ES3064374T3 - Cariprazine pharmaceutical composition, preparation method and application thereof - Google Patents

Abstract

A pharmaceutical composition containing cariprazine, a method of preparation, and its application are described. The pharmaceutical composition comprises solid cariprazine pamoate particles with particle sizes of Dv(10) ≤ 30 µm, Dv(50) ≤ 50 µm, and Dv(90) ≤ 100 µm. When used, the cariprazine-containing pharmaceutical composition is presented as an aqueous suspension with a moderate concentration of the cariprazine free base. By injecting a specific volume of the pharmaceutical composition, a prolonged effect can be achieved, thereby reducing the frequency of administration and improving patient adherence to treatment. Furthermore, the pharmaceutical composition exhibits high bioavailability and promising commercialization prospects.

Description

[0001] DESCRIPTION

[0002] Pharmaceutical composition of cariprazine, method of preparation and application thereof

[0003] Technical field

[0004] The present description relates to the field of medical chemistry, and in particular to a pharmaceutical composition containing cariprazine, a method of preparing the same and its use.

[0005] Background

[0006] Cariprazine hydrochloride, which has the chemical structure of the following formula I, is a novel atypical antipsychotic that has an antagonistic effect on the dopamine D3 receptor, the dopamine D2 receptor, and the 5-hydroxytryptamine 2B receptor. It can be used to treat schizophrenia and bipolar I disorder. Cariprazine hydrochloride capsules are currently available on the market. This product is an oral preparation that must be taken daily to maintain its plasma concentration. However, patient compliance is poor due to the need for frequent administration.

[0009]

[0011] Patent reference CN108261394A describes an injectable preparation of cariprazine hydrochloride, including both aqueous suspension and lyophilized forms, capable of achieving sustained release for at least one week or more. However, the inventors discovered during research that cariprazine hydrochloride is not very stable in aqueous solution, dissociating under slightly acidic to alkaline conditions. This dissociation in the aqueous suspension alters the product's properties and quality, as well as the drug's dissolution and absorption, thus affecting its therapeutic effect and safety in patients. Furthermore, the administration concentration of cariprazine in the injectable preparation and the plasma concentration in the animal studies described in patent reference CN108261394A are too high. Since the clearance of cariprazine varies considerably from species to species as shown by the original research data (approximately 2-4 hours in rats, and 3-9 days in humans), excessive plasma concentrations can lead to stronger toxic and side effects and excessive accumulation of the drug in the human body.

[0012] To date, no injectable preparation of slightly soluble cariprazine salts with improved properties has been described.

[0013] Patent CN 108261394 A describes a pharmaceutical composition comprising cariprazine hydrochloride. The composition is an injection preparation comprising 1.08 g of cariprazine hydrochloride, 0.2 g of Tween 20, 0.035 g of Span 20, 0.03 g of sodium dihydrogen phosphate monohydrate, 0.005 g of sodium carboxymethylcellulose (0.5 mg/ml), 0.100 g of sodium hydroxide, and 10.0 ml of water for injection (see Example 1). According to patent CN 108261394 A, the particle size of the cariprazine hydrochloride particles in the aqueous suspension after milling are Dv(10) 0.258 µm, Dv(50) 0.905 µm and Dv(90) 4.067 µm. The pharmaceutical composition is described for use in the treatment of schizophrenia and/or bipolar disorder in adults.

[0014] US patent 2005/032836 A describes pamoate formulations of haloperidol, olanzapine, and aripiprazole that provide extended release of the active ingredients due to the limited solubility of the pamoate salts. CN patent 105218484 A describes a pharmaceutical composition comprising the crystalline form of cariprazine tartrate.

[0015] Summary

[0016] To alleviate the problems of the prior art, the present description provides a pharmaceutical composition, wherein the pharmaceutical composition comprises solid particles of cariprazine embonate, wherein the solid particles of cariprazine embonate have particle sizes Dv(10) of ≤30 micrometers, Dv(50) of ≤50 micrometers and Dv(90) of ≤100 micrometers.

[0017] Preferably, the solid particles of cariprazine embonate have particle sizes ≤ 10 micrometers. According to one embodiment of the present description, embonic acid is also known as pamoic acid, CAS No. 130-85-8.

[0018] According to one embodiment of the present description, solid cariprazine particles may be in crystalline or amorphous form.

[0019] According to one embodiment of the present description, cariprazine embonate is the crystalline form A of cariprazine embonate.

[0020] Cariprazine embonate is selected from one or more crystalline forms A, F, D, B, C, E, G and I of cariprazine embonate.

[0021] A powder X-ray diffraction plot of the A crystalline form of cariprazine embonate 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°. Furthermore, a powder X-ray diffraction plot of the A crystalline form of cariprazine embonate 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.

[0022] Furthermore, a powder X-ray diffraction plot of the crystalline form A of cariprazine embonate 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.

[0023] Furthermore, a powder X-ray diffraction plot of the crystalline form A of cariprazine embonate is substantially as shown in Figure 2.

[0024] A differential scanning calorimetry analysis chart of the crystalline form A of cariprazine embonate is substantially as shown in Figure 3, indicating a melting point of approximately 166.5 °C.

[0025] A thermogravimetric analysis chart of the crystalline form A of cariprazine embonate is substantially as shown in Figure 4, indicating two weight losses before 115 °C, which are attributed to surface solvent loss and channel water, and one weight loss of approximately 1.1% at 115-165 °C, which is attributed to water of crystallization loss.

[0026] A nuclear magnetic resonance plot of the A crystalline form of cariprazine embonate is substantially as shown in Figure 5, indicating that cariprazine and embonic acid form the salt in a 1:1 molar ratio.

[0027] According to one embodiment of the present description, a method of preparation for the crystalline form A of cariprazine embonate is as follows:

[0028] (1) add cariprazine embonate to a solvent, and stir the mixture so that the cariprazine embonate crystallizes to form crystalline form A of cariprazine embonate;

[0029] where the solvent is methanol;

[0030] (2) Dissolving the cariprazine embonate in a good solvent, gradually adding an antisolvent, and stirring the mixture so that the cariprazine embonate crystallizes to form crystalline form A of cariprazine embonate; wherein the good solvent is dibutyl ketone;

[0031] the antisolvent is n-heptane.

[0032] According to one embodiment of the present description, cariprazine embonate is the F crystalline form of cariprazine embonate.

[0033] A powder X-ray diffraction plot of the F crystalline form of cariprazine embonate 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°. Furthermore, a powder X-ray diffraction plot of the F crystalline form of cariprazine embonate 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.

[0034] Furthermore, according to one embodiment of the present description, a powder X-ray diffraction plot of the F crystalline form of cariprazine embonate has characteristic peaks at 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°, 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.

[0035] Furthermore, a powder X-ray diffraction plot of the F crystalline form of cariprazine embonate is substantially as shown in Figure 6.

[0036] A differential scanning calorimetry analysis chart of the F crystalline form of cariprazine embonate is substantially as shown in Figure 7, indicating a melting point of approximately 166.6 °C.

[0037] A thermogravimetric analysis chart of the crystalline form F of cariprazine embonate is substantially as shown in Figure 8, indicating a weight loss of approximately 1.3% before 115°C, which is attributed to channel water loss, and a weight loss of approximately 1.3% at 115-175°C, which is attributed to water of crystallization loss.

[0038] A nuclear magnetic resonance plot of the F crystal form of cariprazine embonate is substantially as shown in Figure 9, indicating that cariprazine and embonic acid form the salt in a 1:1 molar ratio.

[0039] According to one embodiment of the present description, a method of preparation for the crystalline form F of cariprazine embonate is as follows:

[0040] forming a suspension of the crystalline form A of cariprazine embonate in a solvent, stirring the suspension so that the cariprazine embonate crystallizes to form the crystalline form F of cariprazine embonate; wherein the solvent is ethyl acetate, isopropyl acetate, methyl tert-butyl ether or n-heptane.

[0041] According to one embodiment of the present description, cariprazine embonate is the D crystalline form of cariprazine embonate.

[0042] A powder X-ray diffraction plot of the D crystalline form of cariprazine embonate 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. Furthermore, a powder X-ray diffraction plot of the D crystalline form of cariprazine embonate 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°.

[0043] Furthermore, according to one embodiment of the present description, a powder X-ray diffraction plot of the D crystalline form of cariprazine embonate has characteristic peaks at 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°, 20.7°±0.2°, 21.1°±0.2°, 21.9°±0.2°, 23.5°±0.2°, 24.5°±0.2°, 25.3°±0.2 °, etc. Furthermore, a powder X-ray diffraction plot of the D crystalline form of cariprazine embonate is substantially as shown in Figure 10.

[0044] A differential scanning calorimetry analysis chart of the D crystalline form of cariprazine embonate is substantially as shown in Figure 11, indicating a melting point of approximately 164.6 °C. A thermogravimetric analysis chart of the D crystalline form of cariprazine embonate is substantially as shown in Figure 12, indicating a weight loss of approximately 4% before 190 °C, which is attributed to the loss of water and ethanol.

[0045] A nuclear magnetic resonance plot of the D crystal form of cariprazine embonate is substantially as shown in Figure 13, indicating that cariprazine and embonic acid form the salt in a 1:1 molar ratio.

[0046] According to one embodiment of the present description, a method of preparation for the crystalline form D of cariprazine embonate is as follows:

[0047] Stir the cariprazine embonate in ethanol so that the cariprazine embonate crystallizes to form the D crystalline form of cariprazine embonate.

[0048] According to one embodiment of the present description, cariprazine embonate is the B crystalline form of cariprazine embonate.

[0049] A powder X-ray diffraction pattern of the B crystalline form of cariprazine embonate 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°.

[0050] Furthermore, a powder X-ray diffraction plot of the B crystalline form of cariprazine embonate is substantially as shown in Figure 14.

[0051] According to one embodiment of the present description, cariprazine embonate is the C crystalline form of cariprazine embonate.

[0052] A powder X-ray diffraction pattern of the C crystalline form of cariprazine embonate 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°.

[0053] Furthermore, a powder X-ray diffraction plot of the C crystalline form of cariprazine embonate is substantially as shown in Figure 15.

[0054] According to one embodiment of the present description, cariprazine embonate is the E crystalline form of cariprazine embonate.

[0055] A powder X-ray diffraction pattern of the E crystalline form of cariprazine embonate 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°, and.

[0056] Furthermore, a powder X-ray diffraction plot of the E crystalline form of cariprazine embonate is substantially as shown in Figure 16.

[0057] According to one embodiment of the present description, cariprazine embonate is the G crystalline form of cariprazine embonate.

[0058] A powder X-ray diffraction pattern of the G crystalline form of cariprazine embonate 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°, and 25.1°±0.2°.

[0059] Furthermore, a powder X-ray diffraction plot of the G crystalline form of cariprazine embonate is substantially as shown in Figure 17.

[0060] According to one embodiment of the present description, cariprazine embonate is crystalline form I of cariprazine embonate.

[0061] A powder X-ray diffraction pattern of the crystalline form I of cariprazine embonate 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°, and 24.5°±0.2°.

[0062] Furthermore, a powder X-ray diffraction plot of the crystalline form I of cariprazine embonate is substantially as shown in Figure 18.

[0063] According to one embodiment of the present description, the pharmaceutical composition of cariprazine may further comprise an excipient, which may be selected from one or more of a suspending agent, a wetting agent, an osmotic pressure regulator, a solvent, a stabilizer, a buffer, and a surfactant.

[0064] According to one embodiment of the present description, the suspending agent is at a concentration in the range of 0 mg/ml to 10 mg/ml, preferably 3.5 mg/ml to 5 mg/ml, for example, 3.5 mg/ml, 4.0 mg/ml, 4.5 mg/ml or 5.0 mg/ml.

[0065] According to one embodiment of the present description, the suspending agent is selected from one or more of sodium carboxymethylcellulose, methylcellulose, and polyvinylpyrrolidone, preferably sodium carboxymethylcellulose.

[0066] According to one embodiment of the present description, the wetting agent is at a concentration in the range of 1 mg/ml to 10 mg/ml, preferably from 1 mg/ml to 5 mg/ml, for example, 1 mg/ml, 1.5 mg/ml, 2.0 mg/ml, 2.5 mg/ml, 3.0 mg/ml, 3.5 mg/ml, 4.0 mg/ml, 4.5 mg/ml or 5.0 mg/ml.

[0067] According to one embodiment of the present description, the wetting agent is selected from one or more of tween 20, tween 80 and poloxamer 188, preferably tween 20.

[0068] According to one embodiment of the present description, the osmotic pressure regulator is at a concentration in the range of 20 mg/ml to 30 mg/ml, preferably 23 mg/ml to 26 mg/ml, for example, 23 mg/ml, 24.7 mg/ml or 26 mg/ml.

[0069] According to one embodiment of the present description, the osmotic pressure regulator is selected from one or more of sodium chloride, mannitol, and sucrose.

[0070] According to one embodiment of the present description, the stabilizer is at a concentration in the range of 0 mg/ml to 30 mg/ml, preferably from 1 mg/ml to 10 mg/ml, for example, 1 mg/ml, 3 mg/ml, 5 mg/ml or 7.0 mg/ml.

[0071] According to one embodiment of the present description, the stabilizer is PVP K12.

[0072] According to one embodiment of the present description, the buffer is selected from one or more of phosphoric acid, phosphate, citric acid, sodium citrate, hydrochloric acid, and sodium hydroxide.

[0073] According to one embodiment of the present description, the surfactant is sodium deoxycholate. According to one embodiment of the present description, the solvent is water, for example, water for injection.

[0074] By way of example, the composition of cariprazine may comprise:

[0075] (a) cariprazine embonate;

[0076] (b) sodium carboxymethylcellulose;

[0077] (c) tween 20;

[0078] (d) disodium phosphate;

[0079] (e) monosodium phosphate; and

[0080] (f) mannitol;

[0081] and, optionally, the composition of cariprazine may comprise sodium hydroxide or hydrochloric acid.

[0082] According to one embodiment of the present description, the composition of cariprazine is a cariprazine injection, such as a long-acting cariprazine injection.

[0083] According to one embodiment of the present description, in the cariprazine composition or in the cariprazine long-acting injection, the solid particles of cariprazine are at a concentration of not less than 15 mg/ml.

[0084] According to one embodiment of the present description, the method of preparation for the composition of cariprazine comprises the following steps:

[0085] (1) sequentially dissolve the wetting agent, buffering agent and osmotic pressure regulator in water for injection;

[0086] (2) add the solid cariprazine particles to obtain an aqueous suspension of coarse particles;

[0087] (3) grinding the above-described aqueous suspension of coarse particles with a ball mill to obtain a suspension; and

[0088] (4) Add the suspending agent to the suspension described above, mix the suspension thoroughly, adjusting the pH to 4.0-9.0 with sodium hydroxide or hydrochloric acid, and bringing the suspension to volume to obtain an aqueous suspension.

[0089] According to one embodiment of the preparation method described herein, in step (1), the wetting agent, buffer, and osmotic pressure regulator can be dissolved sequentially in the solvent, e.g., water for injection.

[0090] According to one embodiment of the preparation method described herein, in step (4), the pH can be adjusted to 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5 or 9.0.

[0091] This description provides for the use of the pharmaceutical composition of cariprazine to manufacture a drug to treat and/or prevent psychosis, bipolar disorder, and acute mania.

[0092] This description also provides a method for treating and/or preventing psychosis, bipolar disorder, and acute mania, comprising administering the cariprazine pharmaceutical composition to a patient in need. According to one embodiment of this description, “Dv(10)”, “Dv(50)”, and “Dv(90)” refer to volume-weighted particle diameters, wherein 10% v/v, 50% v/v, or 90% v/v cumulatively of the particles have diameters equal to or smaller than this when measured. For example, if the Dv(50) of a particle population is approximately 25 micrometers, then 50% by volume of the particles have a diameter less than or equal to approximately 25 micrometers.

[0093] The preferred conditions described above may be combined by those skilled in the art to obtain the preferred embodiments of the present description without departing from the spirit of the present description.

[0094] The reagents and starting materials used in this description are commercially available. According to one embodiment of this description, ambient temperature refers to an ambient temperature of 10-35 °C.

[0095] Advantageous effects

[0096] After extensive research, selection, and trials, the inventors finally discovered that cariprazine embonate, one of the very slightly soluble salts of cariprazine, has the advantages of long-acting sustained-release preparations and can be made into an injectable suspension, while the risk of dissociation with cariprazine hydrochloride can be overcome and a prolonged-acting effect, as well as relatively low plasma concentrations in rats, can be achieved, greatly improving patient compliance and the bioavailability and safety of the drug.

[0097] The characteristics of the cariprazine pharmaceutical composition described herein include sustained release, high bioavailability, good stability in solution, administration of small volumes, etc. After a single dose, the release of cariprazine can last at least one week or more. The cariprazine pharmaceutical composition described herein has good commercial prospects.

[0098] Brief description of the figures

[0099] Figure 1 is an XRPD graph of amorphous cariprazine embonate;

[0100] Figure 2 is an XRPD plot of the A crystalline form of cariprazine embonate;

[0101] Figure 3 is a DSC plot of the A crystalline form of cariprazine embonate;

[0102] Figure 4 is a TGA plot of the A crystalline form of cariprazine embonate;

[0103] Figure 5 is an <1>H NMR plot of the A crystalline form of cariprazine embonate;

[0104] Figure 6 is an XRPD plot of the F crystal form of cariprazine embonate;

[0105] Figure 7 is a DSC plot of the F crystal form of cariprazine embonate;

[0106] Figure 8 is a TGA plot of the F crystal form of cariprazine embonate;

[0107] Figure 9 is an <1>H NMR plot of the F crystal form of cariprazine embonate;

[0108] Figure 10 is an XRPD plot of the D crystal form of cariprazine embonate;

[0109] Figure 11 is a DSC plot of the D crystal form of cariprazine embonate;

[0110] Figure 12 is a TGA plot of the D crystal form of cariprazine embonate;

[0111] Figure 13 is an <1>H NMR plot of the D crystal form of cariprazine embonate;

[0112] Figure 14 is an XRPD plot of the B crystalline form of cariprazine embonate;

[0113] Figure 15 is an XRPD plot of the C crystal form of cariprazine embonate;

[0114] Figure 16 is an XRPD plot of the E crystal form of cariprazine embonate;

[0115] Figure 17 is an XRPD plot of the G crystal form of cariprazine embonate;

[0116] Figure 18 is an XRPD plot of the crystal form I of cariprazine embonate;

[0117] Figure 19 is an XRPD plot of the crystalline form I of cariprazine hydrochloride;

[0118] Figure 20 is a graph showing the results of in vitro dissolution simulation experiments (■ for amorphous cariprazine embonate); ◆ for crystalline form A of cariprazine embonate; ● for crystalline form B of cariprazine embonate; and ▲ for crystalline form G of cariprazine embonate);

[0119] Figure 21 is an overlay of XRPD plots of cariprazine embonate and cariprazine hydrochloride at pH 7.4 in comparative example 4 (A for cariprazine free base; B for crystalline form I of cariprazine hydrochloride; C for crystalline form I of cariprazine hydrochloride that has been shaken in a medium at pH 7.4; D for crystalline form A of cariprazine embonate; and E for crystalline form A of cariprazine embonate that has been shaken in a medium at pH 7.4);

[0120] Figure 22 is a graph showing a relationship between the mean plasma concentration of cariprazine and time in a rat, for an oral sample of the preparation of example 44 of the present description;

[0121] Figure 23 is a graph showing the relationships between mean plasma concentration of cariprazine and time in rats, for injection samples of the preparations of Examples 40-43 of the present description (■ for amorphous cariprazine embonate); ◆ for crystalline form A of cariprazine embonate; ● for crystalline form B of cariprazine embonate; and ▲ for crystalline form E of cariprazine embonate);

[0122] Figure 24 is a partial and enlarged view of Figure 23 (showing the relationships between mean plasma concentration of cariprazine and time from 0 to 24 h) (■ for amorphous cariprazine embonate;

[0123] ◆ for crystalline form A of cariprazine embonate; ● for crystalline form B of cariprazine embonate; and ▲ for the E crystalline form of cariprazine embonate).

[0124] Detailed description

[0125] The present description is further illustrated by the following examples; however, these examples should not be interpreted as limiting the present description. Experimental procedures without conditions specified in the following examples are carried out according to conventional procedures and conditions, or according to the manufacturer's manual.

[0126] Unless otherwise stated, the starting materials and reagents in the following examples are either commercially available or prepared by a person skilled in the art according to methods known in the art.

[0127] The salt compounds in the examples were analyzed by nuclear magnetic resonance (<1>H NMR), powder X-ray diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-phase polarized light microscopy (PLM), and high-performance liquid chromatography (HPLC), and the test parameters are as follows:

[0128] (1) <1>H NMR measurements were performed on a Bruker Advance III 500 M nuclear magnetic resonance spectrometer at a frequency of 400 Mz with deuterated DMSO as the solvent.

[0129] (2) DSC measurements were performed on a sealed tray device in the TA Instruments model Q2000: samples (approximately 1-2 mg) were weighed into aluminum containers and transferred to the instrument for measurement. The test parameters were as follows: the instrument was equilibrated at 30 °C and heated to 300 °C at a rate of 10 °C/min, data were collected, and the experiments were performed in a nitrogen atmosphere. (3) TGA measurements were performed on a TA Instruments model Q500 device: samples (approximately 2-5 mg) were weighed into aluminum containers and transferred to the instrument for measurement. The test parameters were as follows: the instrument was heated to 350 °C at a rate of 10 °C/min, data were collected, and the experiments were performed in a nitrogen atmosphere.

[0130] (4) XRPD measurements were performed on a Bruker Model D8 Advance powder X-ray diffractometer using a zero-round-bottom monocrystalline silicon sample stage. The scan parameters are as follows: voltage, 40 kV; current, 40 mA; scan interval, 3–45°; scan increment, 0.02°; scan mode, continuous scan.

[0131] (5) PLM analyses were performed using a Shanghai Dian Ying Optical Instruments model DYP990/TPH350 hot phase polarizing microscope: a small amount of sample was dispersed on a glass slide and photographed using an eyepiece lens at 10× magnification and an objective lens at 5-40× magnification.

[0132] (6) Methods for measuring HPLC content and detecting related substances:

[0133] Content Method:

[0135]

[0137] Content gradient elution program table:

[0139]

[0141] Related Substances Method:

[0143]

[0145] Related gradient elution program table:

[0147]

[0149] Unless otherwise stated, aqueous suspensions of the cariprazine pharmaceutical composition in the context of this description were measured on a particle size analyzer under the following conditions:

[0150] Injector: SCF-105B Substance: cariprazine composition

[0151] Refractive index of particles: 1.595 Refractive index of dispersant: 1.333 Dispersant: water Background test time: 10 s

[0152] Sample test time: 10 s Darkening: 10-20 %

[0153] Stirring speed: 700-2000 rpm Analysis model: universal

[0154] Measurement range: 0.02-2100 µm Particle absorption rate: 0.1

[0155] The measurement was performed in triplicate, and an average value was obtained.

[0156] Example 1: Preparation of cariprazine embonate

[0157] 4000 mg (9.36 mmol) of cariprazine were dissolved in 200 mL of a phosphoric acid solution (5.4 mg/mL) to give solution A. 3634 mg (9.36 mmol) of embonic acid were dissolved in 100 mL of a sodium hydroxide solution (7.5 mg/mL) to give solution B. 100 mL of solution B were added to 200 mL of solution A for 30 minutes under stirring. The product was isolated by filtration, washed with water, and dried under vacuum at 40 °C for 12 h to give a pale yellow solid (5840 mg, 76% yield (calculated on a free basis)).

[0158] The structure and molar ratio of the cariprazine embonate of the present description were confirmed by hydrogen nuclear magnetic resonance.

[0159] <1>H NMR (400 MHz, DMSO-d6): δ8.38 (s, 2 H), 8.16 (d, 2 H), 8.80 (d, 2 H), 7.39-7.13 (m, 7 H), 5.86 (d, 1 H), 4.76 (s, 2 H), 3.40-3.32 (m, 3 H), 3.22-3.18 (m, 4 H), 2.75 (s, 6 H), 1.76 (t, 4 H), 1.63-1.57 (m, 2 H), 1.25-1.16 (m, 3 H), 1.04-0.96 (m, 2 H).

[0160] The nuclear magnetic resonance result shows that cariprazine and embonic acid formed the salt in a molar ratio of 1:1.

[0161] The sample described above was analyzed by solid-state characterization. The XRPD plot is shown in Figure 1. The result indicates an amorphous form.

[0162] Example 2: Preparation of amorphous cariprazine embonate

[0163] 20 g (46.8 mmol) of cariprazine and 18.17 g (46.8 mmol) of embonic acid were dissolved in 170 mL of a mixed solvent of THF:MeOH (2:1) at 60 °C. The mixture was filtered and concentrated under reduced pressure to remove the solvent, and then 300 mL of methanol were added to dissolve the residue at 60 °C. The solution was concentrated under reduced pressure to remove the solvent, and the residue was dried under vacuum at 40 °C for 12 h to give amorphous cariprazine embonate (36.6 g).

[0164] Example 3: Preparation of cariprazine hemiembonate (not part of the claimed invention)

[0165] 200 mg (0.468 mmol) of cariprazine was dissolved in 10 mL of phosphoric acid solution (5.4 mg/mL) to give solution A. 90.85 mg (0.234 mmol) of embonic acid was dissolved in 2.5 mL of sodium hydroxide solution (7.5 mg/mL) to give solution B. 2.5 mL of solution B was added to 10 mL of solution A and stirred for 30 minutes. The product was isolated by filtration, washed with water, and dried under vacuum at 40 °C for 12 h to give a pale yellow solid (204 mg, 70% yield). The structure and molar ratio of the cariprazine embonate of the present description were confirmed by hydrogen nuclear magnetic resonance.

[0166] <1>H NMR (400 MHz, DMSO-d6): δ8.25 (s, 1 H), 8.18 (d, 1 H), 7.69 (d, 1 H), 7.38-7.31 (m, 2 H), 7.22-7.14 (m, 2 H), 7.05 (t, 1 H), 5.86 (d, 1 H), 4.71 (s, 1 H), 3.39-3.22 (m, 5 H), 2.75 (s, 6 H), 1.75 (t, 4 H), 1.59-1.54 (m, 2 H), 1.25-1.15 (m, 3 H), 1.04-0.95 (m, 2 H).

[0167] The nuclear magnetic resonance result shows that cariprazine and embonic acid formed the salt in a molar ratio of 2:1.

[0168] The sample described above was analyzed by PLM, and the result shows that the sample was an amorphous solid with no polarization of light.

[0169] Example 4: Preparation of cariprazine 1-hydroxy-2-naphthoate (not part of the claimed invention) 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, thoroughly dissolved by stirring, and filtered. Three volumes of n-heptane were added. The solvent was evaporated at room temperature to give an oil. The oil was dried under vacuum at 40 °C for 4 h to give a solid.

[0170] PLM analysis showed that the solid had a polarization of light and began to melt at approximately 200 °C. <1>H NMR (400 MHz, DMSO-d6): δ8.23 (d, 1 H), 7.80-7.74 (m, 2 H), 7.57-7.53 (m, 1 H), 7.48-7.44 (m, 1 H), 7.38-7.31 (m, 2 H), 7.20-7.16 (m, 2 H), 5.86 (d, 1 H), 3.36-3.09 (m, 10 H), 2.75 (s, 6 H), 1.74 (t, 4 H), 1.61-1.56 (m, 2 H), 1.33-1.15 (m, 5 H), 1.02-0.83 (m, 3 H).

[0171] The nuclear magnetic resonance result shows that cariprazine and 1-hydroxy-2-naphthoic acid formed the salt in a molar ratio of 1:1.

[0172] Example 5: Preparation of cariprazine laurate (not part of the claimed invention)

[0173] 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 solution was stirred at room temperature for 12 h. Two volumes of water were added. The mixture was filtered. The solid was dried under vacuum at 40 °C for 12 h to give cariprazine laurate.

[0174] Example 6: Preparation of cariprazine palmitate (not part of the claimed invention)

[0175] 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 solution was stirred at room temperature for 12 h. A volume of water was added. The mixture was filtered. The solid was dried under vacuum at 40 °C for 12 h to give cariprazine palmitate.

[0176] Example 7: Preparation of cariprazine sebacate, cariprazine succinate, cariprazine malate, cariprazine lactate, cariprazine undecanoate, and cariprazine heptanoate (not part of the claimed invention) Cariprazine and acid were measured in a molar ratio of 1:1.1. Each acid was dissolved in methanol solvent, and the resulting acid reagent was added to a solution of cariprazine in methanol at room temperature to initiate a salt formation reaction. After 12 h of stirring at room temperature, the solvent was allowed to volatilize at room temperature, and the residue was dried to give the corresponding cariprazine salt.

[0177] Example 8: Preparation of the crystalline form A of cariprazine embonate

[0178] 2000 mg of the cariprazine embonate prepared in Example 1 was measured and added to 20 mL of methanol. The mixture was stirred at room temperature for 24 h to crystallize the cariprazine embonate. The solid was collected by filtration and dried under vacuum at 55 °C to give crystalline form A of cariprazine embonate (1900 mg, 95% yield).

[0179] Its powder X-ray diffraction plot is shown in Figure 2.

[0180] Its differential scanning calorimetry plot is shown in Figure 3, indicating a melting point of 166.5 °C. Its thermogravimetric analysis plot is shown in Figure 4, indicating two weight losses before 115 °C, which are attributed to surface solvent loss and channel water, and a weight loss of approximately 1.1% at 115–165 °C, which is attributed to water of crystallization loss.

[0181] Its nuclear magnetic resonance graph is shown in Figure 5, indicating that cariprazine and embonic acid formed the salt in a molar ratio of 1:1.

[0182] Example 9: Preparation of the crystalline form A of cariprazine embonate

[0183] A 30 g sample of the amorphous solid of cariprazine embonate prepared in Example 2 was measured and added to 300 mL of methanol. The mixture was stirred at 10 °C for 24 h to crystallize the cariprazine embonate. The solid was collected by filtration and dried under vacuum at 55 °C to give crystalline form A of cariprazine embonate (28.5 g). Example 10: Preparation of crystalline form B of cariprazine embonate

[0184] 200 mg of the crystalline form A of cariprazine embonate obtained in Example 9 was measured and prepared as a suspension in methanol solvent. In the suspension, the weight/volume ratio of crystalline form A of cariprazine embonate to dissolve was 40 mg/mL. The suspension was stirred for 3 days to allow the cariprazine embonate to crystallize to form crystalline form B of cariprazine embonate (180 mg).

[0185] Its powder X-ray diffraction plot is shown in Figure 14.

[0186] Its nuclear magnetic resonance result shows that it was a methanol solvate.

[0187] Example 11: Preparation of the B crystalline form of cariprazine embonate

[0188] Two grams of the crystalline form A of cariprazine embonate prepared in Example 9 were measured and added to 50 mL of methanol. The mixture was stirred at room temperature for 72 h to crystallize the cariprazine embonate. The solid was collected by filtration and dried under vacuum at 55 °C to give crystalline form B of cariprazine embonate (1.9 mg). Example 12: Preparation of crystalline form C of cariprazine embonate

[0189] The crystalline form A of cariprazine embonate obtained in Example 8 was measured and a suspension of it was prepared in acetone solvent. In the suspension, the weight/volume ratio of crystalline form A of cariprazine embonate to dissolve was 40 mg/mL. The suspension was stirred for 3 days to allow the cariprazine embonate to crystallize to form crystalline form C of cariprazine embonate.

[0190] Its powder X-ray diffraction plot is shown in Figure 15.

[0191] Its nuclear magnetic resonance result shows that it was an acetone solvate.

[0192] Example 13: Preparation of the D crystalline form of cariprazine embonate

[0193] 200 mg of the crystalline form of cariprazine embonate A prepared in Example 8 was measured and added to 2 mL of ethanol. The mixture was stirred at room temperature for 48 h to crystallize the cariprazine embonate. The solid was collected by filtration and dried under vacuum at 55 °C to give the crystalline form D of cariprazine embonate (190 mg, 95% yield).

[0194] Its powder X-ray diffraction plot is shown in Figure 10.

[0195] Its differential scanning calorimetry plot is shown in Figure 11, indicating a melting point of 164.6 °C. Its thermogravimetric analysis plot is shown in Figure 12, indicating a weight loss of approximately 4% before 190 °C, which is attributed to the loss of water and ethanol.

[0196] Its nuclear magnetic resonance plot is shown in Figure 13, indicating that cariprazine and embonic acid formed the salt in a 1:1 molar ratio, and the salt contained approximately 0.67 molecules of ethanol. Example 14: Preparation of the E crystalline form of cariprazine embonate

[0197] The crystalline form A of cariprazine embonate obtained in Example 8 was measured and a suspension of it was prepared in acetonitrile solvent. In the suspension, the weight/volume ratio of crystalline form A of cariprazine embonate to dissolve was 40 mg/mL. The suspension was stirred for 3 days to allow the cariprazine embonate to crystallize to form crystalline form E of cariprazine embonate. Its powder X-ray diffraction pattern is shown in Figure 16.

[0198] Example 15: Preparation of the E crystalline form of cariprazine embonate

[0199] Two grams of the crystalline form A of cariprazine embonate prepared in Example 9 were measured and added to 50 mL of acetonitrile. The mixture was stirred at room temperature for 72 h to crystallize the cariprazine embonate. The solid was collected by filtration and dried under vacuum at 55 °C to give the crystalline form E of cariprazine embonate (1.8 g).

[0200] Example 16: Preparation of the F crystalline form of cariprazine embonate

[0201] 200 mg of the crystalline form A of cariprazine embonate prepared in Example 8 was measured and added to 20 mL of isopropyl acetate. The mixture was stirred at room temperature for 12 h to crystallize the cariprazine embonate. The solid was collected by filtration and dried under vacuum at 55 °C to give the crystalline form F of cariprazine embonate (180 mg, 90% yield).

[0202] Its powder X-ray diffraction plot is shown in Figure 6.

[0203] Its differential scanning calorimetry plot is shown in Figure 7, indicating a melting point of approximately 166.6 °C.

[0204] Their thermogravimetric analysis chart is shown in Figure 8, indicating a weight loss of approximately 1.3% before 115°C, which is attributed to channel water loss, and a weight loss of approximately 1.3% at 115-175°C, which is attributed to water of crystallization loss.

[0205] Its nuclear magnetic resonance graph is shown in Figure 9, indicating that cariprazine and embonic acid formed the salt in a molar ratio of 1:1.

[0206] Example 17: Preparation of the G crystalline form of cariprazine embonate

[0207] 200 mg of the crystalline form A of cariprazine embonate obtained in Example 8 was measured and added to 5 mL of acetonitrile to form a suspension. The suspension was shaken for 5 days to allow the cariprazine embonate to crystallize to form the crystalline form G of cariprazine embonate.

[0208] Its powder X-ray diffraction plot is shown in Figure 17.

[0209] Its nuclear magnetic resonance result shows that it was an acetonitrile solvate.

[0210] Example 18: Preparation of the crystalline form I of cariprazine embonate

[0211] A 15 mg sample of the amorphous solid of cariprazine embonate obtained in Example 1 was measured and illuminated for 10 days to give crystalline form I of cariprazine embonate.

[0212] Its powder X-ray diffraction plot is shown in Figure 18.

[0213] Example 19: Preparation of crystalline form I of cariprazine hydrochloride (not part of the claimed invention)

[0214] Preparation of a sample of the crystalline form I of cariprazine hydrochloride according to the original patent for cariprazine hydrochloride:

[0215] One g of commercially available cariprazine free base was added to a 25 mL round-bottom flask. Two mL of methanol and eight mL of water were added. The mixture was stirred in an oil bath at 70 °C for 0.5 h. A mixed solution of 0.226 mL of concentrated hydrochloric acid and 0.35 mL of water was added. After complete dissolution, the solution was filtered while hot. Heating was stopped, and the solution was cooled naturally overnight to give a whitish solid (0.8 g).

[0216] Its powder X-ray diffraction plot is shown in Figure 19, indicating the I crystalline form of cariprazine hydrochloride.

[0217] Comparative Example 1: Comparisons of the stability of related substances and crystalline forms

[0218] The amorphous cariprazine embonate prepared in Example 1, the crystalline form A of cariprazine embonate prepared in Example 8, the crystalline form B of cariprazine embonate prepared in Example 10, the crystalline form F of cariprazine embonate prepared in Example 16, the crystalline form G of cariprazine embonate prepared in Example 17, and the crystalline form I of cariprazine hydrochloride prepared in Example 19 were left to stand under high temperature (60 °C), high humidity (25 °C/ 90 % RH), accelerated (40 °C/ 75 % RH), and illuminated (1.2 x 10<6> lux·h) conditions, and samples were made on Day 0, Day 5, Day 7, and Day 10 and analyzed by HPLC or XRPD.

[0219] The results for the related substances are shown in Table 1, indicating that the crystalline form A of cariprazine embonate, crystalline form B of cariprazine embonate, crystalline form G of cariprazine embonate, and crystalline form A of cariprazine embonate of the present description are relatively stable; the total of related substances remained substantially unchanged when left to stand under these conditions for 10 days, whereas the amorphous cariprazine embonate was unstable and showed a greater increase in impurities under high temperature conditions.

[0220] The results of the stability of the crystalline form are shown in Table 2, indicating that crystalline form A of cariprazine embonate of the present description had more excellent crystalline form stability than the known crystalline form I of cariprazine hydrochloride: when crystalline form A was left to stand under these conditions for 10 days, its crystalline form did not change and its crystallinity did not change significantly; and that crystalline form F of cariprazine embonate of the present description was relatively stable under high temperature and illuminated conditions—its crystalline form did not change—and would change to crystalline form A of cariprazine embonate under high humidity and accelerated conditions.

[0221] Table 1. Related Substances Results

[0223]

[0224]

[0227] Table 2. Crystalline form stability results

[0229]

[0232] Comparative Example 2: Solubility Comparison

[0234] The amorphous cariprazine embonate prepared in Example 1, the amorphous cariprazine hemiembonate prepared in Example 3, the amorphous cariprazine laurate prepared in Example 5, the cariprazine palmitate prepared in Example 6, the cariprazine sebacate, cariprazine succinate, cariprazine malate, cariprazine lactate, cariprazine undecanoate, and cariprazine heptanoate prepared in Example 7, the crystal form A of cariprazine embonate prepared in Example 8, the crystal form B of cariprazine embonate prepared in Example 10, the crystal form F of cariprazine embonate prepared in Example 16, the crystal form G of cariprazine embonate prepared in Example 17, the crystal form I of cariprazine hydrochloride Cariprazine prepared in Example 19 and cariprazine were each added to a corresponding medium. The mixtures were stirred at 37 °C for 24 h and filtered through 0.45 µm aqueous-phase filter membranes. The filtrates were collected, and solubility was determined by high-performance liquid chromatography. pH3, pH4, pH5, and pH6 represent acetate buffer solutions, and pH7, pH7.4, pH8, and pH9 represent phosphate buffer solutions.

[0236] The results are shown in Table 3, indicating that the solubilities of cariprazine embonate and the crystalline forms thereof and of cariprazine hemiembonate prepared in the present description were all significantly lower - the solubility of cariprazine embonate in water was 3-10 µg/ml, which is equivalent to one-eighteenth to one-sixtieth of the solubility of cariprazine (approximately 180 µg/ml) and one-thousandth to one-thirty-six hundredth of the solubility of cariprazine hydrochloride (approximately 11 mg/ml) - and all were relatively low in media having different pH values. Because they have sustained-release effects, their equivalent solubilities in media with different pH values allow the release rate to be minimally pH-dependent. This avoids the influence of pH environments in different body areas on drug release rates, prevents sudden releases or excessive plasma concentrations in local areas, and reduces differences in drug release between individuals. Furthermore, since cariprazine embonate has relatively good crystalline stability, it is suitable for use in extended-release preparations, allowing for lower doses and thus improving patient compliance. Cariprazine embonate has good commercial prospects.

[0237] Table 3. Solubility Results

[0239]

[0240]

[0242] Comparative Example 3: In vitro dissolution simulation experiment

[0243] The amorphous cariprazine embonate prepared in Example 1, the crystalline form A of cariprazine embonate prepared in Example 8, the crystalline form B of cariprazine embonate prepared in Example 10, and the crystalline form G of cariprazine embonate prepared in Example 17 were each mixed with a phosphate buffer solution having a pH of 7.4. The mixtures were stirred at 37 °C. Spot samples were taken at 1 h, 3 h, 5 h, 7 h, and 24 h, and the solubility was determined.

[0244] The results are shown in Table 4 and Figure 20, indicating that the composite samples of both crystalline form A of cariprazine embonate and crystalline form B of cariprazine embonate prepared in the present description dissolved more smoothly at pH 7.4 than the amorphous sample of cariprazine embonate and had a small 24 h solubility, indicating that the compounds in crystalline form are more suitable for use as pharmaceutically acceptable salts to avoid excessive plasma concentrations.

[0245] Table 4. Results of the in vitro dissolution simulation experiment

[0247]

[0249] Comparative Example 4: Comparison of solution stability

[0250] The crystalline form A of cariprazine embonate prepared in Example 8 and the crystalline form I of cariprazine hydrochloride prepared in Example 19 were each added to the corresponding media, such as pH 6, pH 7, pH 7.4, pH 8, pH 9, etc. The mixtures were stirred at 37 °C for 4 h and centrifuged. The residues were analyzed by XRPD, and the results show that the crystalline form A of cariprazine embonate did not change, while the crystalline form I of cariprazine hydrochloride dissociated into cariprazine free base. The results of the comparison at pH 7.4 are shown in Figure 21 (others are not shown). As can be seen from the results, crystalline form A of cariprazine embonate is more stable in solution compared to crystalline form I of cariprazine hydrochloride and therefore can effectively prevent changes in efficacy caused by changes in crystalline form after administration, thus improving drug safety. Examples 20-25: Aqueous suspensions of cariprazine embonate with different amounts of suspending agent

[0251] Amount (mg)

[0252] Component Example Example Example Example Example Example 20 21 22 23 24 25 Crystalline form A of embonate of

[0253] cariprazine (example 8 or example 9)<573>

[0254] Tween 20 100

[0255] Disodium phosphate 45

[0256] Monosodium phosphate 9

[0257] Mannitol 247

[0258] Sodium carboxymethylcellulose 15 25 35 50 75 100 Aqueous solution of sodium hydroxide (1 N) Appropriate amount

[0259] Aqueous solution of hydrochloric acid (1 N) Appropriate quantity

[0260] Water for injection qs 10.0 ml

[0262] Preparation process:

[0264] (1) Measured quantities of the formula of tween 20, disodium phosphate, monosodium phosphate and mannitol were added to water for injection, which was approximately 60% of the total amount of preparation, and dissolved and dispersed by stirring.

[0266] (2) The amount of the formula of the crystalline form A of cariprazine embonate was added to obtain aqueous suspensions of coarse particles.

[0268] (3) The above described coarse particle aqueous suspensions were ground in a ball mill to obtain suspensions having Dv(90) less than or equal to 10 micrometers.

[0270] (4) The amounts of sodium carboxymethylcellulose from the formula were added to the suspensions described above and thoroughly dispersed by shaking. Optionally, the pH was adjusted to 4.0-9.0 with sodium hydroxide or hydrochloric acid. The suspensions were brought to volume to obtain the suspensions of Examples 20-25.

[0272] The injectability, suspendability, settling ratio, and redispersibility of the formula samples prepared in Examples 20-25 were investigated, and the investigation revealed that all of the above-described suspension samples could pass through 0.45 x 15 mm syringe needles and had good suspendability, and that the samples in Examples 22-25 had good settling and 24-hour redispersibility ratios.

[0273] Examples 26-30: Aqueous suspensions of cariprazine embonate with different amounts of wetting agent

[0275] <Component>Quantity (mg)

[0276] Example 26 Example 27 Example 28 Example 29 Example 30 Crystalline form A of embonate of

[0277] cariprazine (example 8 or example 9)<573>

[0278] Tween 20 10 25 50 75 100 Disodium phosphate 45

[0279] Monosodium phosphate 9

[0280] Mannitol 247

[0281] Sodium carboxymethylcellulose 50

[0282] Aqueous solution of hydroxide Quantity

[0283] sodium (1 N) adequate

[0284] Aqueous hydrochloric acid solution Quantity

[0285] acid (1 N) suitable

[0286] Water for injection qs 10.0 ml

[0288] Preparation process:

[0290] (1) Measured quantities of the formula of tween 20, disodium phosphate, monosodium phosphate and mannitol were added to water for injection, which was approximately 60% of the total amount of the preparation, and dissolved and dispersed by stirring.

[0291] (2) The amount of the formula of the crystalline form A of cariprazine embonate was added to obtain aqueous suspensions of coarse particles.

[0292] (3) The above described coarse particle aqueous suspensions were ground in a ball mill to obtain suspensions having Dv(90) less than or equal to 10 micrometers.

[0293] (4) The amount of sodium carboxymethylcellulose from the formula was added to the suspensions described above and thoroughly dispersed by shaking. Optionally, the pH was adjusted to 4.0-9.0 with sodium hydroxide or hydrochloric acid. The suspensions were brought to volume to obtain the suspensions of Examples 26-30.

[0294] The injectability, suspendability, settling ratio, and wettability of the formula samples prepared in Examples 26-30 were investigated, and the investigation revealed that all of the above-described suspension samples could pass through 0.45 × 15 mm syringe needles and had good suspendability, settling ratios, and wettability.

[0295] Examples 31-34: Aqueous suspensions of cariprazine embonate of different particle sizes

[0297] <Component>Quantity (mg)

[0298] Example 31/Example 32/Example 33/Example 34 Crystalline form A of cariprazine embonate

[0299] (example 8 or example 9)<573>

[0300] Tween 20 100

[0301] Disodium phosphate 45

[0302] Monosodium phosphate 9

[0303] Mannitol 247 Sodium carboxymethylcellulose 50

[0304] Water for injection qs 10.0 ml

[0305] Preparation process:

[0306] (1) Measured quantities of the formula of tween 20, disodium phosphate, monosodium phosphate and mannitol were added to water for injection, which was approximately 60% of the total amount of preparation, and dissolved and dispersed by stirring.

[0307] (2) The amount of the formula of the crystalline form A of cariprazine embonate was added to obtain aqueous suspensions of coarse particles.

[0308] (3) The aqueous suspensions of coarse particles obtained above in Examples 31-34 were crushed and dispersed using a ball mill.

[0309] (4) The amount of sodium carboxymethylcellulose from the formula was added to the suspensions described above and thoroughly dispersed by shaking. The suspensions were brought to volume to obtain suspensions of Examples 32-35 having a pH of 7.4 ± 0.2.

[0310] (5) The particle size distribution of the ground example samples was measured on an OMEC LS-909 particle size analyzer, and the results are shown in the following table.

[0311] Example Dv10 (µm) Dv50 (µm) Dv90 (µm) Example 31 9,338 27,446 79,618

[0312] Example 32 1,257 4,794 14,601

[0313] Example 33 0.714 1.747 4.635

[0314] Example 34 0.715 1.097 2.097

[0315] From the results in the table above, it can be observed that in aqueous suspensions of the same formula, aqueous suspensions of particles of different particle sizes (Dv90) can be prepared by controlling the grinding parameters.

[0316] Examples 35-37: Aqueous suspensions of different crystalline forms of cariprazine embonate

[0317]

[0320] Preparation process:

[0322] (1) Measured quantities of the formula of tween 20, disodium phosphate, monosodium phosphate and mannitol were added to water for injection, which was approximately 60% of the total amount of the preparation, and dissolved and dispersed by stirring.

[0324] (2) The quantities from the corresponding sample formulas of cariprazine embonate were added to obtain aqueous suspensions of coarse particles.

[0326] (3) The aqueous suspensions of coarse particles obtained above in Examples 35-37 were crushed and dispersed using a ball mill.

[0328] (4) The amount of sodium carboxymethylcellulose from the formula was added to the suspensions described above and thoroughly dispersed by shaking. The suspensions were brought to volume to obtain suspensions of Examples 35-37 having a pH of 7.4 ± 0.2.

[0330] (5) The particle size distribution of the ground example samples was measured on an OMEC LS-909 particle size analyzer, and the results are shown in the following table.

[0332] Example Dv10 (µm) Dv50 (µm) Dv90 (µm) Example 35 0.833 2.684 6.825

[0333] Example 36 0.880 2.652 5.613

[0334] Example 37 0.879 2.586 5.867

[0336] The injectability, suspendability, settling ratio, and wettability of the formula samples prepared in Examples 35-37 were investigated, and the investigation revealed that all of the above-described suspension samples could pass through 0.45 × 15 mm syringe needles and had good suspendability, settling ratios, and wettability.

[0338] According to the results in the table above and the investigation of injectability, suspendability, settling ratio and wettability, aqueous suspensions of the same formula and the same milling parameters apply to different crystalline forms of cariprazine embonate.

[0340] Example 38: Aqueous suspension of cariprazine hydrochloride

[0342] Component Quantity (mg) Example 38 Cariprazine hydrochloride 326

[0343] Tween 20 100

[0344] Disodium phosphate 45

[0345] Monosodium phosphate 9

[0346] Mannitol 247 Sodium carboxymethylcellulose 50

[0347] Water for injection qs 10.0 ml

[0349] Preparation process:

[0350] (1) Measured quantities of the formula of tween 20, disodium phosphate, monosodium phosphate and mannitol were added to water for injection, which was approximately 60% of the total amount of preparation, and dissolved and dispersed by stirring.

[0352] (2) The amount of cariprazine hydrochloride from the formula was added to obtain an aqueous suspension of coarse particles.

[0354] (3) The aqueous suspension of coarse particles obtained above was crushed and dispersed using a ball mill.

[0355] (4) The quantity of sodium carboxymethylcellulose formula was added to the suspension described above and thoroughly dispersed by shaking. The suspension was brought to volume to obtain a suspension of Examples 38 having a pH of 7.4 ± 0.2.

[0357] (5) The particle size distribution of the ground illustrative sample was measured on an OMEC LS-909 particle size analyzer, and the results are shown in the following table.

[0359] Example Dv10 (µm) Dv50 (µm) Dv90 (µm) Example 38 0.769 1.992 5.336

[0361] Example 39: Investigation of the stability of aqueous suspensions of cariprazine embonate and cariprazine hydrochloride at 60 °C

[0363] The particle size at 0 days, 5 days and 10 days and related substances of cariprazine embonate prepared in Example 33 and the aqueous suspension of cariprazine hydrochloride prepared in Example 38 were measured at 60 °C, and the results are shown in the table below.

[0365] Example Time Point Total Impurities (%) Dv10 (µm) Dv50 (µm) Dv90 (µm)

[0366] 0 days 1.59 0.714 1.747 4.635 Example 33 5 days 2.21 1.045 3.345 6.428

[0367] 10 days 2.39 1.027 3.384 6.577 0 days 0.45 0.769 1.992 5.336 Example 38 5 days 1.15 49.172 98.002 201.336

[0368] 10 days 2.08 33,926 71,004 128,207

[0369] From the results in the table above, it can be observed that in aqueous suspensions of the same formula, the aqueous suspension of cariprazine embonate was significantly more stable than the aqueous suspension of cariprazine hydrochloride with respect to impurity and particle size.

[0371] Examples 40-44: Pharmacokinetic study of the cariprazine embonate suspension formula in rats

[0373] <Component>Quantity (mg)

[0374] Example 40 Example 41 Example 42 Example 43 Example 44 Cariprazine embonate in the form

[0375] amorphous (example 2)<573 - - - ->Cariprazine embonate in the form

[0376] crystalline A (Example 8)<- 573 - - 9.5>Cariprazine embonate in the form

[0377] crystalline B (example 11)<- - 573 - ->Cariprazine embonate in the form

[0378] crystalline E (example 15)<- - - 573 ->Tween 20 100 100 100 100 250 Disodium phosphate 45 45 45 45

[0379] Monosodium phosphate 9 9 9 9

[0380] Mannitol 247 247 247 247 Sodium carboxymethylcellulose 50 50 50 50 175 Water for injection qs 10.0 ml qs 50.0 ml

[0381] 1. Procedure for preparing injectable suspensions of examples 40-43:

[0382] (1) Measured quantities of tween 20 formula, disodium phosphate, monosodium phosphate, mannitol, and sodium carboxymethylcellulose were added to water for injection which was approximately 60% of the total amount of preparation, and dissolved and dispersed upon stirring.

[0383] (2) The quantities of cariprazine embonate from the corresponding sample formulas were added and thoroughly dispersed by shaking. The mixtures were brought to volume to obtain injectable suspensions of Examples 40-43 having a pH of 7.4 ± 0.2.

[0384] (3) The particle size distribution of the samples from Examples 41-43 was measured on an OMEC LS-909 particle size analyzer, and the results are shown in the table below.

[0385] Example Dv10 (µm) Dv50 (µm) Dv90 (µm) Example 41 12,215 26,987 48,348

[0386] Example 42 1,842 6,713 13,673

[0387] Example 43 0.827 2.682 6.831

[0388] 2. Procedure for preparing the oral suspension of example 44:

[0389] (1) Measured quantities of the tween 20 formula and sodium carboxymethylcellulose were added to water for injection which was approximately 60% of the total amount of preparation, and dissolved and dispersed upon stirring.

[0390] (2) The amount of cariprazine embonate from the formula was added to obtain an aqueous suspension of coarse particles. The pH was adjusted from 5.0 to 5.5 with hydrochloric acid. The suspension was brought to volume to finally obtain the oral suspension of Example 44.

[0391] Example 45: Pharmacokinetic experiment

[0392] An in vivo experiment was carried out in rats with different concentrations of cariprazine embonate samples from the formula prepared in Examples 40-44 as follows:

[0393] 15 male SD rats were divided into five groups, of which four groups were given single doses of sample formulas of different crystalline forms of cariprazine embonate by intramuscular injection at 9 mg/kg and plasma was collected 0 h, 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; the remaining group was given orally and intragastric single doses of sample formula of crystalline form A of cariprazine embonate at 0.3 mg/kg and plasma was collected 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h and 24 h after administration. Throughout the experiment, animals in the intramuscular injection group were given ad libitum access to food and water, and those in the oral intragastric group were fasted overnight before administration and given access to food 4 h after administration.

[0394] Plasma sample collection: Approximately 150 μl of blood was collected from the jugular vein (whole blood was centrifuged for 30 minutes to isolate the plasma) and placed in a tube containing the anticoagulant EDTA-K2, and after treatment, the plasma was stored in a freezer at -70 °C prior to use.

[0395] Plasma sample pretreatment: 200 μl of internal standard solution (40 ng/ml glipizide acetonitrile solution) was added to 30 μl of plasma sample; the mixture was vortexed for 1 min and centrifuged at 5800 rpm at 4 °C for 10 min; 100 μl of supernatant was transferred to a fresh plate and 1 μl of solution was taken for analysis by LC-MS/MS.

[0396] Chromatographic conditions:

[0397] Mobile phase composition: Mobile phase A: 0.025% formic acid in water - 1 mM ammonium acetate Mobile phase B: 0.025% methanoic acid in methanol - 1 mM ammonium acetate

[0398] Gradient elution:

[0400]

[0401]

[0403] Chromatography column: Waters ACQUITY UPLC BEH C18 (2.1 × 50 mm, 1.7 µm);

[0404] Flow rate: 0.60 ml/min;

[0405] Injection volume: 1 µl;

[0406] Column compartment: 60 °C;

[0407] Retention time: cariprazine: 1.16 min; Glipizide: 1.22 min.

[0408] Mass spectrometry conditions:

[0409] Secondary mass spectrometry analysis was performed using an electrospray ion source (Turbo spray) in multiple reaction monitoring (MRM) mode under positive ion detection mode. The operating parameters and ion source parameters for the mass spectrometry analysis are shown in the following table.

[0411]

[0413] As can be seen in Figures 22-24, the oral group of cariprazine embonate achieved rapid absorption within 24 h of drug administration, while all injection groups of cariprazine embonate achieved at least 11 days of sustained release compared to the oral group and, given interspecies differences, are expected to be able to achieve at least 30 days of release in humans. Meanwhile, among the crystalline forms of cariprazine embonate, crystalline form A of cariprazine embonate achieved the best duration of release.

[0414] From the experimental results of the present description, it can be observed that after the injectable preparations of cariprazine embonate provided by the present description were formulated in aqueous suspensions, the cariprazine embonate had a relatively small granularity and was uniformly distributed, having good injectability and also the characteristic of continuously releasing the drug for a prolonged time (at least one week in SD rats).

Claims (13)

1. CLAIMS 1. A pharmaceutical composition, wherein the pharmaceutical composition comprises solid cariprazine embonate particles, wherein the solid cariprazine embonate particles have particle sizes Dv(10) of ≤30 micrometers, Dv(50) of ≤50 micrometers and Dv(90) of ≤100 micrometers; wherein the cariprazine embonate is selected from one or more of the crystalline forms A, F, D, B, C, E, G and I of cariprazine embonate, wherein: A powder X-ray diffraction plot of the A crystalline form of cariprazine embonate 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°; A powder X-ray diffraction plot of the F crystalline form of cariprazine embonate 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°; A powder X-ray diffraction plot of the D crystalline form of cariprazine embonate 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°; A powder X-ray diffraction plot of the B crystalline form of cariprazine embonate 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°; A powder X-ray diffraction plot of the C crystalline form of cariprazine embonate 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°; A powder X-ray diffraction plot of the E crystalline form of cariprazine embonate 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°; A powder X-ray diffraction plot of the G crystalline form of cariprazine embonate 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°; A powder X-ray diffraction plot of the crystalline form I of cariprazine embonate 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°. 2. The pharmaceutical composition according to claim 1, wherein: A powder X-ray diffraction plot of the A crystalline form of cariprazine embonate 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°; A powder X-ray diffraction plot of the F crystalline form of cariprazine embonate 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°; A powder X-ray diffraction plot of the D crystalline form of cariprazine embonate 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°. 3. The pharmaceutical composition according to claim 1 or 2, wherein the composition is an injectable preparation; The composition further comprises an auxiliary material selected from one or more of a suspending agent, a wetting agent, an osmotic pressure regulator, a solvent, a stabilizer, a buffer, and a surfactant. 4. The pharmaceutical composition according to claim 3, wherein the suspending agent is at a concentration in the range of 0 mg/ml to 10 mg/ml. The suspending agent is selected from one or more of sodium carboxymethylcellulose, methylcellulose, and polyvinylpyrrolidone. 5. The pharmaceutical composition according to claim 3, wherein the suspending agent is at a concentration in the range of 3.5 mg/ml to 5 mg/ml; The suspending agent is sodium carboxymethylcellulose. 6. The pharmaceutical composition according to claim 3, wherein the wetting agent is at a concentration in the range of 1 mg/ml to 10 mg/ml; The wetting agent is selected from one or more of tween 20, tween 80, and poloxamer 188. 7. The pharmaceutical composition according to claim 3, wherein the wetting agent is at a concentration in the range of 1 mg/ml to 5 mg/ml; The wetting agent is Tween 20. 8. The pharmaceutical composition according to claim 3, wherein the osmotic pressure regulator is at a concentration in the range of 20 mg/ml to 30 mg/ml; and/or, The osmotic pressure regulator is selected from one or more of sodium chloride, mannitol, and sucrose; and/or, The stabilizer is at a concentration in the range of 0 mg/ml to 30 mg/ml; I, the stabilizer is PVP K12; I, The buffer is selected from one or more of phosphoric acid, phosphate, citric acid, sodium citrate, hydrochloric acid, and sodium hydroxide; I, The surfactant is sodium deoxycholate; I, The solvent is water for injection. 9. The pharmaceutical composition according to claim 3, wherein The osmotic pressure regulator is at a concentration in the range of 23 mg/ml to 26 mg/ml; and/or the stabilizer is at a concentration in the range of 1 mg/ml to 10 mg/ml. 10. The pharmaceutical composition according to claim 3, wherein the composition comprises: (a) cariprazine embonate; (b) sodium carboxymethylcellulose; (c) tween 20; (d) disodium phosphate; (e) monosodium phosphate; and (f) mannitol; and Optionally, the composition of cariprazine comprises sodium hydroxide or hydrochloric acid. 11. The pharmaceutical composition according to claim 3, wherein the solid cariprazine embonate particles are at a concentration of not less than 15 mg/ml. 12. A method of preparing the pharmaceutical composition according to any one of claims 3-11, comprising the following steps: (1) sequentially dissolve the wetting agent, buffering agent and osmotic pressure regulator in water for injection; (2) add the solid particles of cariprazine embonate to obtain an aqueous suspension of coarse particles; (3) grinding the aqueous suspension of coarse particles described above with a ball mill to obtain a suspension; and (4) Add a certain concentration of the suspending agent to the suspension described above, mix the suspension homogeneously, adjust the pH to 4.0-9.0 with sodium hydroxide or hydrochloric acid, and bring the suspension to volume to obtain an aqueous suspension. 13. The pharmaceutical composition according to any one of claims 1-11 for use as a medicament to treat and/or prevent psychosis, bipolar disorder or acute mania.