peak time Tmax and mean residence time (MRTlast) compared with the oral group, with Tmax extended from several hours to several days, and MRTlast of 4.5 days, 6.5 days, and 5.4 days, respectively, which were 39, 57, and 47 times that of the oral experimental group, showing a significant sustained-release effect.

[0321] Example 42: Two groups, three male SD rats and three female SD rats, were each administered a single dose of 9 mg / kg cariprazine mono-1-hydroxy-2-naphthoate (Example 42) via intramuscular injection. Plasma was collected 1 hour, 3 hours, 7 hours, 24 hours, 4 days, 7 days, 10 days, 13 days, 16 days, 19 days, 22 days, 25 days, and 28 days after administration. Throughout the experiment, the animals had free access to food and water.

[0322] Plasma Sample Collection: Blood samples were placed on ice after collection and centrifuged within 1 hour (6800 g, 6 minutes, 2-8°C) to separate plasma into tubes containing the anticoagulant EDTA-K2. Plasma samples were stored at -80°C until analysis. After pretreatment, plasma samples were aspirated for LC-MS / MS analysis.

[0323] The pharmacokinetic parameters in animals are shown in Tables 8 and 9, and the drug-time curves are shown in Figures 20 and 21 .

[0324] The results showed that the two groups of rats of different sexes in the injection group of Example 42 showed significantly prolonged peak time Tmax and mean residence time (MRTlast) compared with the oral group (Example 48, the blood drug concentration reached a peak Cmax of 20 ng / ml within 1 hour, decreased to 1 ng / ml after 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, respectively, which were 51 and 57 times that of the oral experimental group, showing a significant sustained-release effect.

[0325] 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 preparations prepared in this patent would not cause safety hazards such as excessive blood drug concentration after administration, leading to adverse drug reactions; the Cmax value of the injection group of Example 47 was higher, at 50.5 ng / ml, which may pose a safety hazard of certain adverse reaction events.

[0326] In addition, from the perspective of maintaining blood drug concentration, the injection groups of Examples 42, 45 and 46 maintained about 1 ng / ml within 15 to 20 days after administration, while Example 47 could only maintain it for 11 days, indicating that Examples 42, 45 and 46 exerted their efficacy in vivo for a longer time and had a better sustained-release effect than Example 47.

[0327] Furthermore, the AUClast values ​​of male rats in the injection groups of Examples 42, 45 and 46 were 138, 68 and 168 day*ng / mL, respectively, indicating that Examples 42 and 46 have greater advantages in bioavailability than Example 45.

[0328] Table 4. Pharmacokinetic parameters of suspension of cariprazine mono-1-hydroxy-2-naphthoate dihydrate crystalline form A (Example 45) injected intramuscularly in rats

[0329] Pharmacokinetic parameters unit Rat#1 Rat#2 Rat#3 average Standard deviation SD Coefficient of variation (%) <![CDATA[T max ]]> day 4.00 0.292 0.125 1.47 2.19 149 <![CDATA[C max ]]> ng / mL 24.3 3.21 11.5 13.0 10.6 81.7 <![CDATA[T 1 / 2 ]]> day 4.09 NA 2.50 3.30 NA NA <![CDATA[AUC last ]]> day*ng / mL 177 3.48 23.9 68.3 95.1 139 <![CDATA[AUC INF ]]> day*ng / mL 178 NA 25.2 102 NA NA <![CDATA[MRT INF ]]> day 5.93 NA 3.78 4.85 NA NA <![CDATA[MRT last ]]> day 5.79 NA 3.18 4.49 NA NA

[0330] Table 5. Pharmacokinetic parameters of cariprazine bis-1-hydroxy-2-naphthoate dihydrate suspension Form A (Example 46) after intramuscular injection in rats

[0331]

[0332] Table 6. Pharmacokinetic parameters of cariprazine pamoate amorphous suspension (Example 47) injected intramuscularly in rats

[0333]

[0334] Table 7. Pharmacokinetic parameters of oral administration of cariprazine hydrochloride crystal form I oral solution (Example 48) in rats

[0335]

[0336] Table 8. Pharmacokinetic parameters of suspension of cariprazine mono-1-hydroxy-2-naphthoate dihydrate crystalline form A (Example 42) injected intramuscularly in male rats

[0337]

[0338] Table 9. Pharmacokinetic parameters of suspension of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, Form A (Example 42) injected intramuscularly into female rats

[0339]

[0340] The above is an exemplary description of the implementation methods of the technical solution of the present invention. It should be understood that the scope of protection of the present invention is not limited to the above implementation methods. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present invention shall be included in the scope of protection of the claims of this application.

Claims

1. A pharmaceutically acceptable salt of cariprazine, wherein the pharmaceutically acceptable salt is selected from cariprazine mono-1-hydroxy-2-naphthoate salt represented by the following formula (I), cariprazine bis-1-hydroxy-2-naphthoate salt represented by the following formula (II), or cariprazine pamoate salt represented by the following formula (III):

2. The pharmaceutically acceptable salt according to claim 1, wherein The pharmaceutically acceptable salt is selected from at least one of the following forms: 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°, and 19.5°±0.2°; Amorphous form of cariprazine bis-1-hydroxy-2-naphthoate; an amorphous form of cariprazine pamoate; The crystalline form H of cariprazine pamoate has an X-ray powder diffraction pattern of the crystalline form H of cariprazine pamoate having 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°, and 22.9°±0.2°.

3. The pharmaceutically acceptable salt according to claim 1, wherein 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.; Preferably, the X-ray powder diffraction pattern of the crystalline form B of the 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 the crystalline form B of the 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 the crystalline form B of the 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°, and 24.3°±0.2°; More preferably, the crystalline form B of cariprazine mono-1-hydroxy-2-naphthoate has an X-ray powder diffraction pattern substantially as shown in FIG4 ; Preferably, the crystalline form B of cariprazine mono-1-hydroxy-2-naphthoate has a differential scanning calorimetry pattern substantially as shown in FIG5 ; Preferably, the melting point of the crystalline form B of cariprazine mono-1-hydroxy-2-naphthoate is about 106.8°C.

4. The pharmaceutically acceptable salt of any one of claims 1 to 3, wherein the crystalline Form H of cariprazine pamoate has an X-ray powder diffraction pattern substantially as shown in Figure 13; Alternatively, the cariprazine pamoate is in an amorphous form, preferably having an X-ray powder diffraction pattern substantially as shown in FIG. 14 .

5. A method for preparing the crystalline form B of cariprazine mono-1-hydroxy-2-naphthoate according to claim 2 or 3, comprising the following steps: (b1) mixing cariprazine and 1-hydroxy-2-naphthoic acid with a solvent in a molar ratio of 1:1; (b2) stirring at 25-70° C. to obtain the cariprazine mono-1-hydroxy-2-naphthoate crystalline form B; Preferably, the solvent is a mixture of methanol, ethanol or acetone and water; Preferably, the volume ratio of methanol, ethanol or acetone to water may be 2:1 to 1:2, such as 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, such as 1 g:0.5-1.5 mL, for example 1 g:1 mL.

6. A combination of a pharmaceutically acceptable salt of cariprazine, wherein the combination comprises: At least one, for example two or three, of the pharmaceutically acceptable salts of any one of claims 1 to 4; and the optional presence or absence of other pharmaceutically acceptable salts of cariprazine, or other forms of said cariprazine mono-1-hydroxy-2-naphthoate, cariprazine bis-1-hydroxy-2-naphthoate, or cariprazine pamoate; Preferably, based on the total weight of the pharmaceutically acceptable salt of cariprazine in the combination, 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 4 is greater than the content of other salt forms or crystalline forms of cariprazine; For example, based on the total weight of the pharmaceutically acceptable salt of cariprazine in the combination, 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 4 is above 80%, preferably above 90%, more preferably above 95% or 99%.

7. A pharmaceutical composition comprising the pharmaceutically acceptable salt according to any one of claims 1 to 4, preferably comprising cariprazine mono-1-hydroxy-2-naphthoate, cariprazine bis-1-hydroxy-2-naphthoate, cariprazine pamoate or one of their crystalline forms. Preferably, the pharmaceutical composition comprises cariprazine solid particles, the particle size of the cariprazine solid particles is Dv(10)≤30 microns, Dv(50)≤50 microns and Dv(90)≤100 microns, preferably ≤50 microns; wherein, The cariprazine solid particles can be selected from the cariprazine mono-1-hydroxy-2-naphthoate, cariprazine bis-1-hydroxy-2-naphthoate, cariprazine pamoate or one of their crystalline forms according to any one of claims 1 to 4; Preferably, the pharmaceutical composition of cariprazine may comprise the following components: (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; (f) mannitol; Also, optionally, the pharmaceutical composition of cariprazine may comprise a pH adjuster, such as sodium hydroxide or hydrochloric acid; Preferably, the pH of the cariprazine pharmaceutical composition may be 4.0 to 9.0; More preferably, the pharmaceutical composition of cariprazine is a suspension or a suspending agent, preferably an aqueous suspension or an aqueous suspending agent; More preferably, the pharmaceutical composition of cariprazine is an injection, such as a long-acting injection; For example, in the pharmaceutical composition or injection of cariprazine, the mass volume concentration of the cariprazine solid particles is not less than 30 mg / mL, such as 30 to 120 mg / mL, preferably 90 mg / mL.

8. Use of a combination of the pharmaceutically acceptable salt of any one of claims 1 to 4, the pharmaceutically acceptable salt of cariprazine according to claim 6, or the pharmaceutical composition according to claim 7 in the preparation of a medicament, wherein the medicament is used to treat and / or prevent cognitive impairment or mental disorders, such as psychosis, bipolar disorder, or acute mania.

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