Cariprazine Medicinal Salt and Its Crystal Forms, Pharmaceutical Composition, Preparation Method and Use

Abstract

The present invention provides 1-hydroxy-2-naphthoate or pamoate of cariprazine, and / or its new solid forms, as well as its pharmaceutical compositions, preparation methods and uses. The salts and solid forms of cariprazine provided by the present invention, especially cariprazine 1-hydroxy-2-naphthoate among the poorly soluble salts of cariprazine, conform to the advantages of long-acting sustained-release preparations, can be developed into suspension injections, and at the same time can overcome the risks of dissociation of existing salt forms such as cariprazine hydrochloride or the problem of not having a sustained-release effect, can achieve the effect of long-term drug administration, and greatly improve the compliance of patients as well as the bioavailability and drug safety of the drug.

Description

[0001] This application claims the priority benefit of a prior application with the application number 202210162007.8 and the title "Cariprazine Medicinal Salt and Its Crystal Forms, Pharmaceutical Composition, Preparation Method and Use", which was filed by the applicant with the China National Intellectual Property Administration on February 22, 2022. The full text of the above prior application is incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of chemical medicine, and specifically relates to cariprazine medicinal salt and its crystal forms, pharmaceutical composition, preparation method and use. Background Art

[0003] Cariprazine, whose chemical structure is shown below, is a novel atypical antipsychotic drug that antagonizes dopamine D3, dopamine D2 and serotonin 2B receptors. It can be used for the treatment of schizophrenia and type 1 bipolar disorder. Currently, the marketed product is cariprazine hydrochloride capsules, which are oral preparations and need to be administered daily to maintain its blood drug concentration. However, due to the need for frequent administration, the medication compliance of patients is poor.

[0004]

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

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

[0007] Patent WO2020056929A discloses a new crystal form of cariprazine hydrochloride, which mentions that cariprazine hydrochloride will quickly dissociate into free base in a pH 6.5 buffer solution.

[0008] Patent document CN108261394A discloses a cariprazine injection preparation, including the forms of suspension aqueous solution and freeze-dried agent, and can obtain sustained release for at least 1 week or longer. However, the inventors found during the research process that: the stability of the cariprazine aqueous solution is not ideal enough, and dissociation will occur under weak acidic to alkaline conditions. Therefore, there is a risk of dissociation in the suspension aqueous solution, which is likely to cause changes in the properties and quality of the product, resulting in changes in drug dissolution and absorption, affecting the efficacy of the drug and the medication safety of patients, and is not suitable for long-acting sustained-release preparations. Moreover, the cariprazine concentration in the cariprazine injection preparation disclosed in patent document CN108261394A, the dosing concentration, and the blood drug concentration in the animal pK experiment are too high. Considering the large inter-species differences in the elimination of cariprazine in the original research data (about 2 - 4 hours in rats and 3 - 9 days in humans), the too high blood drug concentration may lead to greater toxic and side effects and excessive accumulation of drugs in the human body.

[0009] Currently, no reports on injection preparations of poorly soluble salts of cariprazine with improved performance have been found.

[0010] In view of the deficiencies in the existing technology, finding cariprazine pharmaceutical salts and their crystal forms with low solubility, suitable for long-acting drug administration, high stability, good clinical effects, and / or suitable for commercialization is a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0011] To improve the above problems existing in the prior art, the present invention provides pharmaceutically acceptable salts of cariprazine, especially 1-hydroxy-2-naphthoate of cariprazine or ditanate of cariprazine, and / or their new solid forms, as well as their pharmaceutical compositions, preparation methods, and uses.

[0012] According to an embodiment of the present invention, the 1-hydroxy-2-naphthoate of cariprazine is selected from cariprazine mono-1-hydroxy-2-naphthoate shown in the following formula (I) or cariprazine bis-1-hydroxy-2-naphthoate shown in the following formula (II):

[0013]

[0014] According to an embodiment of the present invention, the cariprazine 1-hydroxy-2-naphthoate is polymorph A of cariprazine mono-1-hydroxy-2-naphthoate, preferably polymorph A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably polymorph A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate; wherein, the X-ray powder diffraction pattern of polymorph A of cariprazine mono-1-hydroxy-2-naphthoate, preferably polymorph A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably polymorph 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] Further, the X-ray powder diffraction pattern of polymorph A of cariprazine mono-1-hydroxy-2-naphthoate, preferably polymorph A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably polymorph 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.

[0016] Further, the X-ray powder diffraction pattern of polymorph A of cariprazine mono-1-hydroxy-2-naphthoate, preferably polymorph A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably polymorph 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.

[0017] Still further, the X-ray powder diffraction pattern of polymorph A of cariprazine mono-1-hydroxy-2-naphthoate, preferably polymorph A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably polymorph A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate has absorption peaks at 2θ values of 4.4°±0.2°, 8.6°±0.2°, 9.7°±0.2°, 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.

[0018] Furthermore, the crystal form A of cariprazine mono-1-hydroxy-2-naphthoate, preferably the crystal form A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably the crystal form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate has substantially as Figure 1 the X-ray powder diffraction pattern shown.

[0019] Preferably, the crystal form A of cariprazine mono-1-hydroxy-2-naphthoate, preferably the crystal form A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably the crystal form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate has substantially as Figure 2 the differential scanning calorimetry pattern shown.

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

[0021] Preferably, the crystal form A of cariprazine mono-1-hydroxy-2-naphthoate, preferably the crystal form A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably the crystal form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate has substantially as Figure 2 the thermogravimetric analysis pattern shown, which shows a weight loss of about 4.82% before 100 °C.

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

[0023] Furthermore, in the crystal form A of cariprazine mono-1-hydroxy-2-naphthoate, preferably the crystal form A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably the crystal form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, cariprazine and 1-hydroxy-2-naphthoic acid form a salt in a molar ratio of 1:1, and its 1 1H-NMR spectrum is substantially as Figure 3 shown.

[0024] The present invention also provides a single crystal of the crystal form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate. 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.

[0025] Further, 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.

[0026] Further, 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.

[0027] 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°, 29.6° ± 0.2°, etc.

[0028] According to an embodiment of the present invention, there is also 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 following steps:

[0029] (a1) Dissolve cariprazine in an aqueous phosphoric acid solution, and filter to obtain solution A; mix an aqueous solution of 1-hydroxy-2-naphthoic acid with an aqueous sodium hydroxide solution, and filter to obtain solution B;

[0030] (a2) Add solution B to solution A according to a solute molar ratio of 1:1, and stir 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.

[0031] Alternatively, the 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, comprises the following steps:

[0032] (a3) Mix cariprazine with 1-hydroxy-2-naphthoic acid in a molar ratio of 1:1 with a solvent;

[0033] (a4) Stir at 25 - 70 °C to obtain polymorph A of cariprazine mono-1-hydroxy-2-naphthoate, preferably polymorph A of cariprazine mono-1-hydroxy-2-naphthoate hydrate, more preferably polymorph A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate.

[0034] According to an embodiment of the present invention, the solvent is a mixed system 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.

[0035] Preferably, the mass-volume ratio of cariprazine to the total volume of the solvent system is 1 g:5 - 30 mL, such as 1 g:5 - 20 mL, for example 1 g:10 mL.

[0036] According to an embodiment of the present invention, the cariprazine 1-hydroxy-2-naphthoate is polymorph B of cariprazine mono-1-hydroxy-2-naphthoate, and the X-ray powder diffraction pattern of polymorph 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.

[0037] Furthermore, the X-ray powder diffraction pattern of polymorph 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.

[0038] Furthermore, the X-ray powder diffraction pattern of polymorph 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.

[0039] Further, 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°, etc.

[0040] Further, crystalline form B of cariprazine mono-1-hydroxy-2-naphthoate has substantially as Figure 4 the X-ray powder diffraction pattern shown.

[0041] Preferably, crystalline form B of cariprazine mono-1-hydroxy-2-naphthoate has substantially as Figure 5 the differential scanning calorimetry pattern shown.

[0042] Preferably, the melting point of crystalline form B of cariprazine mono-1-hydroxy-2-naphthoate is about 106.8 °C.

[0043] Further, in crystalline form B of 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 1 1H-NMR spectrum is substantially as Figure 6 shown.

[0044] According to an embodiment of the present invention, the preparation method of crystalline form B of cariprazine mono-1-hydroxy-2-naphthoate comprises the following steps:

[0045] (b1) Mix cariprazine and 1-hydroxy-2-naphthoic acid in a molar ratio of 1:1 with a solvent;

[0046] (b2) Stir at 25-70 °C to obtain crystalline form B of cariprazine mono-1-hydroxy-2-naphthoate.

[0047] According to an embodiment of the present invention, the solvent is a mixed system 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.

[0048] Preferably, the mass-to-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.

[0049] 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, 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.

[0050] Furthermore, 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.

[0051] Furthermore, 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°, 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.

[0052] Even further, according to an embodiment of the present invention, 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°, 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.

[0053] Even further, the crystalline form C of cariprazine mono-1-hydroxy-2-naphthoate has substantially as Figure 7 shown in the X-ray powder diffraction pattern.

[0054] Preferably, the crystalline form C of cariprazine mono-1-hydroxy-2-naphthoate has substantially as Figure 8 shown in the differential scanning calorimetry chart.

[0055] Preferably, the melting point of the crystalline form C of cariprazine mono-1-hydroxy-2-naphthoate is about 103.4 °C.

[0056] According to an embodiment of the present invention, in the crystalline form C of 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 1 1H-NMR spectrum is substantially as Figure 9 shown.

[0057] According to an embodiment of the present invention, the method for preparing the crystalline form C of cariprazine mono-1-hydroxy-2-naphthoate comprises the following steps:

[0058] (c1) Mixing cariprazine and 1-hydroxy-2-naphthoic acid in a molar ratio of 1:1 with a solvent;

[0059] (c2) Stirring at 25-70 °C to obtain the crystalline form C of cariprazine mono-1-hydroxy-2-naphthoate.

[0060] According to an embodiment of the present invention, the solvent is a mixed system 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.

[0061] Preferably, the mass-volume ratio of cariprazine to the total volume of the solvent system is 1 g:5-30 mL, such as 1 g:5-20 mL, for example 1 g:10 mL.

[0062] According to an embodiment of the present invention, the cariprazine 1-hydroxy-2-naphthoate is the cariprazine bis-1-hydroxy-2-naphthoate as shown in the above formula (II), wherein the molar ratio of cariprazine to 1-hydroxy-2-naphthoic acid is 1:2.

[0063] According to an embodiment of the present invention, the cariprazine bis-1-hydroxy-2-naphthoate can be in a solid form, such as an amorphous or crystalline form.

[0064] 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, and 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°, 20.8°±0.2°, etc.

[0065] 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.

[0066] 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.

[0067] Still further, 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°, etc.

[0068] Still further, crystalline form A of cariprazine bis(1-hydroxy-2-naphthoate) has substantially as Figure 10 shown in the X-ray powder diffraction pattern.

[0069] Preferably, crystalline form A of cariprazine bis(1-hydroxy-2-naphthoate) has substantially as Figure 11 shown in the differential scanning calorimetry chart.

[0070] Preferably, the melting point of crystalline form A of cariprazine bis(1-hydroxy-2-naphthoate) is about 86.3 °C.

[0071] Preferably, the thermogravimetric analysis chart of crystalline form A of cariprazine bis(1-hydroxy-2-naphthoate) is substantially as Figure 11 shown, showing a weight loss of about 1.31% before 100 °C.

[0072] Preferably, crystalline form A of cariprazine bis(1-hydroxy-2-naphthoate) is a hydrate of cariprazine bis(1-hydroxy-2-naphthoate).

[0073] Preferably, the 1 1H-NMR chart of crystalline form A of cariprazine bis(1-hydroxy-2-naphthoate) is substantially as Figure 12 shown, showing that cariprazine forms a salt with 1-hydroxy-2-naphthoic acid in a molar ratio of 1:2.

[0074] 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:

[0075] 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 crystalline form A of cariprazine bis(1-hydroxy-2-naphthoate).

[0076] The solvent is a mixed system 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.

[0077] Preferably, the mass-to-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.

[0078] According to an embodiment of the present invention, the cariprazine bis(hydroxynaphthoate) has the structure shown in the following formula (III):

[0079]

[0080] According to an embodiment of the present invention, in the cariprazine bis(hydroxynaphthoate), the molar ratio of cariprazine to bis(hydroxynaphthoic acid) is 1:1.

[0081] According to an embodiment of the present invention, the cariprazine bis(hydroxynaphthoate) is crystalline form H of cariprazine bis(hydroxynaphthoate), and the X-ray powder diffraction pattern of crystalline form H of cariprazine bis(hydroxynaphthoate) 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.

[0082] Furthermore, crystalline form H of the cariprazine bis(hydroxynaphthoate) has an X-ray powder diffraction pattern substantially as Figure 13 shown.

[0083] According to an embodiment of the present invention, the cariprazine bis(hydroxynaphthoate) is an amorphous substance, which preferably has an X-ray powder diffraction pattern substantially as Figure 14 shown.

[0084] According to an embodiment of the present invention, the solid form includes crystalline or amorphous (non-crystalline) forms of pharmaceutically acceptable salts of cariprazine, which may be anhydrates, hydrates or solvates. When present, the molar ratio of the salt to water molecules or solvent molecules in its solid form can vary within the range of 1:0.5 to 1:5 (such as 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3), and this molar ratio can also be obtained by detection methods well-known to those skilled in the art.

[0085] The present invention also provides a combination of pharmaceutically acceptable salts of cariprazine, which includes at least one of the pharmaceutically acceptable salts of cariprazine or its solid forms described above, such as two or three, 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.

[0086] According to an embodiment of the present invention, based on the total weight of the pharmaceutically acceptable salts of cariprazine in the combination, the weight percentage content of the crystalline form of the above-mentioned cariprazine mono-1-hydroxy-2-naphthoate or cariprazine bis-1-hydroxy-2-naphthoate is greater than the content of other salt forms or crystalline forms of cariprazine.

[0087] For example, based on the total weight of the pharmaceutically acceptable salts of cariprazine in the combination, the weight percentage content of the crystalline form of the above-mentioned cariprazine mono-1-hydroxy-2-naphthoate or cariprazine bis-1-hydroxy-2-naphthoate is above 80%, preferably above 90%, more preferably 95% or 99% or above.

[0088] The present invention also provides a pharmaceutical composition, which contains the pharmaceutically acceptable salts of cariprazine as described above, preferably contains one of cariprazine mono-1-hydroxy-2-naphthoate, cariprazine bis-1-hydroxy-2-naphthoate, cariprazine pamoate or its crystalline form.

[0089] The present invention also provides a pharmaceutical composition of cariprazine, which contains cariprazine solid particles, and the particle size Dv(10) of the cariprazine solid particles ≤ 30 microns, Dv(50) ≤ 50 microns and Dv(90) ≤ 100 microns, preferably ≤ 50 microns;

[0090] The cariprazine solid particles can be selected from one of the cariprazine mono-1-hydroxy-2-naphthoate, cariprazine bis-1-hydroxy-2-naphthoate, cariprazine pamoate or its crystalline form as described above.

[0091] 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 ditartrate.

[0092] According to an embodiment of the present invention, the solid particles of cariprazine can be in amorphous or crystalline form.

[0093] According to an embodiment of the present invention, the pharmaceutical composition of cariprazine may further include excipients, and the excipients can be selected from one or more of suspending agents, wetting agents, osmotic pressure regulators, solvents, and buffers.

[0094] 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, such as 5.0 mg / mL or 7.5 mg / mL.

[0095] According to an embodiment of the present invention, the suspending agent is selected from one or more of sodium carboxymethyl cellulose, methyl cellulose, and polyvinylpyrrolidone, and preferably sodium carboxymethyl cellulose.

[0096] 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.

[0097] 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, and preferably poloxamer 188.

[0098] According to an embodiment of the present invention, the concentration range of the osmotic pressure regulator is 20 to 30 mg / mL, preferably 23 mg / mL to 26 mg / mL, such as 23 mg / mL, 24.7 mg / mL, or 26 mg / mL.

[0099] According to an embodiment of the present invention, the osmotic pressure regulator is selected from one or more of sodium chloride, mannitol, and sucrose.

[0100] 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, such as 1 mg / mL, 3 mg / mL, 5 mg / mL, or 7.0 mg / mL.

[0101] According to an embodiment of the present invention, the buffer is selected from one or more of phosphoric acid, phosphates, citric acid, sodium citrate, hydrochloric acid, and sodium hydroxide.

[0102] According to an embodiment of the present invention, the solvent is water, such as water for injection.

[0103] As an example, the pharmaceutical composition of cariprazine may comprise the following components:

[0104] (a) Cariprazine 1-hydroxy-2-naphthoate;

[0105] (b) Sodium carboxymethylcellulose or PVP K30;

[0106] (c) Tween 20 or poloxamer 188;

[0107] (d) Disodium hydrogen phosphate;

[0108] (e) Sodium dihydrogen phosphate;

[0109] (f) Mannitol;

[0110] And, optionally, the pharmaceutical composition of cariprazine may comprise a pH adjuster, such as sodium hydroxide or hydrochloric acid.

[0111] According to an embodiment of the present invention, the pH of the pharmaceutical composition of cariprazine may be 4.0 to 9.0, such as 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5 or 9.0.

[0112] According to an embodiment of the present invention, the pharmaceutical composition of cariprazine is an injection, such as a long-acting injection.

[0113] 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.

[0114] 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.

[0115] According to an embodiment of the present invention, the preparation method of the pharmaceutical composition of cariprazine comprises mixing the components.

[0116] Preferably, the preparation method of the pharmaceutical composition of cariprazine comprises the following steps:

[0117] (1) Optionally, dissolve the suspending agent, wetting agent, buffer, and osmotic pressure regulator in the solvent;

[0118] (2) Add cariprazine solid particles to obtain a suspension aqueous solution of coarse particles;

[0119] (3) Optionally, grind the above-mentioned coarse particle suspension aqueous solution using a ball mill to obtain a fine particle suspension;

[0120] (4) Optionally, add a suspending agent to the above-mentioned fine particle suspension, mix well, optionally adjust the pH to 4.0 - 9.0 with sodium hydroxide or hydrochloric acid, and make up the volume to obtain a suspension aqueous solution.

[0121] 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 the solvent in sequence, for example, dissolved in water for injection.

[0122] According to an embodiment of the preparation method of the present invention, in step (4), the adjusted pH can be 4.0 - 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.

[0123] The present invention provides the use of the above-mentioned cariprazine mono-1-hydroxy-2-naphthoate, cariprazine bis-1-hydroxy-2-naphthoate, cariprazine dinaphthoate or its crystal form, a combination of pharmaceutically acceptable salts of cariprazine, or one of the pharmaceutical compositions of cariprazine in the preparation of a drug, wherein the drug is used for the treatment and / or prevention of cognitive impairment or mental disorders, such as psychosis, bipolar disorder, and acute mania.

[0124] The present invention also provides a method for the treatment and / or prevention of cognitive impairment or mental disorders, such as psychosis, bipolar disorder, or acute mania, comprising administering to a patient in need one of the above-mentioned cariprazine mono-1-hydroxy-2-naphthoate, cariprazine bis-1-hydroxy-2-naphthoate, cariprazine dinaphthoate or its crystal form, or the pharmaceutical composition of cariprazine.

[0125] According to an embodiment of the present invention, the "Dv(10)", "Dv(50)", "Dv(90)", and "Dv(100)" refer to volume-weighted particle diameters, wherein when measuring, 10 v / v%, 50 v / v%, 90 v / v%, or 100 v / v% of the particles have equal or smaller diameters respectively. For example, if the Dv(50) of a particle population is about 25 microns, then 50% of the volume of the particles has a diameter less than or equal to about 25 microns.

[0126] On the basis of not violating the spirit of the present invention, those skilled in the art can combine the above-mentioned preferred conditions to obtain various preferred examples of the present invention.

[0127] The reagents and raw materials used in the present invention are all commercially available.

[0128] According to an embodiment of the present invention, the room temperature refers to an ambient temperature of 10°C to 35°C.

[0129] Beneficial effects

[0130] Through a large amount of research, screening, and experimentation, the inventors found that the salts of cariprazine and their solid forms provided by the present invention, especially cariprazine 1-hydroxy-2-naphthoate in poorly soluble salts of cariprazine, meet the advantages of long-acting sustained-release formulations and can be developed into suspension injections. At the same time, it can overcome the risks of dissociation of existing salt forms such as cariprazine hydrochloride or the problem of non-sustained release effect, achieving the effect of long-acting drug administration, greatly improving patient compliance, as well as the bioavailability and drug safety of the drug.

[0131] The salts of cariprazine and their pharmaceutical compositions of the present invention have characteristics such as sustained release effect, high bioavailability, good solution stability, and small administration volume. Administering once can sustain the release of cariprazine for at least three weeks or longer. Therefore, it has good market prospects. Description of the drawings

[0132] Figure 1 XRPD pattern of crystal form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate;

[0133] Figure 2 DSC / TGA pattern of crystal form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate;

[0134] Figure 3 For the crystal form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate 1 1H-NMR spectrum;

[0135] Figure 4 XRPD pattern of crystal form B of cariprazine mono 1-hydroxy-2-naphthoate;

[0136] Figure 5 DSC pattern of crystal form B of cariprazine mono 1-hydroxy-2-naphthoate;

[0137] Figure 6 For the crystal form B of cariprazine mono 1-hydroxy-2-naphthoate 1 1H-NMR spectrum;

[0138] Figure 7 XRPD pattern of crystal form C of cariprazine mono 1-hydroxy-2-naphthoate;

[0139] Figure 8 DSC pattern of crystal form C of cariprazine mono 1-hydroxy-2-naphthoate;

[0140] Figure 9For the 1 1 H-NMR spectrum of cariprazine bis(1-hydroxy-2-naphthoate) polymorph C;

[0141] Figure 10 XRPD pattern of cariprazine bis(1-hydroxy-2-naphthoate) hydrate polymorph A;

[0142] Figure 11 DSC / TGA pattern of cariprazine bis(1-hydroxy-2-naphthoate) hydrate polymorph A;

[0143] Figure 12 For the 1 1 H-NMR spectrum of cariprazine bis(1-hydroxy-2-naphthoate) hydrate polymorph A;

[0144] Figure 13 XRPD pattern of cariprazine bis(1-hydroxy-2-naphthoate) polymorph H;

[0145] Figure 14 XRPD pattern of amorphous cariprazine bis(1-hydroxy-2-naphthoate);

[0146] Figure 15 XRPD pattern of cariprazine hydrochloride polymorph I;

[0147] Figure 16 Overlay XRPD pattern of the dissociation study of cariprazine hydrochloride under pH 7.4 conditions in Example 44, where A is cariprazine free base; B is cariprazine hydrochloride polymorph I; C is the sample of cariprazine hydrochloride polymorph I after oscillation in pH 7.4 medium;

[0148] Figure 17 Graph showing the relationship between the average plasma concentration of cariprazine and time for the oral liquid sample of the formulation in Example 48 of the present invention in rats;

[0149] Figure 18 Graph showing the relationship between the average plasma concentration of cariprazine and time for the injection samples of the formulations in Examples 45 - 47 of the present invention in rats, where ■ is cariprazine mono(1-hydroxy-2-naphthoate) dihydrate polymorph A; is cariprazine bis(1-hydroxy-2-naphthoate) hydrate polymorph A; ◆ is amorphous cariprazine bis(1-hydroxy-2-naphthoate);

[0150] Figure 19 : Figure 18 Partial enlarged view (graph showing the relationship between the average plasma concentration of cariprazine and time from 0 to 24 hours, where ■ is cariprazine mono(1-hydroxy-2-naphthoate) dihydrate polymorph A; is cariprazine bis(1-hydroxy-2-naphthoate) hydrate polymorph A; ◆ is amorphous cariprazine bis(1-hydroxy-2-naphthoate);

[0151] Figure 20 : To describe the relationship diagram of the average blood drug concentration of cariprazine with time for the injection sample of the formulation in Example 42 of the present invention in male and female rats. Among them, ■ is the relationship diagram of crystalline form A of cariprazine monohydrate 1-hydroxy-2-naphthoate dihydrate in male rats; ▲ is the relationship diagram of crystalline form A of cariprazine monohydrate 1-hydroxy-2-naphthoate dihydrate in female rats;

[0152] Figure 21 : Figure 18 Partial enlarged view (relationship diagram of the average blood drug concentration of cariprazine with time from 0 to 24 hours. Among them, ■ is the relationship diagram of crystalline form A of cariprazine monohydrate 1-hydroxy-2-naphthoate dihydrate in male rats; ▲ is the relationship diagram of crystalline form A of cariprazine monohydrate 1-hydroxy-2-naphthoate dihydrate in female rats;

[0153] Figure 22 is the X-ray diffraction pattern of single crystal of crystalline form A of cariprazine monohydrate 1-hydroxy-2-naphthoate dihydrate;

[0154] Figure 23 is the ellipsoid diagram of the three-dimensional molecular structure of the single crystal of cariprazine monohydrate 1-hydroxy-2-naphthoate dihydrate;

[0155] Figure 24 is the projection diagram of the unit cell packing of the single crystal of cariprazine monohydrate 1-hydroxy-2-naphthoate dihydrate along the b-axis direction. Detailed implementation mode

[0156] The present invention will be further described below by way of examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0157] Nuclear magnetic resonance ( 1 1H-NMR), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and high performance liquid chromatography (HPLC) were respectively used to test the salt-type compounds of the examples, and the test parameters are as follows:

[0158] (1) 1 The 1H-NMR test was carried out on a Bruker NMR spectrometer model Bruker Advance III 500M, the measurement frequency was 400 Mz, and the solvent used was deuterated DMSO.

[0159] (2) The DSC measurement was carried out on a hermetic pan device of TA Instruments model 25. The sample (about 1 - 2 mg) was 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 heated to 230 - 300 °C at a rate of 10 - 20 °C / min, and data was collected. The experimental atmosphere was nitrogen.

[0160] (3) The TGA measurement was carried out on a TA Instruments model 55 device. The sample (about 2 - 5 mg) was 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 was collected. The experimental atmosphere was nitrogen.

[0161] (4) The XRPD measurement was carried out on a Bruker D8 Advance X-ray powder diffractometer and a circular zero-background single-crystal silicon sample stage was used. 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° - 45°, scanning step 0.02°, and the scanning mode was continuous scanning.

[0162] (5) Single-crystal detection method: Referring to the first method in General Chapter 0451 of the Fourth Part of the Chinese Pharmacopoeia 2020 Edition, single-crystal X-ray diffraction analysis was carried out 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°, and the scanning mode was scanning step 0.5°.

[0163] (6) HPLC content and related substances detection method:

[0164] Content method:

[0165]

[0166] Content gradient elution program table:

[0167]

[0168]

[0169] Related substances method:

[0170]

[0171] Related gradient elution program table:

[0172] 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

[0173] Unless otherwise specified, the detection conditions of the particle size detection instrument for the suspension aqueous solution of the cariprazine pharmaceutical composition in the context of the present invention are as follows:

[0174] Name of injector: SCF-105B Substance name: Pharmaceutical composition of cariprazine

[0175] Particle refractive index: 1.595 Dispersant refractive index: 1.333

[0176] Dispersant: Water Background test time: 10 s

[0177] Sample test time: 10 s Light obscuration: 10 - 20%

[0178] Stirring speed: 600 - 2000 r / min Analysis model: General

[0179] Measurement range: 0.02 - 2100 μm Particle absorption rate: 0.1

[0180] Measure three times repeatedly and create an average value.

[0181] Example 1A: Preparation of polymorph A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate

[0182] Take 0.5 g of cariprazine free base in a 10 mL centrifuge tube, add 4 mL of pure aqueous solution, then add 1 mL of phosphoric acid solution with a concentration of 100 mL / mL, dissolve by ultrasound, filter into a 30 mL vial to obtain solution A; take 0.22 g of 1-hydroxy-2-naphthoic acid in a 5 mL centrifuge tube, add 4 mL of pure aqueous solution, then add 0.936 mL of sodium hydroxide solution with a concentration of 50 mg / mL, dissolve by ultrasound to obtain solution B. Slowly filter solution B into solution A under stirring conditions, a grayish-brown solid precipitates, stir overnight at room temperature, filter by suction, and dry under reduced pressure at 40 °C overnight to obtain 0.7 g of cariprazine mono-1-hydroxy-2-naphthoate polymorph A, with a yield of 97% and an HPLC purity of 99.19%.

[0183] Its X-ray powder diffraction pattern is as Figure 1 shown.

[0184] Its differential scanning calorimetry analysis pattern is as Figure 2 shown, showing a melting point of about 101.3 °C.

[0185] Its thermogravimetric analysis pattern is as Figure 2 shown, showing a weight loss of about 4.82% before 100 °C, attributed to the loss of crystal water and adsorbed water, and this polymorph A is cariprazine mono-1-hydroxy-2-naphthoate dihydrate.

[0186] Its NMR spectrum is as Figure 3 Figure 3As shown, cariprazine forms a salt with 1-hydroxy-2-naphthoic acid in a molar ratio of 1:1.

[0187] Example 1B: Preparation of single crystal of polymorph A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate

[0188] Take 0.25 g of cariprazine free base and 0.1075 g of 1-hydroxy-2-naphthoic acid, add 2.5 mL of acetone:water = 6:4 mixed reagent, stir at 70 °C for 0.5 hour, dissolve, filter, disconnect the heating and let stand overnight, and send the sample for single crystal testing.

[0189] Referring to General Rule 0451, Part IV of the Chinese Pharmacopoeia (2020 Edition), single crystal X-ray diffraction analysis was carried out using a Bruker single crystal X-ray diffractometer model SMART APEX-II. The test conditions were: CuKα radiation, voltage 40 kv, current 30 mA, scanning range 4.31 - 66.50°, and the scanning mode was The scanning step size was 0.5°.

[0190] The single crystal X-ray diffraction pattern of the obtained sample is as Figure 22 shown, the ellipsoid diagram of the single crystal molecular three-dimensional structure is as Figure 23 shown, and the projection diagram of the crystal cell packing in the b-axis direction of the single crystal is as Figure 24 shown.

[0191] Example 2: Preparation of polymorph A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate

[0192] Take 100 g of cariprazine free base and 43 g of 1-hydroxy-2-naphthoic acid, add 1000 mL of ethanol:water = 1:1 mixed reagent, stir and dissolve at 70 °C, disconnect the heating and cool down to precipitate, continue to stir for 5 hours, filter by suction, and dry under reduced pressure at 40 °C overnight to obtain 13.6 g of polymorph A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, with a yield of 95% and an HPLC purity of 99.59%.

[0193] By nuclear magnetic resonance hydrogen spectrum, X-ray powder diffraction, differential scanning calorimetry and thermogravimetric analysis, its chemical structure and crystal structure are consistent with those of Example 1A, the melting point is about 103.7 °C, and there is a weight loss of about 4.45% before 100 °C.

[0194] Example 3: Preparation of polymorph B of cariprazine mono-1-hydroxy-2-naphthoate

[0195] 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, disconnect the heating and let stand at room temperature overnight, filter by suction, and dry under reduced pressure at 60 °C for 1 hour to obtain 1.27 g of polymorph B of cariprazine mono-1-hydroxy-2-naphthoate, with a yield of 89%.

[0196] Its X-ray powder diffraction pattern is as follows Figure 4 shown.

[0197] Its differential scanning calorimetry pattern is as follows Figure 5 shown, showing a melting point of about 106.8 °C.

[0198] Its NMR pattern is as follows Figure 6 shown, showing that cariprazine forms a salt with 1-hydroxy-2-naphthoic acid in a molar ratio of 1:1.

[0199] Example 4: Preparation of cariprazine mono-1-hydroxy-2-naphthoate crystal form C

[0200] 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, disconnect the heating and let stand overnight at room temperature, filter with suction, and dry under reduced pressure at 60 °C for 5 hours to obtain 10.8 g of cariprazine mono-1-hydroxy-2-naphthoate crystal form C, with a yield of 76%.

[0201] Its X-ray powder diffraction pattern is as follows Figure 7 shown.

[0202] Its differential scanning calorimetry pattern is as follows Figure 8 shown, showing a melting point of about 103.4 °C.

[0203] Its NMR pattern is as follows Figure 9 shown, showing that cariprazine forms a salt with 1-hydroxy-2-naphthoic acid in a molar ratio of 1:1.

[0204] Example 5: Preparation of cariprazine bis-1-hydroxy-2-naphthoate hydrate crystal form A

[0205] 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, disconnect the heating and continue stirring for 3 hours, filter with suction, and dry under reduced pressure overnight at 40 °C to obtain 1.63 g of cariprazine bis-1-hydroxy-2-naphthoate crystal form A, with a yield of 88% and an HPLC purity of 99.44%.

[0206] Its X-ray powder diffraction pattern is as follows Figure 10 shown.

[0207] Its differential scanning calorimetry pattern is as follows Figure 11 shown, showing a melting point of about 86.3 °C.

[0208] Its thermogravimetric analysis pattern is as follows Figure 11As shown, there is about 1.31% weight loss before 100°C, which is attributed to the loss of crystal water and adsorbed water. Therefore, this crystal form A is cariprazine bis(1-hydroxy-2-naphthoate) hydrate.

[0209] Its NMR spectrum is as Figure 12 shown, indicating that cariprazine and 1-hydroxy-2-naphthoic acid form a salt in a molar ratio of 1:2.

[0210] Example 6: Preparation of cariprazine bis(1-hydroxy-2-naphthoate) crystal form H

[0211] 2 g of commercially available cariprazine free base and 1.62 g of 1-hydroxy-2-naphthoic acid were added to 80 mL of a tetrahydrofuran:methanol (2:1) solvent, dissolved at 60°C, filtered, and the solvent was removed by rotary evaporation to obtain a yellow solid. The yellow solid was dissolved in 30 mL of methanol at 60°C, the solvent was removed by rotary evaporation, and the solid was dried to obtain a pale yellow solid. 0.1 g of the above pale yellow solid was taken, dissolved in 2.5 mL of dibutyl ketone at 60°C, filtered, and 5 volumes of n-heptane were slowly added under stirring at room temperature. Stirring was carried out for 1 month, and then filtered to obtain 0.08 g of cariprazine bis(1-hydroxy-2-naphthoate) crystal form H, with a yield of 80%.

[0212] Its X-ray powder diffraction pattern is as Figure 13 shown, indicating cariprazine bis(1-hydroxy-2-naphthoate) crystal form H.

[0213] Example 7: Preparation of amorphous cariprazine bis(1-hydroxy-2-naphthoate)

[0214] 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 1-hydroxy-2-naphthoic 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 minutes under stirring, the product was separated by filtration and washed with water, and vacuum dried at 40°C for 12 hours to obtain 5840 mg of a light yellow solid, with a yield of 76% (calculated based on the free base).

[0215] The structure and molar ratio of the cariprazine bis(1-hydroxy-2-naphthoate) described in the present invention were confirmed by 1H NMR.

[0216] 11H-NMR (400 MHz, DMSO-d6): δ 8.38 (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).

[0217] The NMR results showed that cariprazine and pamoic acid formed a salt in a molar ratio of 1:1.

[0218] The above sample was subjected to solid-phase characterization detection. The XRPD pattern is shown in Figure 14 , and the detection results showed that it was the amorphous form of cariprazine pamoate.

[0219] Example 8: Preparation of Cariprazine Hydrochloride Polymorph I

[0220] A sample of cariprazine hydrochloride polymorph I was prepared according to the original research patent of cariprazine hydrochloride:

[0221] 1 g of commercially available cariprazine free base was added to a 25 mL round-bottom flask, 2 mL of methanol and 8 mL of water were added, and it 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 dissolving clearly, it was filtered while hot, and the heating was turned off and it was allowed to cool naturally overnight. 0.8 g of a white solid was obtained.

[0222] Its X-ray powder diffraction pattern is as shown in Figure 15 , showing cariprazine hydrochloride polymorph I.

[0223] Example 9: Comparison of Related Substances and Polymorph Stability

[0224] The polymorph A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate prepared in Example 2, the polymorph A of cariprazine bis-1-hydroxy-2-naphthoate hydrate prepared in Example 5, the amorphous form of cariprazine pamoate prepared in Example 7, and the polymorph I of cariprazine hydrochloride prepared in Example 8 were respectively taken and placed under the conditions of high temperature (60 °C), high humidity (25 °C / 90% RH), acceleration (40 °C / 75% RH), and light (1.2×10 6 Lux·hr). Samples were taken at 0 day and 10 days for HPLC or XRPD detection.

[0225] The results of the related substances detection are shown in Table 1, which shows that for the polymorph A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate and the hydrate polymorph A of cariprazine bis-1-hydroxy-2-naphthoate of the present invention, the changes in related substances after being placed under high temperature, high humidity, and accelerated conditions for 10 days are all within 0.3%, and the increase under high temperature conditions is less than that of the pamoate; similar to the pamoate, the impurities increase slightly under light, indicating that appropriate light avoidance measures can still maintain good stability.

[0226] The results of the polymorph stability are shown in Table 2, which shows that compared with the known polymorph I of cariprazine hydrochloride, the polymorph A of the hydrate of cariprazine bis-1-hydroxy-2-naphthoate of the present invention has more excellent polymorph stability. After being placed under various conditions for 10 days, the polymorph has not changed, and the crystallinity has also not changed significantly. The polymorph A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate of the present invention is relatively stable under high humidity, light, and accelerated conditions, and the polymorph has not changed, but it will transform into the polymorph C of cariprazine mono-1-hydroxy-2-naphthoate under high temperature conditions.

[0227] Table 1 Results of related substances

[0228]

[0229] Table 2 Results of polymorph stability

[0230]

[0231]

[0232] Example 10: Comparison of solubilities at different pH values

[0233] Respectively take the polymorph A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate prepared in Example 1A, the polymorph C of cariprazine semi-mono-1-hydroxy-2-naphthoate prepared in Example 4, the polymorph A of the hydrate of cariprazine bis-1-hydroxy-2-naphthoate prepared in Example 5, the amorphous form of cariprazine pamoate prepared in Example 7, the polymorph I of cariprazine hydrochloride prepared in Example 8, and cariprazine free base (commercially available), and add them to the following media with different pH values respectively. Oscillate at 37 °C for 24 hours, filter with a 0.45 μm aqueous phase filter membrane, collect the filtrate, and use high performance liquid chromatography for solubility determination. Among them, 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.

[0234] The solubility test results are shown in Table 3, indicating that the solubility of cariprazine mono-1-hydroxy-2-naphthoate and its crystal form prepared by the present invention, as well as that of cariprazine bis-1-hydroxy-2-naphthoate, is relatively low in the pH range of 3 to 9. Moreover, in the pH range of 3 to 6, the solubility is significantly lower than that of the hydrochloride salt, and in the pH range of 7 to 9, the solubility is significantly lower than that of the pamoate salt. The relatively low solubility enables the release rate of the said salt form and crystal form to minimally depend on pH, thereby avoiding the influence on its drug release rate in the pH environments of different regions in the body, preventing the occurrence of sudden release phenomenon or excessive blood drug concentration in local regions of the body, and reducing the inter-individual differences in drug release. Additionally, the crystal form of cariprazine 1-hydroxy-2-naphthoate has good stability, is suitable for use in long-acting preparations, can reduce the frequency of drug administration, improve the medication compliance of patients, and has good market prospects.

[0235] Table 3 Solubility Results at Different pH Values

[0236]

[0237] Examples 11 - 14: Suspension Aqueous Solutions with Different Dosages of Cariprazine Mono-1-hydroxy-2-naphthoate

[0238]

[0239]

[0240] Preparation Process:

[0241] (1) Weigh the prescribed amounts of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethylcellulose and dissolve and disperse them in about 60% of the total volume of injection water, and stir.

[0242] (2) Add the prescribed amount of crystal form C of cariprazine mono-1-hydroxy-2-naphthoate, optionally adjust the pH to 4.0 - 9.0 with sodium hydroxide or hydrochloric acid, make up the volume, and stir until completely dispersed to obtain the suspensions of Examples 11 - 14.

[0243] Respectively take the prescription samples prepared in Examples 11 - 14 and conduct investigations on needle penetration, suspension property, sedimentation ratio and redispersibility. It is found that the above suspension samples can all pass through a 0.45 * 15 mm syringe needle, have good suspension property, a sedimentation ratio greater than 0.9 for at least ten minutes and good redispersibility (can be quickly dispersed after shaking the sediment).

[0244] Examples 15 - 19: Suspension Aqueous Solutions of Cariprazine Mono-1-hydroxy-2-naphthoate with Different Dosages of Tween

[0245]

[0246] Preparation Process:

[0247] (1) Weigh the prescribed amount of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethylcellulose and dissolve and disperse them in about 60% of the total injection water volume, and stir.

[0248] (2) Add the prescribed amount of crystalline form C of cariprazine mono-1-hydroxy-2-naphthoate, and optionally adjust the pH to 4.0 - 9.0 with sodium hydroxide or hydrochloric acid, make up the volume, and stir until completely dispersed to obtain the suspensions of Examples 15 - 19.

[0249] Respectively take the prescription samples prepared in Examples 15 - 19 and conduct investigations on needle penetration, suspension property, wettability, sedimentation ratio and redispersibility. It is found that the above suspension samples can all pass through a 0.45 * 15 mm syringe needle, with good suspension property. The sedimentation ratio of the samples of Examples 15 - 19 is greater than 0.9 for at least ten minutes and the redispersibility is good (it can be quickly dispersed after shaking after sedimentation). For the samples of Examples 16 - 19, less drug adheres to the inner wall of the vial and the wettability is good.

[0250] Examples 20 - 25: Suspension aqueous solutions of cariprazine 1-hydroxy-2-naphthoate with different amounts of poloxamer

[0251]

[0252] Preparation process:

[0253] (1) Weigh the prescribed amount of poloxamer 188, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethylcellulose and dissolve and disperse them in about 60% of the total injection water volume, and stir.

[0254] (2) Add the prescribed amount of crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate or crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate hydrate, and optionally adjust the pH to 4.0 - 9.0 with sodium hydroxide or hydrochloric acid, make up the volume, and stir until completely dispersed to obtain the suspensions of Examples 20 - 25.

[0255] Respectively take the prescription samples prepared in Examples 20 - 25 and conduct investigations on needle penetration, suspension property, wettability, sedimentation ratio and redispersibility. It is found that the above suspension samples can all pass through a 0.45 * 15 mm syringe needle, with good suspension property and less drug adhering to the inner wall of the vial and good wettability. The sedimentation ratio of the samples of Examples 20 - 25 is greater than 0.9 for at least ten minutes and the redispersibility is good (it can be quickly dispersed after shaking after sedimentation).

[0256] Examples 26 - 31: Suspension aqueous solutions of cariprazine mono-1-hydroxy-2-naphthoate with different amounts of sodium carboxymethylcellulose

[0257]

[0258]

[0259] Preparation process:

[0260] (1) Weigh the prescribed amounts of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethylcellulose and add them to about 60% of the total injection water volume, stir to dissolve and disperse;

[0261] (2) Add the prescribed amount of crystalline form C of cariprazine mono-1-hydroxy-2-naphthoate, optionally adjust the pH to 4.0 - 9.0 with sodium hydroxide or hydrochloric acid, make up the volume, stir until completely dispersed, and obtain the suspensions of Examples 26 - 31.

[0262] Respectively take the prescription samples prepared in Examples 26 - 31, and conduct investigations on needle penetration, suspension property, sedimentation ratio and redispersibility. It is found that the above suspension samples can all pass through a 0.45 * 15 mm syringe needle, have good suspension property, and the samples of Examples 26 - 31 have a sedimentation ratio greater than 0.9 for at least ten minutes and good redispersibility (can be quickly dispersed after shaking the sediment).

[0263] Examples 32 and 33: Suspension aqueous solutions of cariprazine mono-1-hydroxy-2-naphthoate with different amounts of PVP K30

[0264]

[0265] Preparation process:

[0266] (1) Weigh the prescribed amounts of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, PVP K30 and add them to about 60% of the total injection water volume, stir to dissolve and disperse;

[0267] (2) Add the prescribed amount of crystalline form A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, optionally adjust the pH to 4.0 - 9.0 with sodium hydroxide or hydrochloric acid, make up the volume, stir until completely dispersed, and obtain the suspensions of Examples 32 and 33.

[0268] Respectively take the prescription samples prepared in Examples 32 and 33, and conduct investigations on needle penetration, suspension property, sedimentation ratio and redispersibility. It is found that the above suspension samples can all pass through a 0.45 * 15 mm syringe needle, have good suspension property, and the samples of Examples 32 and 33 have a sedimentation ratio greater than 0.9 for at least ten minutes and good redispersibility (can be quickly dispersed after shaking the sediment).

[0269] Examples 34 - 37: Suspension aqueous solutions of cariprazine mono-1-hydroxy-2-naphthoate with different particle sizes

[0270]

[0271]

[0272] Preparation process:

[0273] (1) Weigh the prescribed amounts of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol and dissolve and disperse them in approximately 60% of the total injection water preparation amount with stirring;

[0274] (2) Add the prescribed amount of crystalline form C of cariprazine mono-1-hydroxy-2-naphthoate to obtain a suspension aqueous solution of coarse particles;

[0275] (3) Grind and disperse the suspension aqueous solutions of the coarse particles obtained in Examples 34 - 37 above using a ball mill respectively;

[0276] (4) Add the prescribed amount of sodium carboxymethylcellulose to the above suspensions respectively, stir until completely dispersed, make up the volume to obtain the suspensions of Examples 34 - 37 with pH 7.4 ± 0.2;

[0277] (5) Use an OMEC LS-909 particle size analyzer to measure the particle size distribution of the samples of Examples 34 - 37, and the results are shown in the following table:

[0278] 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

[0279] According to the results in the above table, it can be seen that in the suspension aqueous solutions with the same prescription, by controlling the grinding parameters, suspension aqueous solutions with different particle sizes (Dv90) can be prepared.

[0280] Examples 38 - 40: Suspension aqueous solutions of different crystalline forms of cariprazine mono-1-hydroxy-2-naphthoate

[0281]

[0282] Preparation process:

[0283] (1) Weigh the prescribed amounts of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethylcellulose and dissolve and disperse them in approximately 60% of the total injection water preparation amount with stirring;

[0284] (2) Add the above crystalline forms of cariprazine mono-1-hydroxy-2-naphthoate in the prescribed amounts, optionally adjust the pH to 4.0 - 9.0 with sodium hydroxide or hydrochloric acid, make up the volume, and stir until completely dispersed to obtain the suspensions of Examples 38 - 40.

[0285] Take the prescription samples prepared in Examples 38 - 40 respectively, and conduct investigations on needle penetration, suspension property, sedimentation ratio and redispersibility. It is found that the above suspension samples can all pass through a 0.45 * 15 mm syringe needle, have good suspension property, the sedimentation ratio of the samples of Examples 38 - 40 is greater than 0.9 for at least ten minutes and have good redispersibility (can be quickly dispersed after shaking after sedimentation).

[0286] Based on the results in the above table and the investigation of needle penetration, suspension property, sedimentation ratio, and wettability, the mixed aqueous solutions with the same formulation are applicable to different crystal forms of cariprazine mono-1-hydroxy-2-naphthoate.

[0287] Example 41: Investigation on the stability of the suspension aqueous solution of cariprazine 1-hydroxy-2-naphthoate at 60°C

[0288] Take the suspension aqueous solution of cariprazine mono-1-hydroxy-2-naphthoate dihydrate crystal form A prepared in Example 21 and the suspension aqueous solution of cariprazine bis-1-hydroxy-2-naphthoate hydrate crystal form A prepared in Example 24, and detect the related substances at 0, 5, and 10 days under the condition of 60°C. The results are shown in the following table:

[0289]

[0290] Based on the results in the above table, it can be seen that in the suspension aqueous solution with the same formulation, the suspension aqueous solution of cariprazine mono-1-hydroxy-2-naphthoate dihydrate crystal form A is more stable than the suspension aqueous solution of cariprazine bis-1-hydroxy-2-naphthoate hydrate crystal form A.

[0291] Examples 42 - 43: Scale-up and stability of the suspension aqueous solution of cariprazine mono-1-hydroxy-2-naphthoate with different formulations

[0292]

[0293] Preparation process:

[0294] (1) Weigh the prescribed amounts of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethylcellulose /

[0295] PVPK30 and dissolve and disperse them in about 60% of the total amount of injection water, and make up the volume to 200 mL;

[0296] (2) Add the prescribed amount of cariprazine mono-1-hydroxy-2-naphthoate dihydrate crystal form A to obtain a suspension aqueous solution with coarse particles, and make up the volume to 200 mL;

[0297] (3) Grind and disperse the coarse particle suspension aqueous solutions obtained in Examples 42 and 43 above using a sand mill respectively;

[0298] (4) Use an OMEC LS-909 particle size analyzer to measure the particle size distribution of the samples in Examples 42 and 43. The results are shown in the following table:

[0299]

[0300] Based on the results in the above table, it can be seen that by controlling the grinding parameters, a suspension aqueous solution with smaller particle size (Dv90) particles can be prepared.

[0301] The suspension obtained from the above-mentioned examples was subjected to stability testing under conditions such as high temperature (60 °C), light, acceleration (40 °C / 75% RH), long-term (25 °C / 60% RH), and low temperature (2 - 8 °C). The relevant data on related substances, content, and particle size are shown in the following table:

[0302]

[0303] The above data indicate that the related substances, content, and particle size of different prescription sanded samples all have good stability under different conditions. At the same time, the needle-passing property and redispersibility of the above stability samples are both good, and no abnormalities are observed.

[0304] Example 44: Dissociation Study of Hydrochloride

[0305] Take the crystalline form I of cariprazine hydrochloride prepared in Example 8 and add it to the corresponding aqueous media with pH 6, pH 7, pH 7.4, pH 8, pH 9, etc. respectively. Oscillate at 37 °C for 4 hours, centrifuge, and perform XRPD detection on the residue. The results show that the crystalline form I of cariprazine hydrochloride dissociates into cariprazine free base. The comparison results with pH 7.4 as an example are shown in Figure 16 (the rest are not shown). Thus, it can be seen that the crystalline form I of cariprazine hydrochloride is unstable in solution, and there is a change in drug efficacy caused by the change in crystalline form after administration, reducing the safety of drug use.

[0306] Examples 45 - 47: Pharmacokinetic Study of Cariprazine 1-Hydroxy-2-Naphthoate Suspension in Rats

[0307]

[0308] The preparation process of the suspension injection in Example 42 was obtained by referring to Example 42 above.

[0309] 1. Preparation process of the suspension injections in Examples 45 - 46:

[0310] (1) Weigh the prescribed amounts of poloxamer 188, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethylcellulose and add them to about 60% of the total volume of injection water, stir to dissolve and disperse;

[0311] (2) Add the corresponding samples of crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate or crystalline form A of cariprazine bis 1-hydroxy-2-naphthoate hydrate in the prescribed amounts respectively, stir until completely dispersed, and make up the volume to obtain the suspension injections in Examples 45 - 46 with pH 7.4 ± 0.2;

[0312] 2. Preparation process of the suspension injection in Example 47:

[0313] (1) Weigh the prescribed amounts of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethylcellulose and add them to about 60% of the total injection water volume, stir to dissolve and disperse.

[0314] (2) Add the prescribed amount of amorphous cariprazine bis(1-hydroxy-2-naphthoate) respectively, stir until completely dispersed, and make up the volume to obtain the suspension injection of Example 47 with a pH of 7.4 ± 0.2.

[0315] 3. Use an OMEC LS-909 particle size analyzer to measure the particle size distribution of the samples of Examples 45 - 46. The results are shown in the following table:

[0316] Example Dv10 (μm) Dv50 (μm) Dv90 (μm) Example 45 7.625 15.837 38.015 Example 46 5.847 14.654 32.237

[0317] Example 48: Preparation of Oral Solution of Hydrochloride Crystal Form I

[0318] (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 injection water volume, optionally add 0.1% Tween 20 and 0.35% sodium carboxymethylcellulose, and stir to disperse.

[0319] (2) Adjust the pH to 5.0 - 5.5 with hydrochloric acid, and make up the volume to obtain the final clear oral solution of Example 48.

[0320] Example 49: Pharmacokinetic Experiment

[0321] Examples 45 - 48: 12 male SD rats were divided into four groups. Among them, three groups were intramuscularly injected with single-dose 9 mg / kg samples of cariprazine mono(1-hydroxy-2-naphthoate) formulation (Example 45), cariprazine bis(1-hydroxy-2-naphthoate) formulation (Example 46) and cariprazine bis(1-hydroxy-2-naphthoate) formulation (Example 47), and plasma was collected at 0, 1 h, 3 h, 7 h, 24 h, 4 d, 7 d, 15 d, 20 d, 25 d, 30 d after administration; the 4th group was orally gavaged with a single-dose 0.3 mg / kg sample of cariprazine hydrochloride crystal form I formulation (Example 48), and plasma was collected at 5 min, 15 min, 30 min, 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, and the animals in the oral gavage group were fasted overnight before administration and resumed eating 4 hours after administration.

[0322] Plasma sample collection: Collect about 150 μL of jugular vein blood (centrifuge the whole blood to separate plasma within 30 minutes) and place it in a test tube containing the anticoagulant EDTA-K2. After treatment, the plasma is stored in a -70 °C refrigerator for later use. Take 1 μL of the solution for LC-MS / MS analysis after pretreatment of the plasma sample.

[0323] The pharmacokinetic parameters in animals are shown in Tables 4 to 7, and the concentration-time curves are shown in Figures 17 - 19 .

[0324] The results showed that: in the oral formulation group of cariprazine hydrochloride, the peak plasma concentration (Cmax) reached 20 ng / ml within 1 hour after administration, decreased to 1 ng / ml at 12 hours, and the mean residence time (MRTlast) was only 2.75 hours; in the three injection groups of Examples 45, 46, and 47, compared with the oral group, the time to peak (Tmax) and mean residence time (MRTlast) were significantly prolonged. Tmax was extended from several hours to several days, and MRTlast was 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.

[0325] Example 42: Three male SD rats and three female SD rats were divided into one group each, with a total of two groups. They were intramuscularly injected with a single dose of 9 mg / kg of the sample of cariprazine 1-hydroxy-2-naphthoate prescription (Example 42), and plasma was collected at 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. Throughout the experiment, the animals had free access to food and water.

[0326] Plasma sample collection: After blood samples were collected, they were placed on ice and centrifuged to separate plasma within 1 hour (centrifugation conditions: 6800 g, 6 minutes, 2 - 8 °C) and placed in a test tube containing the anticoagulant EDTA-K2. The plasma samples were stored in a -80 °C refrigerator before analysis. After pretreatment of the plasma samples, the solution was taken for LC-MS / MS analysis.

[0327] The pharmacokinetic parameters in animals are shown in Tables 8 to 9, and the concentration-time curves are shown in Figures 20 - 21 .

[0328] The results showed that: in the injection groups of the two different genders of rats in Example 42, compared with the oral group (Example 48, the peak plasma concentration (Cmax) reached 20 ng / ml within 1 hour after administration, decreased to 1 ng / ml at 12 hours, and the mean residence time (MRTlast) was only 2.75 hours), the time to peak (Tmax) and mean residence time (MRTlast) were significantly prolonged. Tmax was extended from several hours to several days, and MRTlast was 5.9 days and 6.5 days respectively, which were 51 and 57 times that of the oral experimental group, showing a significant sustained-release effect.

[0329] For Examples 42, 45, and 46, the Cmax values of the injection groups (26 (male), 29 (female), 13, and 24 ng / ml) showed no significant difference compared to the oral groups, indicating that the preparations obtained in this patent will not cause safety hazards such as excessive blood drug concentration after administration leading to adverse drug reactions; the Cmax value of the injection group in Example 47 was relatively high, at 50.5 ng / ml, and there may be certain safety hazards of adverse reaction events.

[0330] In addition, in terms of the maintenance of blood drug concentration, the injection groups of Examples 42, 45, and 46 maintained at about 1 ng / ml within 15 - 20 days after administration, while Example 47 could only maintain for 11 days, indicating that Examples 42, 45, and 46 have a longer time to exert drug efficacy in vivo and a better sustained-release effect than Example 47.

[0331] Furthermore, for the injection groups of male rats in Examples 42, 45, and 46, the AUClast values were 138, 68, and 168 day*ng / mL in sequence, indicating that Examples 42 and 46 have more advantages in bioavailability than Example 45.

[0332] Table 4. Pharmacokinetic parameters of intramuscular injection of a suspension of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, polymorph A (Example 45) in rats

[0333] Pharmacokinetic Parameters Unit Rat Rat#1 Rat Rat#2 Rat 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[AUCl ast > 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

[0334] Table 5. Pharmacokinetic parameters of intramuscular injection of a suspension of cariprazine bis-1-hydroxy-2-naphthoate dihydrate, polymorph A (Example 46) in rats

[0335]

[0336] Table 6. Pharmacokinetic parameters of intramuscular injection of an amorphous suspension of cariprazine bisnaphthoate (Example 47) in rats

[0337]

[0338] Table 7. Pharmacokinetic parameters of oral administration of cariprazine hydrochloride polymorph I oral solution (Example 48) in rats

[0339]

[0340]

[0341] Table 8. Pharmacokinetic parameters of intramuscular injection of a suspension of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, polymorph A (Example 42) in male rats

[0342]

[0343] Table 9. Pharmacokinetic parameters of intramuscular injection in female rats of the suspension of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, Form A (Example 42)

[0344]

[0345] The above has given an exemplary illustration of the implementation modes of the technical solution of the present invention. It should be understood that the protection scope of the present invention is not limited to the above implementation modes. Any modifications, equivalent replacements, improvements, etc. made by those skilled in the art within the spirit and principle of the present invention shall be included within the protection scope of the claims of this application.

Claims

1. Cariprazine pharmaceutically acceptable salts, wherein the pharmaceutically acceptable salts are selected from: Polymorph A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, whose X-ray powder diffraction pattern 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°; Polymorph C of cariprazine mono-1-hydroxy-2-naphthoate, whose X-ray powder diffraction pattern 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°; Polymorph A of cariprazine bis-1-hydroxy-2-naphthoate hydrate, whose X-ray powder diffraction pattern 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°; Wherein cariprazine mono-1-hydroxy-2-naphthoate has the structure shown in formula (I) below, and cariprazine bis-1-hydroxy-2-naphthoate has the structure shown in formula (II) below: （I） (II).

2. The cariprazine pharmaceutically acceptable salt according to claim 1, wherein: For polymorph A of cariprazine mono-1-hydroxy-2-naphthoate dihydrate, its X-ray powder diffraction pattern has absorption peaks at 2θ values of 4.4° ± 0.2°, 8.6° ± 0.2°, 9.7° ± 0.2°, 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°; For polymorph C of cariprazine mono-1-hydroxy-2-naphthoate, its X-ray powder diffraction pattern 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°; The crystalline form A of cariprazine bis(1-hydroxy-2-naphthoate) hydrate has characteristic peaks in the X-ray powder diffraction pattern 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°.

3. The pharmaceutically acceptable salt of cariprazine according to claim 1, wherein: The crystalline form A of cariprazine mono(1-hydroxy-2-naphthoate) dihydrate has one selected from the following: An X-ray powder diffraction pattern substantially as shown in Figure 1; A differential scanning calorimetry pattern substantially as shown in Figure 2; A thermogravimetric analysis pattern substantially as shown in Figure 2; The crystalline form C of cariprazine mono(1-hydroxy-2-naphthoate) has one selected from the following: An X-ray powder diffraction pattern substantially as shown in Figure 7; A differential scanning calorimetry pattern substantially as shown in Figure 8; The crystalline form A of cariprazine bis(1-hydroxy-2-naphthoate) hydrate has one selected from the following: An X-ray powder diffraction pattern substantially as shown in Figure 10; A differential scanning calorimetry pattern substantially as shown in Figure 11; A thermogravimetric analysis pattern substantially as shown in Figure 11.

4. A pharmaceutically acceptable salt of cariprazine, wherein the pharmaceutically acceptable salt of cariprazine is selected from single crystals of the crystalline form A of cariprazine mono(1-hydroxy-2-naphthoate) dihydrate, and 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°.

5. The method for preparing the pharmaceutically acceptable salt of cariprazine according to any one of claims 1-3, comprising one selected from the following preparation methods: (1) The preparation method of the crystalline form A of cariprazine mono(1-hydroxy-2-naphthoate) dihydrate comprises the following steps: Mix cariprazine with 1-hydroxy-2-naphthoic acid in a molar ratio of 1:1 with a solvent, and stir at 25-70 °C to obtain the crystalline form A of cariprazine mono(1-hydroxy-2-naphthoate) dihydrate; The solvent is a mixed system of methanol or ethanol and water; The volume ratio of methanol or ethanol to water is 2:1 to 1:2; The mass-volume ratio of cariprazine to the total volume of the solvent system is 1 g: 10-30 mL; (2) The preparation method of the crystalline form C of cariprazine mono(1-hydroxy-2-naphthoate) comprises the following steps: Mix cariprazine with 1-hydroxy-2-naphthoic acid in a molar ratio of 1:1 and with a solvent, and stir at 25 - 70 °C to obtain crystalline form C of cariprazine mono-1-hydroxy-2-naphthoate; The solvent is a mixed system of acetone and water; The volume ratio of acetone to water is 2:1 to 1:2; The mass-to-volume ratio of cariprazine to the total volume of the solvent system is 1 g : 5 - 30 mL; (3) The preparation method of crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate hydrate comprises the following steps: Add cariprazine and 1-hydroxy-2-naphthoic acid in a molar ratio of 1:2 to a solvent, and stir at 25 - 70 °C to obtain crystalline form A of cariprazine bis-1-hydroxy-2-naphthoate hydrate; The solvent is a mixed system of methanol or ethanol and water; The volume ratio of methanol or ethanol to water is 1:1; The mass-to-volume ratio of cariprazine to the total volume of the solvent system is 1 g : 20 - 40 mL.

6. A combination of pharmaceutically acceptable salts of cariprazine, wherein the combination comprises: At least one of the pharmaceutically acceptable salts of cariprazine according to any one of claims 1 - 4; and Optionally, other pharmaceutically acceptable salts of cariprazine.

7. A combination of pharmaceutically acceptable salts of cariprazine, wherein the combination comprises: At least one of the pharmaceutically acceptable salts of cariprazine according to any one of claims 1 - 4; and Optionally, other forms of cariprazine mono-1-hydroxy-2-naphthoate and cariprazine bis-1-hydroxy-2-naphthoate.

8. The combination of pharmaceutically acceptable salts of cariprazine according to claim 6, wherein based on the total weight of the pharmaceutically acceptable salts of cariprazine in the combination of pharmaceutically acceptable salts of cariprazine, the weight percentage content of the pharmaceutically acceptable salt of cariprazine according to any one of claims 1 - 4 is greater than the content of other pharmaceutically acceptable salts of cariprazine.

9. The combination of pharmaceutically acceptable salts of cariprazine according to claim 7, wherein based on the total weight of the pharmaceutically acceptable salts of cariprazine in the combination of pharmaceutically acceptable salts of cariprazine, the weight percentage content of the pharmaceutically acceptable salt of cariprazine according to any one of claims 1 - 4 is greater than other crystalline forms of cariprazine mono-1-hydroxy-2-naphthoate and cariprazine bis-1-hydroxy-2-naphthoate.

10. The combination of pharmaceutically acceptable salts of cariprazine according to claim 8 or 9, wherein based on the total weight of the pharmaceutically acceptable salts of cariprazine in the combination, the weight percentage content of the pharmaceutically acceptable salt of cariprazine according to any one of claims 1 - 4 is 80% or more.

11. A pharmaceutical composition comprising one of the pharmaceutically acceptable salts of cariprazine according to any one of claims 1 - 4.

12. A pharmaceutical composition, wherein the pharmaceutical composition comprises cariprazine solid particles, and the particle size Dv(10) of the cariprazine solid particles ≤ 30 microns, Dv(50) ≤ 50 microns, and Dv(90) ≤ 100 microns; Wherein, The cariprazine solid particles are selected from one of the pharmaceutically acceptable salts of cariprazine as described in any one of claims 1-4.

13. The pharmaceutical composition according to claim 12, wherein Dv(90) ≤ 50 μm.

14. The pharmaceutical composition according to claim 12 or 13, wherein the pharmaceutical composition comprises the following components: (a) A pharmaceutically acceptable salt of cariprazine as described in any one of claims 1-4; (b) Sodium carboxymethylcellulose or PVP K30; (c) Tween 20 or poloxamer 188; (d) Disodium hydrogen phosphate; (e) Sodium dihydrogen phosphate; (f) Mannitol; And optionally, the pharmaceutical composition comprises a pH regulator.

15. The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition further comprises one or more selected from suspending agents, wetting agents, osmotic pressure regulators, solvents and buffers; wherein, the concentration range of the suspending agent is 0-10 mg / mL; and / or the concentration range of the wetting agent is 0.2-10 mg / mL; and / or the concentration range of the osmotic pressure regulator is 20-30 mg / mL.

16. The pharmaceutical composition according to claim 15, wherein: the concentration range of the suspending agent is 3.5 mg / mL - 7.5 mg / mL; and / or the concentration range of the wetting agent is 1 mg / mL - 5 mg / mL; and / or the concentration range of the osmotic pressure regulator is 23 mg / mL - 26 mg / mL.

17. The pharmaceutical composition according to claim 15 or 16, wherein: the suspending agent is selected from one or more of sodium carboxymethylcellulose, methylcellulose and polyvinylpyrrolidone; and / or the wetting agent is selected from one or more of Tween 20, Tween 80, poloxamer 188; and / or the osmotic pressure regulator is selected from one or more of sodium chloride, mannitol and sucrose; and / or the buffer is selected from one or more of phosphoric acid, phosphates, citric acid, sodium citrate, hydrochloric acid and sodium hydroxide; and / or the solvent is water.

18. The pharmaceutical composition according to claim 14, wherein the pH regulator is sodium hydroxide or hydrochloric acid.

19. The pharmaceutical composition according to claim 14, wherein the pH of the pharmaceutical composition is 4.0 - 9.

0.

20. The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition is a suspension or a suspending agent.

21. The pharmaceutical composition according to claim 20, wherein the pharmaceutical composition is an aqueous suspension or an aqueous suspending agent.

22. The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition is an injection.

23. The pharmaceutical composition according to claim 22, wherein the pharmaceutical composition is a long-acting injection.

24. The pharmaceutical composition according to claim 14, wherein in the pharmaceutical composition, the mass-volume concentration of the cariprazine solid particles is not less than 30 mg / mL.

25. The pharmaceutical composition according to claim 24, wherein in the pharmaceutical composition, the mass-volume concentration of the cariprazine solid particles is 30 to 120 mg / mL.

26. The pharmaceutical composition according to claim 24, wherein in the pharmaceutical composition, the mass-volume concentration of the cariprazine solid particles is 90 mg / mL.

27. Use of a cariprazine pharmaceutically acceptable salt according to any one of claims 1-4, a combination of cariprazine pharmaceutically acceptable salts according to any one of claims 6-10, or a pharmaceutical composition according to any one of claims 11-26 in the preparation of a medicament for treating and / or preventing cognitive disorders or mental disorders.

28. Use of a cariprazine pharmaceutically acceptable salt according to any one of claims 1-4, a combination of cariprazine pharmaceutically acceptable salts according to any one of claims 6-10, or a pharmaceutical composition according to any one of claims 11-26 in the preparation of a medicament for treating and / or preventing psychosis, bipolar disorder, acute mania.

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