Cariprazine medicinal salt and its crystalline form, preparation method and application

Abstract

This paper describes a pharmaceutical salt of cariprazine, a method for preparing the same, a pharmaceutical composition containing the same, and applications thereof. The pharmaceutical salt of cariprazine is a salt formed from cariprazine free base and an organic acid having six or more carbon atoms, and has good solubility and stability, and is expected to have good market prospects. [Formula 1] JPEG2023540056000024.jpg40169

Description

Detailed Description of the Invention

[0001] This application claims priority to the following earlier applications: Chinese invention patent application filed with the State Intellectual Property Office of China on August 26, 2020 and bearing application number 202010870701.6, Chinese invention patent application filed with the State Intellectual Property Office of China on August 26, 2020 and bearing application number 202010869671.7, Chinese invention patent application filed with the State Intellectual Property Office of China on March 26, 2021 and bearing application number 202110324874.2, and Chinese invention patent application filed with the State Intellectual Property Office of China on March 26, 2021 and bearing application number 202110330670.X, filed with the State Intellectual Property Office of China on March 26, 2021. The above earlier applications are incorporated herein by reference in their entireties.

[0002] [Technical field] The present invention relates to a pharmaceutical salt of cariprazine and its crystalline form, preparation method and application.

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

[0004] [ka]

[0005] Patent document CN101679315A discloses various salts of cariprazine, including monohydrochloride, dihydrochloride, monohydrobromide, maleate and mesylate. Patent document CN105218484A discloses cariprazine tartrate and provides the solubility of cariprazine tartrate, cariprazine hydrochloride, cariprazine maleate, cariprazine besylate and cariprazine phosphate, all of which are greater than 3 mg / mL. Patent document WO2020056929A discloses a new crystalline form of cariprazine hydrochloride and states that cariprazine hydrochloride is rapidly dissociated into free base in a buffer solution of pH 6.5.

[0006] In view of the deficiencies of the prior art, finding a cariprazine medicinal salt and its crystalline form that have low solubility, are suitable for long-acting administration, are highly stable, have good clinical effects, and are suitable for commercialization is a technical problem that is currently urgently needed to be solved in the field.

[0007] Summary of the Invention In order to improve the above technical problems, the present invention provides a pharmaceutical salt of cariprazine selected from the salts formed from cariprazine free base I and an organic acid having 6 or more carbons:

[0008] [ka]

[0009] According to an embodiment of the present invention, the organic acid having 6 or more carbons is caproic acid, heptanoic acid, octanoic acid, nonanoic acid, azelaic acid, decanoic acid, sebacic acid, undecanoic acid, lauric acid (dodecanoic acid), tridecanoic acid, myristic acid (tetradecanoic acid), pentadecanoic acid, palmitic acid (hexadecanoic acid), heptadecanoic acid, stearic acid (octadecanoic acid), nonadecanoic acid, eicosanoic acid (arachidic acid), oleic acid, ... Examples of suitable glyceryl triacetate include, but are not limited to, glyceryl triacetate, glyceryl esters of ...

[0010] According to an embodiment of the present invention, the palmitic acid ester refers to a structure in which palmitic acid is esterified with at least one hydroxyl group of a compound containing both a carboxyl group and a hydroxyl group (e.g., pamoic acid), and the naphthenic acid ester refers to a structure in which naphthoic acid is esterified with at least one hydroxyl group of a compound containing both a carboxyl group and a hydroxyl group (e.g., pamoic acid).

[0011] According to an embodiment of the present invention, the pamoic acid is also called embonic acid, and has a CAS registry number of 130-85-8.

[0012] According to an embodiment of the present invention, the molar ratio of cariprazine to the organic acid in the pharmaceutical salt may be (1:0.5) to (1:2).

[0013] According to an embodiment of the present invention, the cariprazine pharmaceutical salt may be cariprazine monopamoate, cariprazine hemipamoate, cariprazine 1-hydroxy-2-naphthoate, cariprazine laurate, cariprazine palmitate, cariprazine sebacate, cariprazine undecanoate or cariprazine heptanoate.

[0014] According to an embodiment of the present invention, the pamoic acid is pamoic acid, also known as embonic acid, and has a CAS registry number of 130-85-8.

[0015] According to an embodiment of the present invention, the cariprazine pharmaceutical salt may be in crystalline, polycrystalline or amorphous form.

[0016] According to an embodiment of the present invention, the term "polycrystalline" refers to a solid comprising different crystalline forms and other solid molecular forms of the same compound, e.g., two or more crystalline and / or amorphous forms of the cariprazine pharmaceutical salt.

[0017] According to an embodiment of the present invention, the cariprazine medicinal salt includes a solvate with a solvent. The solvate includes a hydrate of the cariprazine medicinal salt and a solvate formed from the cariprazine medicinal salt and an organic solvent. The "organic solvent" in the "solvate formed from the cariprazine medicinal salt and an organic solvent" includes, but is not limited to, a solvent selected from ethanol, acetone, dimethyl sulfoxide, and a mixture thereof.

[0018] The present invention further provides a method for preparing the cariprazine pharmaceutical salt, comprising the steps of: reacting the cariprazine free base with the organic acid having six or more carbons (e.g., neutralization reaction) to obtain the cariprazine pharmaceutical salt.

[0019] The method for preparing the cariprazine pharmaceutical salt can be carried out in a solvent or without a solvent.

[0020] In the method for producing the cariprazine medicinal salt, the organic acid having 6 or more carbon atoms is C6-C 30 The organic acid may be any of the C6 to C 30The organic acids include, but are not limited to, caproic acid, heptanoic acid, octanoic acid, nonanoic acid, azelaic acid, decanoic acid, undecanoic acid, lauric acid (dodecanoic acid), tridecanoic acid, myristic acid (tetradecanoic acid), pentadecanoic acid, palmitic acid (hexadecanoic acid), heptadecanoic acid, stearic acid (octadecanoic acid), nonadecanoic acid, eicosanoic acid (arachidic acid), oleic acid, heneicosanoic acid, docosanoic acid, tricosanoic acid, tetracosanoic acid, pentacosanoic acid, hexacosanoic acid, heptacosanoic acid, octacosanoic acid, nonacosanoic acid, triacontanoic acid (melissic acid), glyceryl triacetate, lignic acid, pamoic acid (palmitic acid ester), 1-hydroxy-2-naphthoic acid, and naphthenic acid derivatives (including, but not limited to, naphthenic acid esters).

[0021] According to an embodiment of the present invention, the cariprazine pharmaceutical salt is cariprazine pamoate.

[0022] According to an embodiment of the present invention, the cariprazine medicinal salt is a cariprazine pamoate salt formed from cariprazine free base and pamoic acid in a molar ratio of 1:1 to 2:1.

[0023] According to an embodiment of the present invention, the method for preparing cariprazine pamoate employs any one of the following methods: (1) dissolving cariprazine and pamoic acid in a first solvent, and removing the solvent or adding a second solvent to obtain cariprazine pamoate; The first solvent is methanol, ethanol, dichloromethane, acetone, dibutyl ketone, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide or a mixture thereof, preferably methanol, ethanol, tetrahydrofuran, dimethyl sulfoxide or a mixture thereof; The second solvent is isopropanol, methyl-t-butyl ether, n-heptane, toluene, isopropyl ether or a mixture thereof, preferably water; (2) dissolving cariprazine in an aqueous phosphoric acid solution to obtain solution A, dissolving pamoic acid in an aqueous sodium hydroxide solution to obtain solution B, adding solution B to solution A, and stirring to react to obtain cariprazine pamoate; The concentration of the phosphoric acid aqueous solution is 1 mg / mL to 6 mg / mL; Preferably, the concentration of the aqueous sodium hydroxide solution is 1 mg / mL to 8 mg / mL.

[0024] According to an embodiment of the invention, the cariprazine pamoate is in crystalline, polycrystalline or amorphous form.

[0025] According to an embodiment of the present invention, the cariprazine pamoate crystals are anhydrous, hydrated or solvated, including but not limited to solvates formed from cariprazine pamoate and one or more of methanol, ethanol, acetonitrile, tetrahydrofuran, and dimethylsulfoxide.

[0026] According to an embodiment of the present invention, the cariprazine pamoate is cariprazine pamoate crystalline form A.

[0027] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the cariprazine pamoate crystalline form A has characteristic peaks at 2θ values ​​of 13.1°±0.2°, 18.7°±0.2°, 21.0°±0.2°, etc.

[0028] Furthermore, the X-ray powder diffraction pattern of the cariprazine pamoate crystalline form A has characteristic peaks at 2θ values ​​of 4.8°±0.2°, 13.1°±0.2°, 18.7°±0.2°, 20.1°±0.2°, 21.0°±0.2°, 26.1°±0.2°, etc.

[0029] Furthermore, the X-ray powder diffraction pattern of the cariprazine pamoate crystalline form A has characteristic peaks at 2θ values ​​of 4.8°±0.2°, 9.7°±0.2°, 12.3°±0.2°, 13.1°±0.2°, 18.7°±0.2°, 20.1°±0.2°, 21.0°±0.2°, 26.1°±0.2°, etc.

[0030] Furthermore, the X-ray powder diffraction pattern of the cariprazine pamoate crystalline form A has absorption peaks at 2θ values ​​of 4.8°±0.2°, 8.2°±0.2°, 9.7°±0.2°, 11.6°±0.2°, 12.3°±0.2°, 13.1°±0.2°, 14.7°±0.2°, 15.1°±0.2°, 16.6°±0.2°, 18.7°±0.2°, 20.1°±0.2°, 20.7°±0.2°, 21.0°±0.2°, 21.6°±0.2°, 22.1°±0.2°, 24.1°±0.2°, 26.1°±0.2°, etc.

[0031] Furthermore, the X-ray powder diffraction pattern of the cariprazine pamoate salt crystalline form A is essentially as shown in FIG.

[0032] The differential scanning calorimetry spectrum of the cariprazine pamoate salt crystalline form A is essentially as shown in FIG. 3, and shows a melting point of about 166.5° C.

[0033] The thermogravimetric analysis spectrum of the cariprazine pamoate crystalline form A is essentially as shown in Figure 4, which shows two stages of weight loss before 115°C, which is due to the loss of surface solvent and channel water, and about 1.1% weight loss from 115 to 165°C, which is due to the loss of crystal water.

[0034] The NMR spectrum of the cariprazine pamoate crystalline form A is essentially as shown in FIG. 5, which shows that cariprazine and pamoic acid formed a salt in a molar ratio of 1:1.

[0035] According to an embodiment of the present invention, the method for preparing the cariprazine pamoate crystalline form A is as follows: (1) adding cariprazine pamoate to a solvent and stirring to crystallize, thereby obtaining the cariprazine pamoate crystalline form A; The solvent is methanol; (2) Cariprazine pamoate is dissolved in a good solvent, a poor solvent is gradually added, and the mixture is stirred to crystallize, thereby obtaining the cariprazine pamoate crystalline form A.

[0036] The good solvent is dibutyl ketone; The anti-solvent is n-heptane.

[0037] According to an embodiment of the present invention, the cariprazine pamoate is cariprazine pamoate crystalline form F.

[0038] According to an embodiment of the present invention, the cariprazine pamoate crystalline form F has an X-ray powder diffraction pattern having characteristic peaks at 2θ values ​​of 4.9°±0.2°, 19.2°±0.2°, 21.0°±0.2°, etc.

[0039] Furthermore, the X-ray powder diffraction pattern of the cariprazine pamoate crystalline form F has characteristic peaks at 2θ values ​​of 4.9°±0.2°, 13.6°±0.2°, 19.2°±0.2°, 21.0°±0.2°, 24.0°±0.2°, 26.3°±0.2°, etc.

[0040] Furthermore, the X-ray powder diffraction pattern of the cariprazine pamoate crystalline form F has characteristic peaks at 2θ values ​​of 4.9°±0.2°, 12.8°±0.2°, 13.6°±0.2°, 19.2°±0.2°, 20.3°±0.2°, 21.0°±0.2°, 24.0°±0.2°, 26.3°±0.2°, etc.

[0041] Further, according to an embodiment of the present invention, the cariprazine pamoate crystalline form F has an X-ray powder diffraction pattern with 2θ values ​​of 4.9°±0.2°, 8.4°±0.2°, 9.7°±0.2°, 10.4°±0.2°, 11.6°±0.2°, 12.8°±0.2°, 13.3°±0.2°, 13.6°±0.2°, 15.0°±0.2°, 15.4°±0.2°, 16.8°±0.2°, 17.0°±0.2°, 18.5°±0.2°, and 20. 0.2°, 18.8°±0.2°, 19.2°±0.2°, 19.5°±0.2°, 20.3°±0.2°, 21.0°±0.2°, 21.9°±0.2°, 22.2°±0.2°, 22.5°±0.2°, 24.0°±0.2°, 25.1°±0.2°, 25.7°±0.2°, 26.3°±0.2°, 26.8°±0.2°, 28.8°±0.2°, 29.6°±0.2°, etc.

[0042] Furthermore, the X-ray powder diffraction pattern of the cariprazine pamoate salt crystalline form F is essentially as shown in FIG.

[0043] The differential scanning calorimetry spectrum of the cariprazine pamoate salt crystalline form F is essentially as shown in FIG.

[0044] The thermogravimetric analysis spectrum of the cariprazine pamoate crystalline form F is essentially as shown in Figure 8, which shows that there is a weight loss of about 1.3% before 115°C, which is due to the loss of channel water, and there is a weight loss of about 1.3% between 115 and 175°C, which is due to the loss of crystal water.

[0045] The NMR spectrum of the cariprazine pamoate crystalline form F is essentially as shown in FIG. 9, which shows that cariprazine and pamoic acid formed a salt in a molar ratio of 1:1.

[0046] According to an embodiment of the present invention, the method for preparing the cariprazine pamoate crystalline form F is as follows: forming a slurry of cariprazine pamoate crystalline form A in a solvent and stirring to crystallize to obtain said cariprazine pamoate crystalline form F; The solvent is ethyl acetate, isopropyl acetate, methyl-t-butyl ether or n-heptane.

[0047] According to an embodiment of the present invention, the cariprazine pamoate is cariprazine pamoate crystalline form D.

[0048] According to an embodiment of the present invention, the cariprazine pamoate crystalline form D has an X-ray powder diffraction pattern having characteristic peaks at 2θ values ​​of 9.6°±0.2°, 11.9°±0.2°, 20.4°±0.2°, etc.

[0049] Furthermore, the X-ray powder diffraction pattern of the cariprazine pamoate crystalline form D has characteristic peaks at 2θ values ​​of 9.6°±0.2°, 11.9°±0.2°, 16.6°±0.2°, 20.4°±0.2°, 24.5°±0.2°, 25.3°±0.2°, etc.

[0050] Furthermore, the X-ray powder diffraction pattern of the cariprazine pamoate crystalline form D has characteristic peaks at 2θ values ​​of 9.6°±0.2°, 11.9°±0.2°, 15.2°±0.2°, 16.6°±0.2°, 20.4°±0.2°, 20.7°±0.2°, 24.5°±0.2°, 25.3°±0.2°, etc.

[0051] Further, according to an embodiment of the present invention, the cariprazine pamoate crystalline form D has an X-ray powder diffraction pattern with 2θ values ​​of 9.6°±0.2°, 10.1°±0.2°, 10.5±0.2°, 11.9°±0.2°, 13.2°±0.2°, 14.5°±0.2°, 15.2°±0.2°, 16.6°±0.2°, 20.4°±0.2°, and 21.4°±0.2°. It has characteristic peaks at 0.2°, 20.7°±0.2°, 21.1°±0.2°, 21.9°±0.2°, 23.5°±0.2°, 18.8°±0.2°, 19.2°±0.2°, 19.5°±0.2°, 20.3°±0.2°, 21.0°±0.2°, 24.5°±0.2°, 25.3°±0.2°, etc.

[0052] Furthermore, the X-ray powder diffraction pattern of the cariprazine pamoate salt crystalline form D is essentially as shown in FIG.

[0053] The differential scanning calorimetry spectrum of the cariprazine pamoate salt crystalline form D is essentially as shown in FIG.

[0054] The thermogravimetric analysis spectrum of the cariprazine pamoate crystalline form D is essentially as shown in FIG. 12, which shows that there is a weight loss of about 4% before 190° C., which is due to the loss of water and ethanol.

[0055] The NMR spectrum of the cariprazine pamoate crystalline form D is essentially as shown in FIG. 13, which shows that cariprazine and pamoic acid formed a salt in a molar ratio of 1:1.

[0056] According to an embodiment of the present invention, the method for preparing the cariprazine pamoate crystalline form D is as follows: Cariprazine pamoate is stirred in ethanol to crystallize, obtaining the cariprazine pamoate crystalline form D.

[0057] According to an embodiment of the present invention, the cariprazine pamoate is cariprazine pamoate crystalline form B.

[0058] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the cariprazine pamoate crystalline form B has characteristic peaks at 2θ values ​​of 5.2°±0.2°, 10.5°±0.2°, 14.0°±0.2°, 14.4°±0.2°, 17.5°±0.2°, 21.3°±0.2°, 21.9°±0.2°, 22.9°±0.2°, 26.2°±0.2°, etc.

[0059] Furthermore, the X-ray powder diffraction pattern of said cariprazine pamoate crystalline form B is essentially as shown in FIG.

[0060] According to an embodiment of the present invention, the cariprazine pamoate is cariprazine pamoate crystalline form C.

[0061] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the cariprazine pamoate crystalline form C has characteristic peaks at 2θ values ​​of 8.6°±0.2°, 13.0°±0.2°, 16.8°±0.2°, 17.3°±0.2°, 18.2°±0.2°, 18.5°±0.2°, 19.8°±0.2°, 22.1°±0.2°, 23.5°±0.2°, etc.

[0062] Furthermore, the X-ray powder diffraction pattern of the cariprazine pamoate salt crystalline form C is essentially as shown in FIG.

[0063] According to an embodiment of the present invention, the cariprazine pamoate is cariprazine pamoate crystalline form E.

[0064] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the cariprazine pamoate crystalline form E has characteristic peaks at 2θ values ​​of 11.0°±0.2°, 12.8°±0.2°, 13.8°±0.2°, 15.5°±0.2°, 15.9°±0.2°, 17.9°±0.2°, 18.4°±0.2°, 20.7°±0.2°, 23.4°±0.2°, etc.

[0065] Furthermore, the X-ray powder diffraction pattern of the cariprazine pamoate salt crystalline form E is essentially as shown in FIG.

[0066] According to an embodiment of the present invention, the cariprazine pamoate is cariprazine pamoate crystalline form G.

[0067] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the cariprazine pamoate crystalline form G has characteristic peaks at 2θ values ​​of 8.7°±0.2°, 10.0°±0.2°, 13.6°±0.2°, 14.3°±0.2°, 17.5°±0.2°, 18.0°±0.2°, 20.3°±0.2°, 23.2°±0.2°, 25.1°±0.2°, etc.

[0068] Furthermore, the X-ray powder diffraction pattern of the cariprazine pamoate salt crystalline form G is essentially as shown in FIG.

[0069] According to an embodiment of the present invention, the cariprazine pamoate is cariprazine pamoate crystalline form I.

[0070] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the cariprazine pamoate crystalline Form I has characteristic peaks at 2θ values ​​of 10.0°±0.2°, 14.9°±0.2°, 16.3°±0.2°, 17.7°±0.2°, 18.5°±0.2°, 19.0°±0.2°, 21.1°±0.2°, 22.1°±0.2°, 24.5°±0.2°, etc.

[0071] Furthermore, the X-ray powder diffraction pattern of the cariprazine pamoate salt crystalline Form I is essentially as shown in FIG.

[0072] According to an embodiment of the present invention, the term "solvate" refers to a molecular complex containing a drug and one or more solvent molecules, stoichiometric or non-stoichiometric, such as ethanol. If the solvent is tightly bound to the drug, the resulting complex has a well-defined stoichiometry independent of humidity. However, if the solvent is weakly bound to the drug, such as channel solvates and hygroscopic compounds, the solvent content depends on humidity and drying conditions. In such cases, the complex is generally non-stoichiometric.

[0073] According to an embodiment of the present invention, the term "hydrate" refers to a solvate containing a drug and stoichiometric or non-stoichiometric water. The term "relative humidity" refers to the ratio, expressed as a percentage, of the amount of water vapor at a given temperature to the maximum amount of water vapor that can be sustained at that temperature and pressure.

[0074] Without departing from the common knowledge in this field, each of the above preferred conditions can be combined in any way to obtain each relatively preferred embodiment of the present invention.

[0075] All of the reagents and raw materials used in the present invention are commercially available.

[0076] According to an embodiment of the present invention, the room temperature is an environmental temperature of 10°C to 35°C.

[0077] Beneficial effects The inventor unexpectedly found that the solubility of the cariprazine medicinal salts disclosed in the prior art is too high, and cariprazine hydrochloride has shortcomings such as not ideal stability in aqueous solution and rapid dissociation into free base in weak acidic or alkaline environment, making such salts unsuitable for long-acting sustained-release preparations. The cariprazine medicinal salt of the present invention improves the above problems, and its properties such as low solubility, good crystal form stability, good storage stability, no dissociation, and easy processing are further conducive to the production of long-acting sustained-release preparations, and have good market prospects.

[0078] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] XRPD pattern of amorphous cariprazine pamoate; [Figure 2] XRPD pattern of cariprazine pamoate crystalline form A; [Figure 3] DSC pattern of cariprazine pamoate crystalline form A; [Figure 4] TGA pattern of cariprazine pamoate crystalline form A; [Figure 5] Cariprazine pamoate crystalline form A 1 H-NMR pattern: [Figure 6] XRPD pattern of cariprazine pamoate crystalline form F; [Figure 7] DSC pattern of cariprazine pamoate crystal form F; [Figure 8] TGA pattern of cariprazine pamoate crystalline form F; [Figure 9] Cariprazine pamoate crystalline form F 1 H-NMR pattern: [Figure 10] XRPD pattern of cariprazine pamoate crystalline form D; [Figure 11] DSC pattern of cariprazine pamoate crystalline form D; [Figure 12] TGA pattern of cariprazine pamoate crystalline form D; [Figure 13] Cariprazine pamoate crystalline form D 1 H-NMR pattern: [Figure 14] XRPD pattern of cariprazine pamoate crystalline form B; [Figure 15] XRPD pattern of cariprazine pamoate crystalline form C; [Figure 16] XRPD pattern of cariprazine pamoate crystalline form E; [Figure 17] XRPD pattern of cariprazine pamoate crystalline form G; [Figure 18] XRPD pattern of cariprazine pamoate crystalline form I; [Figure 19] XRPD pattern of cariprazine hydrochloride crystalline form I; [Figure 20] Results of in vitro dissolution simulation experiment ("black square" is cariprazine pamoate amorphous; "black diamond" is cariprazine pamoate crystal form A; "black circle" is cariprazine pamoate crystal form B; "black triangle" is cariprazine pamoate crystal form G); [Figure 21] Stacked graph of XRPD patterns of cariprazine pamoate and cariprazine hydrochloride under pH 7.4 condition in Comparative Example 4 (A is cariprazine free base; B is cariprazine hydrochloride crystalline form I; C is cariprazine hydrochloride crystalline form I after vibration in a pH 7.4 medium; D is cariprazine pamoate crystalline form A; E is cariprazine pamoate crystalline form A after vibration in a pH 7.4 medium).

[0079] [Figure 22] A graph showing the relationship between the mean blood drug concentration of cariprazine and time in rats for an oral sample of the formulation of Example 44 of the present invention; [Figure 23] A diagram showing the relationship between the average blood drug concentration of cariprazine in the injection samples of the formulations of Examples 40 to 43 of the present invention in rats and time ("black square" is amorphous cariprazine pamoate; "black diamond" is cariprazine pamoate crystalline form A; "black circle" is cariprazine pamoate crystalline form B; "black triangle" is cariprazine pamoate crystalline form E); [Figure 24] A partial enlargement of Figure 23 (a graph showing the relationship between the average blood drug concentration of carlimodine over 0 to 24 hours and time) ("black squares" are amorphous cariprazine pamoate; "black diamonds" are cariprazine pamoate crystal form A; "black circles" are cariprazine pamoate crystal form B; "black triangles" are cariprazine pamoate crystal form E).

[0080] [Mode for carrying out the invention] The present invention will be further described below by way of examples, which are not intended to limit the scope of the present invention. In the following examples, experimental methods without specific conditions are selected according to conventional methods, conditions, or product specifications.

[0081] Unless otherwise stated, materials and reagents in the following examples are either commercially available or can be prepared by those skilled in the art using methods known in the art.

[0082] The base compounds of the examples were subjected to nuclear magnetic resonance ( 1 Measurements were performed using H-NMR, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot stage polarizing microscope (PLM), and high performance liquid chromatography (HPLC), with the following measurement parameters: (1) 1 H-NMR measurements were performed on a Bruker Advance III500M nuclear magnetic resonance spectrometer, the measurement frequency was 400 MHz, and the solvent used was deuterated DMSO.

[0083] (2) DSC measurements were performed in a TA Instruments Model Q2000 closed pan apparatus, and samples (approximately 1-2 mg) were weighed in an aluminum pan and transferred to the instrument for measurement. The measurement parameters were as follows: the instrument was balanced at 30°C and ramped to 300°C at a rate of 10°C / min to collect data, and the experimental atmosphere was nitrogen gas.

[0084] (3) TGA measurements were performed using a TA Instruments Model Q500 instrument. Samples (approximately 2-5 mg) were weighed in aluminum pans and transferred to the instrument for measurement. The measurement parameters were as follows: the instrument was ramped up to 350°C at a rate of 10°C / min to collect data, and the experimental atmosphere was nitrogen gas.

[0085] (4) XRPD measurements were performed on a Bruker model D8 Advance X-ray powder diffractometer using a circular zero-background single crystal silicon sample stage. The scan parameters were as follows: voltage 40 kV, current 40 mA, scan range 3°–45°, scan step 0.02°, and scan mode was continuous scan.

[0086] (5) The PLM measurements were performed with a hot-stage polarizing microscope, model DYP990 / TPH350, manufactured by Shanghai Point Optical Instruments, and a small amount of sample was taken and dispersed on a glass slide, and photographed with a 10x eyepiece and a 5–40x objective lens.

[0087] (6) HPLC content and related substances determination method:

[0088] [Table 1]

[0089] Unless otherwise specified, the detection conditions of the particle size detector for the aqueous suspension of the cariprazine pharmaceutical composition in the present invention are as follows:

[0090] [Table 2]

[0091] Example 1: Preparation of cariprazine pamoate 4000 mg (9.36 mmol) of cariprazine was dissolved in 200 mL (5.4 mg / mL) of phosphoric acid solution to obtain solution A, and 3634 mg (9.36 mmol) of pamoic acid was dissolved in 100 mL (7.5 mg / mL) of sodium hydroxide solution to obtain solution B. Under stirring, 100 mL of solution B was added to 200 mL of solution A within 30 min, the product was filtered off, washed with water and dried in vacuum at 40° C. for 12 h to obtain 5840 mg of a pale yellow solid with a yield of 76% (calculated as the free base).

[0092] The structure and molar ratio of cariprazine pamoate salt described in this invention were confirmed by proton nuclear magnetic resonance.

[0093] 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).

[0094] NMR results showed that cariprazine and pamoic acid formed a salt in a molar ratio of 1:1.

[0095] The sample was subjected to solid state characterization and the XRPD pattern is shown in FIG. 1 and indicated to be amorphous.

[0096] Example 2: Preparation of amorphous cariprazine pamoate Under the condition of 60°C, 20 g (46.8 mmol) of cariprazine and 18.17 g (46.8 mmol) of pamoic acid were dissolved in 170 mL of a mixed solvent of THF:MeOH (2:1), filtered, and concentrated under reduced pressure to remove the solvent. Further, 300 mL of methanol was added, and the solution was dissolved at 60°C, concentrated under reduced pressure to remove the solvent, and dried in vacuum at 40°C for 12 hours to obtain 36.6 g of amorphous cariprazine pamoate.

[0097] Example 3: Preparation of cariprazine hemipamoate salt 200 mg (0.468 mmol) of cariprazine was dissolved in 10 mL (5.4 mg / mL) of phosphoric acid solution to obtain solution A, and 90.85 mg (0.234 mmol) of pamoic acid was dissolved in 2.5 mL (7.5 mg / mL) of sodium hydroxide solution to obtain solution B. Under stirring, 2.5 mL of solution B was added to 10 mL of solution A within 30 min, and the product was filtered off, washed with water and dried in vacuum at 40 °C for 12 h to obtain 204 mg of a pale yellow solid, with a yield of 70%.

[0098] The structure and molar ratio of cariprazine pamoate salt described in this invention were confirmed by proton nuclear magnetic resonance.

[0099] 1 H-NMR (400MHz, DMSO-d6): δ8.25(s, 1H),8.18(d, 1H),7.69(d, 1H),7.38-7.31(m, 2H),7.22-7.14(m, 2H),7.05(t, 1H),5.86(d, 1H),4.71(s, 1H),3.39-3.22(m, 5H),2.75(s, 6H),1.75(t, 4H),1.59-1.54(m, 2H),1.25-1.15(m, 3H),1.04-0.95(m, 2H).

[0100] NMR results showed that cariprazine and pamoic acid formed a salt in a molar ratio of 2:1.

[0101] PLM measurements were performed on the above sample, which showed that the sample was a non-polarizing solid and amorphous.

[0102] Example 4: Preparation of cariprazine 1-hydroxy-2-naphthoate 100 mg (0.234 mmol) of cariprazine and 45 mg (0.234 mmol) of 1-hydroxy-2-naphthoic acid were added to 8 mL of methanol, stirred to dissolve, filtered, and three volumes of n-heptane were added. The solvent was evaporated at room temperature until it became dry, becoming an oil. The oil was then dried in vacuum at 40°C for 4 hours to obtain a solid.

[0103] PLM measurements revealed that the solid had polarized light and began to melt at approximately 200°C.

[0104] 1 H-NMR (400MHz, DMSO-d6): δ8.23(d, 1H),7.80-7.74(m, 2H),7.57-7.53(m, 1H),7.48-7.44(m, 1H),7.38-7.31(m, 2H),7.20-7.16(m, 2H),5.86(d, 1H),3.36-3.09(m, 10H),2.75(s, 6H),1.74(t, 4H),1.61-1.56(m, 2H),1.33-1.15(m, 5H),1.02-0.83(m, 3H).

[0105] The NMR results showed that cariprazine and 1-hydroxy-2-naphthoic acid formed a salt in a molar ratio of 1:1.

[0106] Example 5: Preparation of cariprazine laurate 50 mg (0.117 mmol) of cariprazine and 23.7 mg (0.118 mmol) of lauric acid were added to 5 mL of methanol and dissolved at 50°C. The mixture was stirred at room temperature for 12 hours, and then twice the amount of water was added and the mixture was filtered. The solid was vacuum dried at 40°C for 12 hours to obtain cariprazine laurate.

[0107] Example 6: Preparation of cariprazine palmitate 50 mg (0.117 mmol) of cariprazine and 30.3 mg (0.118 mmol) of palmitic acid were added to 5 mL of methanol and dissolved at 50°C. The mixture was stirred at room temperature for 12 hours, and then one volume of water was added and the mixture was filtered. The solid was dried in vacuum at 40°C for 12 hours to obtain cariprazine palmitate.

[0108] Example 7: Preparation of cariprazine sebacate, cariprazine succinate, cariprazine malate, cariprazine lactate, cariprazine undecanoate, and cariprazine heptanoate Cariprazine and acid were weighed in a molar ratio of 1:1.1. Each acid was dissolved in methanol solvent, and the resulting acidic reagent was added to the cariprazine methanol solution at room temperature to carry out the salt formation reaction. After stirring at room temperature for 12 hours, the mixture was evaporated and dried at room temperature to obtain the corresponding cariprazine salt.

[0109] Example 8: Preparation of cariprazine pamoate crystalline form A 2000 mg of cariprazine pamoate prepared in Example 1 was added to 20 mL of methanol, stirred at room temperature for 24 hours to crystallize, filtered, and dried in vacuum at 55°C to obtain 1900 mg of cariprazine pamoate crystal form A, with a yield of 95%.

[0110] The X-ray powder diffraction pattern is shown in FIG.

[0111] Its differential scanning calorimetry spectrum is shown in FIG. 3 and showed a melting point of 166.5°C.

[0112] Its thermogravimetric analysis spectrum is shown in Figure 4 and shows two steps of weight loss before 115 °C, which was due to the loss of surface solvent and channel water. From 115 to 165 °C, there was a weight loss of about 1.1%, which was due to the loss of crystal water.

[0113] The NMR spectrum is shown in FIG. 5 and indicates that cariprazine and pamoic acid formed a salt in a molar ratio of 1:1.

[0114] Example 9: Preparation of cariprazine pamoate crystalline form A 30 g of the amorphous solid sample of cariprazine pamoate prepared in Example 2 was taken, added to 300 mL of methanol, and stirred at 10° C. for 24 hours to cause crystallization. The crystal was filtered and dried in vacuum at 55° C. to obtain 28.5 g of cariprazine pamoate crystal form A.

[0115] Example 10: Preparation of cariprazine pamoate crystalline form B 200 mg of cariprazine pamoate crystalline form A obtained in Example 9 was slurried in methanol solvent, the weight-volume ratio of cariprazine pamoate crystalline form A to the solvent was 40 mg / mL, and stirred for 3 days for crystallization to obtain 180 mg of cariprazine pamoate crystalline form B.

[0116] The X-ray powder diffraction pattern is shown in FIG.

[0117] NMR results showed it to be a methanol solvate.

[0118] Example 11: Preparation of cariprazine pamoate crystalline form B 2 g of cariprazine pamoate crystalline form A prepared in Example 9 was added to 50 mL of methanol, stirred at room temperature for 72 hours to crystallize, filtered, and dried in vacuum at 55° C. to obtain 1.9 mg of cariprazine pamoate crystalline form B.

[0119] Example 12: Preparation of cariprazine pamoate crystalline form C The cariprazine pamoate crystalline form A obtained in Example 8 was slurried in acetone solvent, and the weight-volume ratio of cariprazine pamoate crystalline form A to the solvent was 40 mg / mL. The slurry was stirred for 3 days for crystallization to obtain cariprazine pamoate crystalline form C.

[0120] The X-ray powder diffraction pattern is shown in FIG.

[0121] NMR results showed it to be an acetone solvate.

[0122] Example 13: Preparation of cariprazine pamoate crystalline form D 200 mg of cariprazine pamoate crystalline form A prepared in Example 8 was added to 2 mL of ethanol, stirred at room temperature for 48 hours to crystallize, filtered, and dried in vacuum at 55°C to obtain 190 mg of cariprazine pamoate crystalline form D, with a yield of 95%.

[0123] The X-ray powder diffraction pattern is shown in FIG.

[0124] Its differential scanning calorimetry spectrum is shown in FIG. 11 and showed a melting point of 164.6°C.

[0125] Its thermogravimetric spectrum is shown in FIG. 12 and indicates that there is a weight loss of about 4% before 190° C., which was due to the loss of water and ethanol.

[0126] The NMR spectrum is shown in FIG. 13 and indicates that cariprazine and pamoic acid form a salt in a molar ratio of 1:1, containing approximately 0.67 ethanol molecules.

[0127] Example 14: Preparation of cariprazine pamoate crystalline form E The cariprazine pamoate crystalline form A obtained in Example 8 was slurried in acetonitrile solvent, and the weight-volume ratio of cariprazine pamoate crystalline form A to the solvent was 40 mg / mL. The slurry was stirred for 3 days for crystallization to obtain cariprazine pamoate crystalline form E.

[0128] The X-ray powder diffraction pattern is shown in FIG.

[0129] Example 15: Preparation of cariprazine pamoate crystalline form E 2 g of cariprazine pamoate crystal form A prepared in Example 9 was added to 50 mL of acetonitrile, stirred at room temperature for 72 hours to crystallize, filtered, and dried in vacuum at 55° C. to obtain 1.8 g of cariprazine pamoate crystal form E.

[0130] Example 16: Preparation of cariprazine pamoate crystalline form F 200 mg of cariprazine pamoate crystal form A prepared in Example 8 was added to 20 mL of isopropyl acetate, stirred at room temperature for 12 hours to crystallize, filtered, and dried in vacuum at 55° C. to obtain 180 mg of cariprazine pamoate crystal form F, with a yield of 90%.

[0131] The X-ray powder diffraction pattern is shown in FIG.

[0132] Its differential scanning calorimetry spectrum is shown in FIG. 7 and indicated a melting point of about 166.6°C.

[0133] Its thermogravimetric analysis spectrum is shown in Figure 8 and shows that there was a weight loss of about 1.3% before 115 °C, which was due to the loss of channel water. Between 115 and 175 °C, there was a weight loss of about 1.3%, which was due to the loss of crystal water.

[0134] The NMR spectrum is shown in FIG. 9 and indicates that cariprazine and pamoic acid formed a salt in a molar ratio of 1:1.

[0135] Example 17: Preparation of cariprazine pamoate crystalline form G 200 mg of cariprazine pamoate crystal form A obtained in Example 8 was taken, and 5 mL of acetonitrile was added thereto to form a slurry, which was stirred for 5 days for crystallization to obtain cariprazine pamoate crystal form G.

[0136] The X-ray powder diffraction pattern is shown in FIG.

[0137] NMR results showed it to be an acetonitrile solvate.

[0138] Example 18: Preparation of cariprazine pamoate crystalline form I A 15 mg sample of the amorphous solid cariprazine pamoate obtained in Example 1 was taken and left to stand for 10 days under light illumination to obtain cariprazine pamoate crystalline form I.

[0139] The X-ray powder diffraction pattern is shown in FIG.

[0140] Example 19: Preparation of cariprazine hydrochloride crystalline form I According to the prior research patent of cariprazine hydrochloride, a sample of cariprazine hydrochloride crystalline form I was prepared: 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 the mixture was stirred in an oil bath pan at 70°C for 0.5 h. A mixed solution of 0.226 mL of concentrated hydrochloric acid and 0.35 mL of water was added, and after dissolution, the mixture was filtered while still hot, and the heating was stopped and the mixture was allowed to cool naturally overnight to obtain 0.8 g of an approximately white solid.

[0141] Its X-ray powder diffraction pattern is shown in FIG. 19 and indicated that it was cariprazine hydrochloride crystalline form I.

[0142] Comparative Example 1: Comparison of stability of related substances and crystalline forms Amorphous cariprazine pamoate prepared in Example 1, crystalline form A of cariprazine pamoate prepared in Example 8, crystalline form B of cariprazine pamoate prepared in Example 10, crystalline form F of cariprazine pamoate prepared in Example 16, crystalline form G of cariprazine pamoate prepared in Example 17, and crystalline form I of cariprazine hydrochloride prepared in Example 19 were analyzed by high temperature (60° C.), high humidity (25° C. / 90% RH), accelerated (40° C. / 75% RH), light illumination (1.2×10 6 The samples were stored at room temperature for 30 min at 20°C for 10 min and then sampled on the 0th, 5th, 7th, and 10th days for HPLC or XRPD detection.

[0143] The results of related substances are shown in Table 1. It can be seen that among the cariprazine pamoate crystalline form A, cariprazine pamoate crystalline form B and cariprazine pamoate crystalline form G of the present invention, cariprazine pamoate crystalline form A is relatively stable, and the total amount of related substances basically did not change even after being left for 10 days under various conditions, whereas cariprazine pamoate amorphous was unstable under high temperature conditions, and the growth of impurities was relatively large.

[0144] The crystal form stability results are shown in Table 2. Compared with the known cariprazine hydrochloride crystal form I, the cariprazine pamoate crystal form A of the present invention has better crystal form stability, and the crystal form does not change even after being left for 10 days under various conditions, and the crystallinity does not change obviously. It is shown that the cariprazine pamoate crystal form F of the present invention is relatively stable under high temperature and light illumination conditions, and the crystal form does not change, but is converted to cariprazine pamoate crystal form A under high humidity and accelerated conditions.

[0145] [Table 3]

[0146] [Table 4]

[0147] Comparative Example 2: Comparison of solubility Amorphous cariprazine pamoate prepared in Example 1, amorphous cariprazine hemipamoate prepared in Example 3, cariprazine laurate prepared in Example 5, cariprazine palmitate prepared in Example 6, cariprazine sebacate, cariprazine succinate, cariprazine malate, cariprazine lactate, cariprazine undecanoate, cariprazine heptanoate prepared in Example 7, cariprazine pamoate crystal form A prepared in Example 8, cariprazine pamoate crystal form B prepared in Example 10, cariprazine pamoate crystal form F prepared in Example 16, cariprazine pamoate crystal form G prepared in Example 17, cariprazine hydrochloride crystal form I prepared in Example 19, and cariprazine were taken, each of which was added to the corresponding medium, shaken under the condition of 37°C for 24 hours, and filtered through a 0.45 μm aqueous phase filtration membrane, the filtrate was collected, and the solubility was measured by high performance liquid chromatography. Among them, pH 3, pH 4, pH 5 and pH 6 were acetate buffers, and pH 7, pH 7.4, pH 8 and pH 9 were phosphate buffers.

[0148] The results are shown in Table 3. The solubilities of cariprazine pamoate and its crystalline form obtained by the present invention and cariprazine hemipamoate were all significantly decreased. The solubility of cariprazine pamoate in water was 3 to 10 μg / mL, which corresponds to 1 / 18 to 1 / 60 (about 180 μg / mL) of cariprazine and 1 / 1000 to 1 / 3600 (about 110 μg / mL) of cariprazine hydrochloride. The solubility of cariprazine pamoate in each pH medium is relatively low, which has a sustained-release effect by itself; at the same time, the solubility of cariprazine pamoate in each pH medium is equivalent, and the release rate is minimally dependent on pH, which avoids the effect of pH environments in different regions of the body on the drug release rate, avoids the burst release phenomenon or excessive blood drug concentration in local regions of the body, and reduces the variability of drug release among individuals; and the crystalline form of cariprazine pamoate has relatively good stability, which is suitable for long-acting formulations, which can reduce the number of administrations and improve patient compliance, and shows good market prospects.

[0149] [Table 5]

[0150] Comparative Example 3: In vitro dissolution simulation experiment Amorphous cariprazine pamoate prepared in Example 1, crystalline form A of cariprazine pamoate prepared in Example 8, crystalline form B of cariprazine pamoate prepared in Example 10, and crystalline form G of cariprazine pamoate prepared in Example 17 were added to a phosphate buffer medium at pH 7.4, and shaken at 37°C. Samples were taken at 1, 3, 5, 7, and 24 hours to measure the solubility.

[0151] The results are shown in Table 4 and FIG. 20. Compared with the amorphous sample of cariprazine pamoate, the two crystalline compound samples of cariprazine pamoate crystalline form A and cariprazine pamoate crystalline form B prepared by the present invention were more slowly dissolved under the condition of pH 7.4 and had a smaller 24-hour solubility, indicating that the crystalline compounds are more suitable as medicinal salts to avoid excessive blood drug concentrations.

[0152] [Table 6]

[0153] Comparative Example 4: Comparison of solution stability Cariprazine pamoate crystalline form A prepared in Example 8 and cariprazine hydrochloride crystalline form I prepared in Example 19 were respectively added to corresponding media such as pH 6, pH 7, pH 7.4, pH 8 and pH 9, and shaken and centrifuged under the condition of 37°C for 4 hours. The residue was subjected to XRPD detection. As a result, cariprazine pamoate crystalline form A was unchanged, but cariprazine hydrochloride crystalline form I was dissociated into cariprazine free base. The comparison result at pH 7.4 is shown in Figure 21 (the rest is not shown). It can be seen that compared with cariprazine hydrochloride crystalline form I, cariprazine pamoate crystalline form A is more stable in solution, and the change in efficacy due to the change in crystal form after administration can be effectively avoided, and the drug safety can be improved.

[0154] Examples 20 to 25: Aqueous suspensions of cariprazine pamoate with different amounts of suspending agent used

[0155] [Table 7]

[0156] Manufacturing Process: (1) The prescribed amounts of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, and about 60% of the total amount of water for injection were weighed out, and the mixture was stirred to dissolve and disperse; (2) A prescribed amount of cariprazine pamoate crystalline form A was added to obtain an aqueous suspension of coarse particles; (3) The suspension of the coarse particles was pulverized using a ball mill to obtain a suspension having a Dv(90) of 10 microns or less; (4) The prescribed amount of sodium carboxymethylcellulose was added to each of the above suspensions, and the mixture was stirred until completely dispersed. If necessary, the pH was adjusted to 4.0 to 9.0 using sodium hydroxide or hydrochloric acid, and the mixture was then volume-controlled to obtain the suspensions of Examples 20 to 25.

[0157] The formulation samples prepared in Examples 20 to 25 were taken and examined for their injection needle permeability, suspendability, sedimentation rate and redispersibility. All of the above suspension samples could pass through a 0.45×15 mm syringe needle and had good suspendability. The 24-hour sedimentation rate and redispersibility of the samples in Examples 22 to 25 were good.

[0158] Examples 26 to 30: Aqueous suspensions of cariprazine pamoate with different amounts of wetting agent

[0159] [Table 8]

[0160] Manufacturing Process: (1) The prescribed amounts of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, and about 60% of the total amount of water for injection were weighed out, and the mixture was stirred to dissolve and disperse; (2) A prescribed amount of cariprazine pamoate crystalline form A was added to obtain an aqueous suspension of coarse particles; (3) The above suspensions of coarse particles were each pulverized using a ball mill to obtain suspensions with Dv(90) of 10 microns or less; (4) The prescribed amount of sodium carboxymethylcellulose was added to each of the above suspensions, and the mixture was stirred until completely dispersed. If necessary, the pH was adjusted to 4.0 to 9.0 using sodium hydroxide or hydrochloric acid, and the mixture was then volume-controlled to obtain the suspensions of Examples 26 to 30.

[0161] The formulation samples prepared in Examples 26 to 30 were taken and examined for their injection needle permeability, suspendability, sedimentation rate and wettability. All of the suspension samples could pass through a 0.45×15 mm syringe needle, and the suspendability, sedimentation rate and wettability were good.

[0162] Examples 31 to 34: Aqueous suspensions of cariprazine pamoate with different particle sizes

[0163] [Table 9]

[0164] Manufacturing Process: (1) The prescribed amounts of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, and about 60% of the total amount of water for injection were weighed out, and the mixture was stirred to dissolve and disperse; (2) A prescribed amount of cariprazine pamoate crystalline form A was added to obtain an aqueous suspension of coarse particles; (3) The aqueous suspensions of the coarse particles obtained in the above Examples 31 to 34 were each pulverized and dispersed using a ball mill; (4) The prescribed amount of sodium carboxymethylcellulose was added to each of the above suspensions, stirred until completely dispersed, and then adjusted to a constant volume to obtain suspensions of Examples 31 to 34 with a pH of 7.4±0.2; (5) Using an OMEC LS-909 particle size analyzer, the particle size distribution of the example samples after grinding was measured, and the results are shown in the following table:

[0165] [Table 10]

[0166] The results in the table above show that even with the same formulation, suspensions with particles of different particle sizes (Dv90) can be produced by controlling the milling parameters.

[0167] Examples 35 to 37: Aqueous suspensions of cariprazine pamoate with different crystalline forms

[0168] [Table 11]

[0169] Manufacturing Process: (1) The prescribed amounts of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, and about 60% of the total amount of water for injection were weighed out, and the mixture was stirred to dissolve and disperse; (2) The corresponding amounts of cariprazine pamoate samples were added to obtain aqueous suspensions of coarse particles; (3) The aqueous suspensions of the coarse particles obtained in Examples 35 to 37 were each pulverized and dispersed using a ball mill; (4) The prescribed amount of sodium carboxymethylcellulose was added to each of the above suspensions, stirred until completely dispersed, and then adjusted to a constant volume to obtain suspensions of Examples 35 to 37 with a pH of 7.4±0.2; (5) Using an OMEC LS-909 particle size analyzer, the particle size distribution of the example samples after grinding was measured, and the results are shown in the following table:

[0170] [Table 12]

[0171] The formulation samples prepared in Examples 35 to 37 were taken and examined for their injection needle permeability, suspendability, sedimentation rate and wettability. All of the suspension samples could pass through a 0.45×15 mm syringe needle, and the suspendability, sedimentation rate and wettability were good.

[0172] According to the results in the above table and the investigation of the needle permeability, suspension property, sedimentation rate and wettability, it can be seen that the same formulation of aqueous suspension and the same grinding parameters can be applied to different crystalline forms of cariprazine pamoate.

[0173] Example 38: Aqueous suspension of cariprazine hydrochloride

[0174] [Table 13]

[0175] Manufacturing Process: (1) The prescribed amounts of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, and about 60% of the total amount of water for injection were weighed out, and the mixture was stirred to dissolve and disperse; (2) A prescribed amount of cariprazine hydrochloride was added to obtain an aqueous suspension of coarse particles; (3) The obtained suspension of the coarse particles was pulverized and dispersed using a ball mill; (4) A prescribed amount of sodium carboxymethylcellulose was added to the above suspension, stirred until completely dispersed, and then adjusted to a constant volume to obtain a suspension of Example 38 with a pH of 7.4±0.2; (5) Using an OMEC LS-909 particle size analyzer, the particle size distribution of the example samples after grinding was measured, and the results are shown in the following table:

[0176] [Table 14]

[0177] Example 39: Study on the stability of aqueous suspensions of cariprazine pamoate and cariprazine hydrochloride at 60°C The aqueous suspensions of cariprazine pamoate prepared in Example 33 and cariprazine hydrochloride prepared in Example 38 were subjected to measurement of particle size at 60° C. for 0, 5 and 10 days. The results are shown in the following table:

[0178] [Table 15]

[0179] From the results in the above table, it can be seen that, even though the aqueous suspensions have the same formulation, the aqueous suspension of cariprazine pamoate is clearly superior to the aqueous suspension of cariprazine hydrochloride in terms of impurity and particle size stability.

[0180] Examples 40-44: Pharmacokinetic study of suspension formulation of cariprazine pamoate in rats

[0181] [Table 16]

[0182] 1. Preparation process of the suspension injection of Examples 40 to 43: (1) The prescribed amounts of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethylcellulose, and about 60% of the total amount of water for injection were weighed out, and the mixture was stirred to dissolve and disperse; (2) Add the corresponding cariprazine pamoate sample in the prescribed amount, stir until completely dispersed, and adjust to the specified volume to obtain the suspension injections of Examples 40 to 43 with pH 7.4±0.2; (3) An OMEC LS-909 particle size analyzer was used to measure the particle size distribution of the samples of Examples 41-43, and the results are shown in the following table:

[0183] [Table 17]

[0184] 2. Preparation process of oral suspension of Example 44: (1) The prescribed amounts of Tween 20, sodium carboxymethylcellulose, and about 60% of the total amount of water for injection were weighed out, and dissolved and dispersed by stirring; (2) The prescribed amount of cariprazine pamoate was added to obtain a suspension of coarse particles, and the pH was adjusted to 5.0 to 5.5 with hydrochloric acid and the volume was adjusted to constant to obtain the oral suspension of Example 44.

[0185] Example 45: Pharmacokinetics Experiments The formulation samples of different concentrations of cariprazine pamoate prepared in Examples 40-44 were selected for in vivo experiments in rats, and the experiments were as follows: Fifteen male SD rats were divided into five groups, four of which were intramuscularly injected with different formulations of cariprazine pamoate crystalline forms at a single dose of 9 mg / kg, and plasma samples were collected at 0, 1 h, 3 h, 7 h, 24 h, 4 d, 7 d, 11 d, 15 d, 20 d, 25 d and 30 d after administration, and the remaining group was orally gavaged with a formulation of cariprazine pamoate crystalline form A at a single dose of 0.3 mg / kg, and plasma samples were collected at 5 min, 15 min, 30 min, 1, 2, 3, 4, 6, 8, 12 and 24 hours after administration. During the experiment, animals in the intramuscular injection group had free access to food and water, and animals in the gavage group were fasted overnight before administration and resumed eating and drinking 4 hours after administration.

[0186] Collection of plasma samples: Approximately 150 μL of blood was collected from the jugular vein (whole blood was centrifuged within 30 min to separate plasma) and placed in a test tube containing the anticoagulant EDTA-K2. The processed plasma was stored in a -70°C refrigerator until use.

[0187] Plasma sample pretreatment: 30 μL of plasma sample was taken and added to 200 μL of internal standard solution (40 ng / mL Glipizide in acetonitrile), vortexed for 1 min, centrifuged at 5800 rpm for 10 min at 4°C, 100 μL of supernatant was taken and transferred to a new plate, and 1 μL of solution was taken for LC-MS / MS analysis.

[0188] Chromatography conditions: Fluid phase composition: Fluid phase A: 0.025% formic acid water - 1 mM ammonium acetate Mobile phase B: 0.025% formic acid in methanol - 1 mM ammonium acetate Gradient elution:

[0189] [Table 18]

[0190] Column: Waters ACQUITY UPLC BEH C18 (2.1×50 mm, 1.7 μm); Flow rate: 0.60 mL / min; Injection volume: 1 μL; Column oven: 60°C; Retention times: Cariprazine: 1.16 min; Glipizide: 1.22 min.

[0191] Mass Spectral Conditions: Secondary mass spectrometry was performed using an electrospray ion source (Turbo spray) in positive ion detection mode, with multichannel multiple reaction monitoring (MRM) mode selected. Mass spectrometry detection operating parameters and ion source parameters are shown in the following table.

[0192] [Table 19]

[0193] As can be seen from Figures 22 to 24, the oral cariprazine pamoate group is rapidly absorbed within 24 hours after administration, while the injection cariprazine pamoate group achieves sustained release for at least 11 days after administration, and is expected to be released for at least 30 days in humans, taking into account the differences between species. At the same time, among the various crystalline forms of cariprazine pamoate, the release time of cariprazine pamoate crystalline form A is the best.

[0194] As can be seen from the experimental results of the present invention, after the cariprazine pamoate injection formulation provided by the present invention is prepared into an aqueous suspension, the cariprazine pamoate has a relatively small particle size and is uniformly distributed, and has good injectability and the characteristic of sustained drug release for a long period of time (at least one week in SD rats). [Brief description of the drawings]

[0195] [Figure 1] XRPD pattern of amorphous cariprazine pamoate; [Diagram 2] 1 is an XRPD pattern of cariprazine pamoate crystalline form A; [Diagram 3]1 is a DSC pattern of cariprazine pamoate crystalline form A; [Figure 4] 1 is a TGA pattern of cariprazine pamoate crystalline form A; [Diagram 5] 1H-NMR pattern of cariprazine pamoate crystalline form A; [Figure 6] 1 is an XRPD pattern of cariprazine pamoate crystalline form F; [Figure 7] 1 is a DSC pattern of cariprazine pamoate crystalline form F; [Figure 8] 1 is a TGA pattern of cariprazine pamoate crystalline form F; [Figure 9] 1H-NMR pattern of cariprazine pamoate crystalline form F; [Figure 10] 1 is an XRPD pattern of cariprazine pamoate crystalline form D; [Figure 11] 1 is a DSC pattern of cariprazine pamoate crystalline form D; [Figure 12] 1 is a TGA pattern of cariprazine pamoate crystalline form D; [Figure 13] 1H-NMR pattern of cariprazine pamoate crystalline form D; [Figure 14] 1 is an XRPD pattern of cariprazine pamoate crystalline form B; [Figure 15] 1 is an XRPD pattern of cariprazine pamoate crystalline form C; [Figure 16] 1 is an XRPD pattern of cariprazine pamoate crystalline form E; [Figure 17] 1 is an XRPD pattern of cariprazine pamoate crystalline form G; [Figure 18] 1 is an XRPD pattern of cariprazine pamoate crystalline form I; [Figure 19] 1 is an XRPD pattern of cariprazine hydrochloride crystalline form I; [Figure 20]Result diagram of in vitro dissolution simulation experiment ("black square" is cariprazine pamoate amorphous; "black diamond" is cariprazine pamoate crystal form A; "black circle" is cariprazine pamoate crystal form B; "black triangle" is cariprazine pamoate crystal form G); [Figure 21] FIG. 1 is a stacked graph of XRPD patterns of cariprazine pamoate and cariprazine hydrochloride under pH 7.4 conditions in Comparative Example 4 (A is cariprazine free base; B is cariprazine hydrochloride crystalline form I; C is cariprazine hydrochloride crystalline form I after vibration in a pH 7.4 medium; D is cariprazine pamoate crystalline form A; E is cariprazine pamoate crystalline form A after vibration in a pH 7.4 medium). [Figure 22] FIG. 2 is a graph showing the relationship between the mean blood drug concentration of cariprazine and time in rats for an oral sample of the formulation of Example 44 of the present invention; [Diagram 23] FIG. 1 shows the relationship between the average blood drug concentration of cariprazine in rats and time for the injection samples of the formulations of Examples 40 to 43 of the present invention ("black squares" are amorphous cariprazine pamoate; "black diamonds" are cariprazine pamoate crystalline form A; "black circles" are cariprazine pamoate crystalline form B; "black triangles" are cariprazine pamoate crystalline form E); [Figure 24] FIG. 23 is an enlarged partial view (a graph showing the relationship between the average blood drug concentration of carlimodine over 0 to 24 hours and time) ("black squares" are amorphous cariprazine pamoate; "black diamonds" are cariprazine pamoate crystal form A; "black circles" are cariprazine pamoate crystal form B; "black triangles" are cariprazine pamoate crystal form E).

Claims

1. A pharmaceutical salt of cariprazine represented by formula I: 【Chemistry 1】 The cariprazine pharmaceutical salt is selected from at least one of cariprazine pamoate crystalline forms A, F, D, B, C, E, and G; The X-ray powder diffraction pattern of the cariprazine pamoate crystalline form A has characteristic peaks at 2θ values ​​of 4.8°±0.2°, 13.1°±0.2°, 18.7°±0.2°, 20.1°±0.2°, 21.0°±0.2°, and 26.1°±0.2°, and the cariprazine pamoate is formed from cariprazine and pamoic acid in a molar ratio of 1:1; The cariprazine pamoate crystalline form F has characteristic peaks at 2θ values ​​of 4.9°±0.2°, 13.6°±0.2°, 19.2°±0.2°, 21.0°±0.2°, 24.0°±0.2°, and 26.3°±0.2°, and the cariprazine pamoate is formed from cariprazine and pamoic acid in a molar ratio of 1:1; The cariprazine pamoate crystalline form D has characteristic peaks at 2θ values ​​of 9.6°±0.2°, 11.9°±0.2°, 16.6°±0.2°, 20.4°±0.2°, 24.5°±0.2°, and 25.3°±0.2°, and the cariprazine pamoate is formed of cariprazine and pamoic acid in a molar ratio of 1:1 and contains 0.67 ethanol molecules; The X-ray powder diffraction pattern of crystalline form B of cariprazine pamoate methanol solvate has characteristic peaks at 2θ values ​​of 5.2°±0.2°, 10.5°±0.2°, 14.0°±0.2°, 14.4°±0.2°, 17.5°±0.2°, 21.3°±0.2°, 21.9°±0.2°, 22.9°±0.2°, and 26.2°±0.2°; The X-ray powder diffraction pattern of the crystalline form C of cariprazine pamoate acetone solvate has characteristic peaks at 2θ values ​​of 8.6°±0.2°, 13.0°±0.2°, 16.8°±0.2°, 17.3°±0.2°, 18.2°±0.2°, 18.5°±0.2°, 19.8°±0.2°, 22.1°±0.2°, and 23.5°±0.2°; The cariprazine pamoate crystalline form E has an X-ray powder diffraction pattern having characteristic peaks at 2θ values ​​of 11.0°±0.2°, 12.8°±0.2°, 13.8°±0.2°, 15.5°±0.2°, 15.9°±0.2°, 17.9°±0.2°, 18.4°±0.2°, 20.7°±0.2°, and 23.4°±0.2°; and The cariprazine medicinal salt, wherein the crystalline form G of cariprazine pamoate acetonitrile solvate has an X-ray powder diffraction pattern having characteristic peaks at 2θ values ​​of 8.7°±0.2°, 10.0°±0.2°, 13.6°±0.2°, 14.3°±0.2°, 17.5°±0.2°, 18.0°±0.2°, 20.3°±0.2°, 23.2°±0.2° and 25.1°±0.2°.

2. The X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at 2θ values ​​of 4.8°±0.2°, 9.7°±0.2°, 12.3°±0.2°, 13.1°±0.2°, 18.7°±0.2°, 20.1°±0.2°, 21.0°±0.2°, and 26.1°±0.2°; The X-ray powder diffraction pattern of crystalline form F has characteristic peaks at 2θ values ​​of 4.9°±0.2°, 12.8°±0.2°, 13.6°±0.2°, 19.2°±0.2°, 20.3°±0.2°, 21.0°±0.2°, 24.0°±0.2°, and 26.3°±0.2°; and 2. The cariprazine medicinal salt of claim 1, wherein the X-ray powder diffraction pattern of crystalline form D has characteristic peaks at 2θ values ​​of 9.6°±0.2°, 11.9°±0.2°, 15.2°±0.2°, 16.6°±0.2°, 20.4°±0.2°, 20.7°±0.2°, 24.5°±0.2° and 25.3°±0.2°.

3. The crystalline form A has (1) an XRPD graph shown in FIG. 2, (2) a DSC graph shown in FIG. 3, or a TGA graph shown in FIG. 4; [Figure 1] The crystalline form F has (1) an XRPD graph shown in FIG. 6, (2) a DSC graph shown in FIG. 7, or a TGA graph shown in FIG. 8; [Figure 2] The crystalline form D has (1) an XRPD graph shown in FIG. 10, (2) a DSC graph shown in FIG. 11, or a TGA graph shown in FIG. 12; [Figure 3] The crystalline form B exhibits the XRPD graph shown in FIG. [Figure 4] The crystalline form C exhibits the XRPD graph shown in FIG. [Figure 5] The crystalline form E exhibits the XRPD graph shown in FIG. [Figure 6] The crystalline form G exhibits the XRPD graph shown in FIG. [Figure 7] The cariprazine medicinal salt according to claim 1.

4. 4. A method for preparing the cariprazine medicinal salt according to any one of claims 1 to 3, comprising the step of reacting cariprazine free base with pamoic acid to obtain said cariprazine pamoic acid.

5. The method for producing the crystalline form A is selected from the following methods (1) and (2): (1) adding cariprazine pamoate to a solvent and stirring the mixture of cariprazine pamoate and the solvent to crystallize cariprazine pamoate to obtain cariprazine pamoate crystalline form A, wherein the solvent is methanol; (2) A method for obtaining cariprazine pamoate crystalline form A by dissolving cariprazine pamoate in a good solvent, gradually adding a poor solvent, and stirring a mixture of the cariprazine pamoate, the good solvent, and the poor solvent to crystallize the cariprazine pamoate, wherein the good solvent is dibutyl ketone and the poor solvent is n-heptane; A method for preparing the cariprazine pamoate crystalline form F includes forming a slurry of cariprazine pamoate crystalline form A in a solvent and stirring the slurry to crystallize cariprazine pamoate to obtain the cariprazine pamoate crystalline form F, wherein the solvent is ethyl acetate, isopropyl acetate, methyl-t-butyl ether, or n-heptane; 5. The method of claim 4, wherein the method comprises stirring cariprazine pamoate in ethanol to crystallize cariprazine pamoate to obtain cariprazine pamoate crystalline form D.

6. A pharmaceutical composition comprising the cariprazine medicinal salt according to any one of claims 1 to 3.

7. Use of the cariprazine medicinal salt according to any one of claims 1 to 3 in the manufacture of a medicament for treating and / or preventing psychotic disorders, bipolar disorder and / or acute mania.

8. The use according to claim 7, characterized in that the dosage form of the drug is selected from the group consisting of tablets, capsules, solution formulations, suspensions, long-acting injections and semi-solid formulations.

9. 9. The use according to claim 8, characterized in that the suspension is a water suspension, an oil suspension or a powder suspension.

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