Crystals of caliprazine medicinal salt, pharmaceutical composition, manufacturing method and use

Abstract

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

Description

Detailed Description of the Invention

[0001] This application claims the priority of a prior application filed by the applicant with the State Intellectual Property Office of China on February 22, 2022, with an application number of 202210162007.8 and a title of "Cariprazine Medicinal Salt and Its Crystal Form, Pharmaceutical Composition, Manufacturing Method and Use". The above prior application is incorporated herein by reference in its entirety.

[0002] 〔Technical Field〕 The present invention belongs to the field of chemical pharmaceuticals, and specifically relates to cariprazine medicinal salts and their crystal forms, pharmaceutical compositions, manufacturing methods and uses.

[0003] 〔Background Art〕 Cariprazine, whose chemical structure is shown below, is a novel atypical antipsychotic drug that has an antagonistic effect on dopamine D3, dopamine D2 and serotonin 2B receptors, and can be used for the treatment of schizophrenia and bipolar type I disorder. The currently commercially available cariprazine hydrochloride capsules are oral preparations and need to be administered daily to maintain the blood drug concentration. However, due to frequent administration, there is a problem that the patient's compliance is poor.

[0004]

Chemical Formula

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

[0006] 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.

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

[0008] Patent document CN108261394A discloses a caliprazine hydrochloride injectable formulation, including in the form of a suspension aqueous solution and a lyophilized formulation, that can achieve sustained release for at least one week. However, in the course of research, the inventors found that the stability of the aqueous solution of caliprazine hydrochloride is not ideal, and dissociation occurs under weakly acidic to alkaline conditions, posing a risk of dissociation in the suspension aqueous solution. As a result, the properties and quality of the product are easily altered, the solubility and absorption of the drug change, affecting the efficacy of the drug and the safety of drug use for patients, making it unsuitable for use in long-acting sustained-release formulations. Furthermore, the caliprazine concentration, administered concentration, and blood drug concentration in animal pK experiments of the caliprazine hydrochloride injectable formulation disclosed in patent document CN108261394A are too high. In line with prior research data showing that caliprazine removal varies greatly among species (approximately 2-4 hours in rats and 3-9 days in humans), excessively high blood drug concentrations can lead to relatively greater toxicity and side effects, and the possibility of excessive accumulation of the drug in the human body.

[0009] There are currently no reports of improved performance in caliprazine poorly soluble salt injection formulations.

[0010] In light of the shortcomings of conventional technology, finding a caliprazine medicinal salt and its crystalline form that has low solubility, is suitable for long-acting administration, is highly stable, has good clinical efficacy, and / or is suitable for commercialization is a technical problem that urgently needs to be solved in this field.

[0011] [Summary of the Invention] To solve the problems described above in the prior art, the present invention provides pharmaceutically acceptable salts of caliprazine, particularly 1-hydroxy-2-naphthoate or caliprazine pamoate of caliprazine, and / or novel solid forms thereof, as well as pharmaceutical compositions, methods for producing them, and uses thereof.

[0012] According to embodiments of the present invention, the 1-hydroxy-2-naphthoate of the above-mentioned caliprazine is selected from caliprazine mono-1-hydroxy-2-naphthoate represented by the following formula (I), or caliprazine bis-1-hydroxy-2-naphthoate represented by the following formula (II).

[0013] [ka]

[0014] According to embodiments of the present invention, the above-mentioned caliprazine 1-hydroxy-2-naphthoate is crystal form A of caliprazine mono-1-hydroxy-2-naphthoate, preferably crystal form A of caliprazine mono-1-hydroxy-2-naphthoate hydrate, and more preferably crystal form A of caliprazine mono-1-hydroxy-2-naphthoate dihydrate. Among these, the X-ray powder diffraction pattern of crystal form A of caliprazine mono-1-hydroxy-2-naphthoate, preferably crystal form A of caliprazine mono-1-hydroxy-2-naphthoate hydrate, and more preferably crystal form A of caliprazine mono-1-hydroxy-2-naphthoate dihydrate has characteristic peaks at 2θ values ​​of 15.6°±0.2°, 19.7°±0.2°, 20.7°±0.2°, etc.

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

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

[0017] Furthermore, the X-ray powder diffraction patterns of the above-mentioned caliprazine mono-1-hydroxy-2-naphthoate crystalline form A, preferably caliprazine mono-1-hydroxy-2-naphthoate hydrate crystalline form A, more preferably caliprazine mono-1-hydroxy-2-naphthoate dihydrate crystalline form A, are 2θ values ​​of 4.4°±0.2°, 8.6°±0.2°, 9.7°±0.2°, and 11 Absorption peaks are observed at 0.4°±0.2°, 12.7°±0.2°, 15.6°±0.2°, 16.5°±0.2°, 16.9°±0.2°, 17.3°±0.2°, 18.8°±0.2°, 19.7°±0.2°, 20.2°±0.2°, 20.7°±0.2°, 23.3°±0.2°, 24.3°±0.2°, 24.9°±0.2°, and 29.5°±0.2°, among others.

[0018] Furthermore, the crystal form A of the above-mentioned caliprazine mono-1-hydroxy-2-naphthoate, preferably the crystal form A of caliprazine mono-1-hydroxy-2-naphthoate hydrate, and more preferably the crystal form A of caliprazine mono-1-hydroxy-2-naphthoate dihydrate, basically has the X-ray powder diffraction pattern shown in Figure 1.

[0019] Preferably, the crystalline form A of the above-mentioned caliprazine mono-1-hydroxy-2-naphthoate, preferably the crystalline form A of caliprazine mono-1-hydroxy-2-naphthoate hydrate, and more preferably the crystalline form A of caliprazine mono-1-hydroxy-2-naphthoate dihydrate, basically have the differential scanning calorimetry pattern shown in Figure 2.

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

[0021] Preferably, the crystal form A of the above-mentioned cariprazine mono 1-hydroxy-2-naphthoate, preferably the crystal form A of cariprazine mono 1-hydroxy-2-naphthoate hydrate, more preferably the crystal form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate basically has the thermogravimetric analysis pattern shown in Figure 2, and a weight loss of about 4.82% is shown before 100 °C.

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

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

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

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

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

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

[0028] According to an embodiment of the present invention, there is further provided a method for producing crystal form A of the above caliprazine mono 1-hydroxy-2-naphthoate, preferably crystal form A of caliprazine mono 1-hydroxy-2-naphthoate hydrate, more preferably crystal form A of caliprazine mono 1-hydroxy-2-naphthoate dihydrate, which includes the following steps. (a1) Dissolve caliprazine in an aqueous phosphoric acid solution, filter to obtain solution A, mix an aqueous 1-hydroxy-2-naphthoic acid solution and an aqueous sodium hydroxide solution, and filter to obtain solution B. (a2) Add solution B to solution A at a solute molar ratio of 1:1, stir at room temperature, and obtain crystal form A of the above caliprazine mono 1-hydroxy-2-naphthoate, preferably crystal form A of caliprazine mono 1-hydroxy-2-naphthoate hydrate, more preferably crystal form A of caliprazine mono 1-hydroxy-2-naphthoate dihydrate.

[0029] Alternatively, a method for producing the above-mentioned caliprazine mono-1-hydroxy-2-naphthoate crystalline form A, preferably caliprazine mono-1-hydroxy-2-naphthoate hydrate crystalline form A, more preferably caliprazine mono-1-hydroxy-2-naphthoate dihydrate crystalline form A, comprises the following steps. (a3) Mix caliprazine and 1-hydroxy-2-naphthoic acid with the solvent in a molar ratio of 1:1. (a4) Stir at 25-70°C to obtain crystal form A of the above-mentioned caliprazine mono-1-hydroxy-2-naphthoate, preferably crystal form A of caliprazine mono-1-hydroxy-2-naphthoate hydrate, and more preferably crystal form A of caliprazine mono-1-hydroxy-2-naphthoate dihydrate.

[0030] According to embodiments of the present invention, the solvent is a mixed system of methanol, ethanol, or acetone and water. Preferably, the volume ratio of methanol, ethanol, or acetone to water may be 2:1 to 1:2, for example, 1:1.

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

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

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

[0034] Furthermore, the X-ray powder diffraction pattern of crystal form B of the above-mentioned caliprazine mono-1-hydroxy-2-naphthoate shows characteristic peaks at 2θ values ​​of 5.5°±0.2°, 11.5°±0.2°, 13.0°±0.2°, 14.6°±0.2°, 16.9°±0.2°, 18.8°±0.2°, 19.5°±0.2°, and 23.7°±0.2°.

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

[0036] Furthermore, the crystal form B of the above-mentioned caliprazine mono-1-hydroxy-2-naphthoate basically has the X-ray powder diffraction pattern shown in Figure 4.

[0037] Preferably, the crystalline form B of the above-mentioned caliprazine mono-1-hydroxy-2-naphthoate has basically the differential scanning calorimetry pattern shown in Figure 5.

[0038] Preferably, the melting point of crystalline form B of the above-mentioned caliprazine mono-1-hydroxy-2-naphthoate is approximately 106.8°C.

[0039] Furthermore, in crystalline form B of the above-mentioned caliprazine mono-1-hydroxy-2-naphthoate, a salt is formed between caliprazine and 1-hydroxy-2-naphthoic acid in a molar ratio of 1:1, and its 1H-NMR spectrum is basically shown in Figure 6.

[0040] According to embodiments of the present invention, a method for producing crystalline form B of the above-mentioned calipradine mono-1-hydroxy-2-naphthoate includes the following steps. (b1) Mix caliprazine and 1-hydroxy-2-naphthoic acid with the solvent in a molar ratio of 1:1. (b2) Stir at 25-70°C to obtain crystalline form B of the above-mentioned caliprazine mono-1-hydroxy-2-naphthoate.

[0041] According to embodiments of the present invention, the solvent is a mixed system of methanol, ethanol, or acetone and water. Preferably, the volume ratio of methanol, ethanol, or acetone to water may be 2:1 to 1:2, for example, 1.5:1.

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

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

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

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

[0046] Furthermore, the crystalline form C of the above-mentioned caliprazine mono-1-hydroxy-2-naphthoate basically has the X-ray powder diffraction pattern shown in Figure 7.

[0047] Preferably, the crystalline form C of the above-mentioned caliprazine mono-1-hydroxy-2-naphthoate basically has the differential scanning calorimetry pattern shown in Figure 8.

[0048] Preferably, the melting point of crystalline form C of the above-mentioned caliprazine mono-1-hydroxy-2-naphthoate is approximately 103.4°C.

[0049] According to embodiments of the present invention, in crystalline form C of the above-mentioned caliprazine mono-1-hydroxy-2-naphthoate, a salt is formed between caliprazine and 1-hydroxy-2-naphthoic acid in a molar ratio of 1:1, and its 1H-NMR spectrum is basically shown in Figure 9.

[0050] According to embodiments of the present invention, a method for producing crystalline form C of the above-mentioned calipradine mono-1-hydroxy-2-naphthoate includes the following steps. (c1) Mix caliprazine and 1-hydroxy-2-naphthoic acid with the solvent in a molar ratio of 1:1. (c2) Stir at 25-70°C to obtain the crystalline form C of the above-mentioned caliprazine mono-1-hydroxy-2-naphthoate.

[0051] According to embodiments of the present invention, the solvent is a mixed system of methanol, ethanol, or acetone and water. Preferably, the volume ratio of methanol, ethanol, or acetone to water may be 2:1 to 1:2, for example, 1.5:1.

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

[0053] According to embodiments of the present invention, the above-mentioned caliprazine 1-hydroxy-2-naphthoate is caliprazine bis-1-hydroxy-2-naphthoate represented by formula (II) above, wherein the molar ratio of caliprazine to 1-hydroxy-2-naphthoic acid is 1:2.

[0054] According to embodiments of the present invention, the above-mentioned calipradine bis-1-hydroxy-2-naphthoate may be in solid form, for example, amorphous or crystalline form. According to embodiments of the present invention, the above-mentioned calipradine bis-1-hydroxy-2-naphthoate is crystalline form A of calipradine bis-1-hydroxy-2-naphthoate, and the X-ray powder diffraction pattern of crystalline form A of calipradine bis-1-hydroxy-2-naphthoate has characteristic peaks at 2θ values ​​of 4.7°±0.2°, 9.4°±0.2°, 20.8°±0.2°, etc.

[0055] Furthermore, the X-ray powder diffraction pattern of crystalline form A of the above-mentioned calipradine bis-1-hydroxy-2-naphthoate exhibits characteristic peaks at 2θ values ​​of 4.7°±0.2°, 9.4°±0.2°, 12.7°±0.2°, 20.1°±0.2°, 20.8°±0.2°, and 27.4°±0.2°.

[0056] Furthermore, the X-ray powder diffraction pattern of crystalline form A of the above-mentioned calipradine bis-1-hydroxy-2-naphthoate exhibits characteristic peaks at 2θ values ​​of 4.7°±0.2°, 9.4°±0.2°, 12.7°±0.2°, 17.1°±0.2°, 19.1°±0.2°, 20.1°±0.2°, 20.8°±0.2°, and 27.4°±0.2°.

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

[0058] Furthermore, the crystalline form A of the above-mentioned calipradine bis-1-hydroxy-2-naphthoate basically has the X-ray powder diffraction pattern shown in Figure 10.

[0059] Preferably, the crystalline form A of the above-mentioned calipradine bis-1-hydroxy-2-naphthoate has basically the differential scanning calorimetry pattern shown in Figure 11.

[0060] Preferably, the melting point of crystalline form A of the above-mentioned calipradin bis-1-hydroxy-2-naphthoate is approximately 86.3°C.

[0061] Preferably, the thermogravimetric analysis pattern of crystalline form A of the above-mentioned calipradine bis-1-hydroxy-2-naphthoate is basically shown in Figure 11, showing a weight loss of approximately 1.31% before 100°C.

[0062] Preferably, the crystalline form A of the above-mentioned calipradin bis-1-hydroxy-2-naphthoate is the hydrate of calipradin bis-1-hydroxy-2-naphthoate.

[0063] Preferably, the 1H-NMR spectrum of crystalline form A of the above-mentioned caliprazine bis-1-hydroxy-2-naphthoate is basically shown in Figure 12, indicating that the salt is formed with caliprazine and 1-hydroxy-2-naphthoic acid in a molar ratio of 1:2.

[0064] According to embodiments of the present invention, a method for producing crystalline form A of the above-mentioned calipradin bis-1-hydroxy-2-naphthoate includes the following steps.

[0065] Caliprazine and 1-hydroxy-2-naphthoic acid are added to the solvent in a molar ratio of 1:2, and the mixture is stirred at 25-70°C to obtain crystalline form A of the above-mentioned caliprazine bis-1-hydroxy-2-naphthoate.

[0066] The solvent described above is a mixture of methanol, ethanol, or acetone and water. Preferably, the volume ratio of methanol, ethanol, or acetone to water may be 2:1 to 1:2, for example, 1:1.

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

[0068] According to embodiments of the present invention, the above-mentioned caliprazine pamoate has the structure shown in the following formula (III).

[0069] [ka]

[0070] According to embodiments of the present invention, in the above-mentioned caliprazine pamoate, the molar ratio of caliprazine to pamoic acid is 1:1.

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

[0072] Furthermore, the crystalline form H of the above-mentioned calipradin pamoate basically has the X-ray powder diffraction pattern shown in Figure 13.

[0073] According to embodiments of the present invention, the above-mentioned calipradin pamoate is amorphous and preferably has an X-ray powder diffraction pattern basically shown in Figure 14.

[0074] According to embodiments of the present invention, the solid form may be a crystalline or amorphous form of a pharmaceutically acceptable salt of caliprazine, and may be an anhydrous, hydrate, or solvate. If present, the molar ratio of the salt to water molecules or solvent molecules in the solid form can vary within the range of 1:0.5 to 1:5 (e.g., 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3), and this molar ratio can be detected by methods known to those skilled in the art.

[0075] The present invention further provides combinations of pharmaceutically acceptable salts of caliprazine, comprising at least one, for example two or three, of the pharmaceutically acceptable salts of caliprazine described above or in their solid forms, and optionally other pharmaceutically acceptable salts of caliprazine present, or other forms of the above-mentioned caliprazine mono-1-hydroxy-2-naphthoate, caliprazine bis-1-hydroxy-2-naphthoate, or caliprazine pamoate.

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

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

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

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

[0080] The above-mentioned caliprazine solid particles may be one selected from the caliprazine mono-1-hydroxy-2-naphthoate, caliprazine bis-1-hydroxy-2-naphthoate, caliprazine pamoate, or their crystalline forms.

[0081] According to embodiments of the present invention, pharmaceutically acceptable salts of caliprazine include, but are not limited to, caliprazine mono-1-hydroxy-2-naphthoate, caliprazine bis-1-hydroxy-2-naphthoate, and caliprazine pamoate.

[0082] According to embodiments of the present invention, the caliplazin solid particles may be amorphous or crystalline.

[0083] According to embodiments of the present invention, the above-mentioned caliprazine pharmaceutical composition may further contain an auxiliary agent, which may be one or more selected from suspending agents, wetting agents, osmotic pressure modifiers, solvents, and buffering agents.

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

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

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

[0087] According to embodiments of the present invention, the wetting agent is one or more selected from Tween20, Tween80, and poloxamer188, and is preferably poloxamer188.

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

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

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

[0091] According to embodiments of the present invention, the buffering agent is one or more selected from phosphoric acid, phosphate, guanoic acid, sodium guanoic acid, hydrochloric acid, and sodium hydroxide.

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

[0093] For example, the above-mentioned caliprazine pharmaceutical composition may contain the following components. (a) Caliprazine 1-hydroxy-2-naphthoate, (b) Sodium carboxymethylcellulose or PVP K30, (c)Tween20 or Poloxamer188, (d) Disodium hydrogen phosphate, (e) Sodium dihydrogen phosphate, (f) Mannitol.

[0094] Furthermore, the above-mentioned pharmacochemical composition of caliprazine may selectively contain a pH adjusting agent such as sodium hydroxide or hydrochloric acid.

[0095] According to embodiments of the present invention, the pH of the above-mentioned caliprazine pharmaceutical composition may be 4.0 to 9.0, for example, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, or 9.0.

[0096] According to embodiments of the present invention, the above-mentioned caliprazine pharmaceutical composition is an injectable preparation, for example, a long-acting injectable preparation.

[0097] According to embodiments of the present invention, the above-mentioned caliprazine pharmaceutical composition is a suspension or a suspension flotation agent, preferably an aqueous suspension or an aqueous suspension flotation agent.

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

[0099] According to embodiments of the present invention, a method for producing the above-mentioned caliprazine pharmaceutical composition includes mixing the above-mentioned components.

[0100] Preferably, the method for producing the above-mentioned caliprazine pharmaceutical composition includes the following steps. (1) Selectively dissolve the suspending agent, wetting agent, buffering agent, and osmotic pressure adjusting agent in the solvent. (2) Add calipladine solid particles to obtain a suspension aqueous solution of coarse particles. (3) Selectively, the aqueous suspension of the coarse particles is polished with a ball mill to obtain a suspension of fine particles. (4) Selectively add the suspending agent to the suspension of the fine particles, mix uniformly, selectively adjust the pH to 4.0-9.0 using sodium hydroxide or hydrochloric acid, and then raise to a fixed volume to obtain an aqueous suspension. According to an embodiment of the manufacturing method of the present invention, in step (1), the suspending agent, wetting agent, buffering agent, and osmotic pressure adjusting agent can be sequentially dissolved in a solvent such as water for injection.

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

[0102] The present invention provides the use of one of the aforementioned caliprazine mono-1-hydroxy-2-naphthoate, caliprazine bis-1-hydroxy-2-naphthoate, caliprazine pamoate or its crystalline form, a combination of pharmaceutically acceptable salts of caliprazine, or a pharmaceutical composition of caliprazine in the manufacture of a drug for treating and / or preventing cognitive or mental disorders such as psychosis, bipolar disorder, and acute mania.

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

[0104] According to embodiments of the present invention, "Dv(10)", "Dv(50)", "Dv(90)", and "Dv(100)" are volume-weighted particle diameters, where particles with 10v / v%, 50v / v%, 90v / v%, and 100v / v% accumulated at the time of measurement have equal or relatively smaller diameters. For example, if the Dv(50) of a particle group is about 25 microns, then particles with 50% volume have a diameter of about 25 microns or less.

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

[0106] The reagents and raw materials used in this invention are all commercially available.

[0107] According to embodiments of the present invention, the above-mentioned room temperature refers to an ambient temperature of 10°C to 35°C.

[0108] Beneficial effects As a result of extensive research, screening, and trials, the inventors have found that the salts of caliprazine and their solid forms provided by the present invention, particularly caliprazine 1-hydroxy-2-naphthoate in the form of the poorly soluble caliprazine salt, possess the characteristics of a long-acting sustained-release formulation and can be developed as a suspension injection. At the same time, it overcomes the problems of conventional salt forms such as caliprazine hydrochloride, which have the risk of dissociation or lack of sustained-release action, thereby achieving the effect of long-acting administration and significantly improving patient compliance, drug bioavailability, and administration safety.

[0109] The caliprazine salt and its pharmaceutical composition of the present invention have characteristics such as sustained release, high bioavailability, good solution stability, and small dose volume, and can sustainably release caliprazine for more than three weeks with a single dose, thus the market outlook is favorable.

[0110] [Brief explanation of the drawing] [Figure 1] XRPD pattern of crystal form A of caliprazine mono-1-hydroxy-2-naphthoate dihydrate.

[0111] [Figure 2] This is the DSC / TGA pattern of crystal form A of caliprazine mono-1-hydroxy-2-naphthoate dihydrate.

[0112] [Figure 3] This is the 1H-NMR pattern of crystal form A of caliprazine mono-1-hydroxy-2-naphthoate dihydrate.

[0113] [Figure 4] XRPD pattern of crystal form B of caliprazine mono-1-hydroxy-2-naphthoate.

[0114] [Figure 5] This is the DSC pattern of crystalline form B of caliprazine mono-1-hydroxy-2-naphthoate.

[0115] [Figure 6] This is the 1H-NMR pattern of crystal form B of caliprazine mono-1-hydroxy-2-naphthoate.

[0116] [Figure 7] XRPD pattern of crystalline form C of caliprazine mono-1-hydroxy-2-naphthoate.

[0117] [Figure 8] This is the DSC pattern of crystalline form C of caliprazine mono-1-hydroxy-2-naphthoate.

[0118] [Figure 9] This is the 1H-NMR pattern of the crystalline form C of calipradine bis-1-hydroxy-2-naphthoate.

[0119] [Figure 10] XRPD pattern of crystal form A of calipradine bis-1-hydroxy-2-naphthoate hydrate.

[0120] [Figure 11] This is the DSC / TGA pattern of crystal form A of calipradine bis-1-hydroxy-2-naphthoate hydrate.

[0121] [Figure 12] This is the 1H-NMR pattern of crystal form A of calipradine bis-1-hydroxy-2-naphthoate hydrate.

[0122] [Figure 13] XRPD pattern of crystalline form H of caliprazine pamoate.

[0123] [Figure 14] Amorphous XRPD pattern of caliprazine pamoate.

[0124] [Figure 15] XRPD pattern of crystalline form I of caliprazine hydrochloride.

[0125] [Figure 16] This is an XRPD pattern overlay of the caliprazine hydrochloride dissociation study under pH 7.4 conditions in Example 44, where A is the free caliprazine base, B is the caliprazine hydrochloride crystalline form I, and C is the caliprazine hydrochloride crystalline form I sample after shaking in a pH 7.4 medium.

[0126] [Figure 17] This figure shows the relationship between the average blood drug concentration of caliprazine in an oral liquid sample of the formulation of Example 48 of the present invention in rats and time.

[0127] [Figure 18] This figure shows the relationship between the average blood drug concentration of caliprazine and time for injection samples of the formulations of Examples 45-47 of the present invention in rats. Of these, ■ represents the crystalline form A of caliprazine mono-1-hydroxy-2-naphthoate dihydrate, ▲ represents the crystalline form A of caliprazine bis-1-hydroxy-2-naphthoate hydrate, and ◆ represents the amorphous form of caliprazine pamoate.

[0128] [Figure 19] Local magnified view of Figure 18 (This diagram shows the relationship between the average blood drug concentration of caliprazine from 0 to 24 hours and time, where ■ represents the crystalline form A of caliprazine mono-1-hydroxy-2-naphthoate dihydrate, ▲ represents the crystalline form A of caliprazine bis-1-hydroxy-2-naphthoate hydrate, and ◆ represents the amorphous form of caliprazine pamoate.

[0129] [Figure 20] This figure shows the relationship between the average blood drug concentration of caliprazine and time in injection samples of the formulation of Example 42 of the present invention in rats of different sexes. Of these, ■ represents the relationship in male rats for crystalline form A of caliprazine mono-1-hydroxy-2-naphthoate dihydrate, and ▲ represents the relationship in female rats for crystalline form A of caliprazine mono-1-hydroxy-2-naphthoate dihydrate.

[0130] [Figure 21] Local emission diagram of Figure 18 (a diagram showing the relationship between the average blood drug concentration of caliprazine and time from 0 to 24 hours, where ■ is the relationship diagram of caliprazine mono-1-hydroxy-2-naphthoate dihydrate crystalline form A in male rats, and ▲ is the relationship diagram of caliprazine mono-1-hydroxy-2-naphthoate dihydrate crystalline form A in female rats.

[0131] [Figure 22] This is the X-ray diffraction pattern of a single crystal of crystal form A of caliprazine mono-1-hydroxy-2-naphthoate dihydrate.

[0132] [Figure 23] This is an elliptical diagram of the single-crystal molecular structure of caliprazine mono-1-hydroxy-2-naphthoate dihydrate.

[0133] [Figure 24] This is a projection view of the stacked unit cells along the b-axis of a single crystal of caliprazine mono-1-hydroxy-2-naphthoate dihydrate.

[0134] [Modes for carrying out the invention] The present invention will be further described below with reference to examples, but this does not limit the present invention to the scope of the examples described. In the following examples, experimental methods for which specific conditions are not specified are selected according to conventional methods and conditions or the product's instructions.

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

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

[0137] (2) DSC measurements were performed using a TA Instruments Model 25 sealed pan apparatus. The sample (approximately 1-2 mg) was weighed in an aluminum pan, transferred to the instrument, and measured. The measurement parameters were as follows: the instrument was equilibrated at 40°C, the temperature was increased to 230-300°C at a rate of 10-20°C / min, data was collected, and the experimental atmosphere was nitrogen gas.

[0138] (3) TGA measurements were performed using a TA Instruments Model 55 instrument. The sample (approximately 2-5 mg) was weighed in an aluminum pan, transferred to the instrument, and measured. As measurement parameters, the instrument was heated to 300°C at a rate of 10°C / min, data was collected, and the experimental atmosphere was nitrogen gas.

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

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

[0141] (6) Method for measuring HPLC content and related substances:

[0142] [Table 1]

[0143] Unless otherwise specified, the detection conditions for the particle size detection device of the suspended aqueous solution of the caliprazine pharmaceutical composition in the present invention are as follows.

[0144] [Table 2]

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

[0146] The X-ray powder diffraction pattern is shown in Figure 1.

[0147] The differential scanning calorimetry pattern is shown in Figure 2, indicating a melting point of approximately 101.3°C.

[0148] The thermogravimetric analysis pattern is shown in Figure 2, showing a weight loss of approximately 4.82% before 100°C, attributed to the loss of crystal water and adsorbed water, and the crystalline form A was the dihydrate of calipladine mono-1-hydroxy-2-naphthoate.

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

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

[0151] Referencing the 2020 edition of the Chinese Pharmacopoeia, General Rules 0451, Method 1, single-crystal X-ray diffraction analysis was performed using a Bruker SMART APEX-II single-crystal X-ray diffractometer. The measurement conditions were: CuKα rays, voltage 40 kV, current 30 mA, scan range 4.31~66.50°, scanning mode φ / ω, and scanning step 0.5°.

[0152] The single-crystal X-ray diffraction pattern of the obtained sample is shown in Figure 22, the elliptical diagram of the single-crystal molecular three-dimensional structure is shown in Figure 23, and the stacked projection of the unit cell along the b-axis of the single crystal is shown in Figure 24.

[0153] Example 2: Preparation of crystalline form A of caliprazine mono-1-hydroxy-2-naphthoate dihydrate 100 g of free caliprazine base and 43 g of 1-hydroxy-2-naphthoic acid were taken, and 1000 mL of a 1:1 ethanol:water mixture was added. The mixture was dissolved with stirring at 70°C, the heating was stopped, and the temperature was allowed to cool to precipitate. Stirring was continued for 5 hours, the mixture was filtered by suction, and dried under reduced pressure at 40°C overnight to obtain 13.6 g of caliprazine mono-1-hydroxy-2-naphthoate dihydrate in crystalline form A. The yield was 95%, and the HPLC purity was 99.59%.

[0154] Proton nuclear magnetic resonance, X-ray powder diffraction, differential scanning calorimetry, and thermogravimetric analysis confirmed that it was consistent with the chemical and crystalline structure of Example 1A, with a melting point of approximately 103.7°C and a weight loss of approximately 4.45% before 100°C.

[0155] Example 3: Preparation of caliprazine mono-1-hydroxy-2-naphthoate crystalline form B Take 1 g of free caliprazine base and 0.43 g of 1-hydroxy-2-naphthoic acid, add 1 mL of a mixed reagent of acetone:water = 6:4, dissolve with stirring at 70°C, filter, stop heating and leave at room temperature overnight, filter by suction, dry under reduced pressure at 60°C for 1 hour to obtain 1.27 g of caliprazine mono-1-hydroxy-2-naphthoate crystalline form B, with a yield of 89%.

[0156] The X-ray powder diffraction pattern is shown in Figure 4.

[0157] The differential scanning calorimetry pattern is shown in Figure 5, indicating a melting point of approximately 106.8°C.

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

[0159] Example 4: Preparation of caliprazine mono-1-hydroxy-2-naphthoate crystalline form C Take 10 g of free caliprazine base and 4.3 g of 1-hydroxy-2-naphthoic acid, add 100 mL of a reagent mixture of acetone:water = 6:4, dissolve with stirring at 70°C, filter, stop heating and leave at room temperature overnight, filter by suction, dry under reduced pressure at 60°C for 5 hours to obtain 10.8 g of caliprazine mono-1-hydroxy-2-naphthoate crystalline form C, with a yield of 76%.

[0160] The X-ray powder diffraction pattern is shown in Figure 7.

[0161] The differential scanning calorimetry pattern is shown in Figure 8, indicating a melting point of approximately 103.4°C.

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

[0163] Example 5: Preparation of crystalline form A of calipradine bis-1-hydroxy-2-naphthoethate hydrate Take 1 g of free caliprazine base and 0.85 g of 1-hydroxy-2-naphthoic acid, add 20 mL of a 1:1 ethanol:water mixture, stir at 70°C for 2 hours, stop heating and continue stirring for 3 hours, filter by suction, dry under reduced pressure at 40°C overnight to obtain 1.63 g of caliprazine bis-1-hydroxy-2-naphthoate in crystalline form A, with a yield of 88% and HPLC purity of 99.44%.

[0164] The X-ray powder diffraction pattern is shown in Figure 10.

[0165] The differential scanning calorimetry pattern is shown in Figure 11, indicating a melting point of approximately 86.3°C.

[0166] The thermogravimetric analysis pattern is shown in Figure 11, and a weight loss of approximately 1.31% was observed before 100°C, which was attributed to the loss of crystal water and adsorbed water. Therefore, crystal form A was identified as calipradine bis-1-hydroxy-2-naphthoate hydrate.

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

[0168] Example 6: Preparation of Caliprazine Pamoate Crystalline Form H 2 g of commercially available free caliprazine base and 1.62 g of pamoic acid were taken, 80 mL of tetrahydrofuran:methanol (2:1) solvent was added, and the mixture was dissolved at 60°C. The mixture was filtered, and the solvent was removed by rotary distillation to obtain a yellow solid. 30 mL of methanol was added, and the mixture was dissolved at 60°C. The solvent was removed by rotary distillation, and the mixture was dried to obtain a pale yellow solid. 0.1 g of the pale yellow solid was taken, 2.5 mL of dibutanone was added, and the mixture was dissolved at 60°C. The mixture was filtered, and 5 times the volume of n-heptane was gradually added while stirring at room temperature. The mixture was stirred for 1 month, filtered, and 0.08 g of caliprazine pamoate crystalline form H was obtained, with a yield of 80%.

[0169] The X-ray powder diffraction pattern is shown in Figure 13, indicating that it is the caliprazine pamoate crystal form H.

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

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

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

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

[0174] Solid-phase characterization detection was performed on the above sample, and the XRPD pattern is shown in Figure 14. The detection result indicated that it was an amorphous form of caliprazine pamoate.

[0175] Example 8: Preparation of Caliprazine Hydrochloride Crystalline Form I In accordance with prior research patents for caliprazine hydrochloride, a sample of caliprazine hydrochloride crystalline form I was prepared.

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

[0177] The X-ray powder diffraction pattern is shown in Figure 15, indicating that it is caliprazine hydrochloride crystal form I.

[0178] Example 9: Comparison of the stability of related substances and their crystal forms Crystalline form A of the caliprazine mono-1-hydroxy-2-naphthoate dihydrate produced in Example 2, crystalline form A of the caliprazine bis-1-hydroxy-2-naphthoate hydrate produced in Example 5, amorphous form of the caliprazine pamoate produced in Example 7, and crystalline form I of the caliprazine hydrochloride produced in Example 8 were each subjected to high temperature (60°C), high humidity (25°C / 90%RH), accelerated temperature (40°C / 75%RH), and light irradiation (1.2 × 10⁻¹⁴). 6 The samples were left to stand under conditions of Lux·hr, and samples were taken on day 0 and day 10 for HPLC or XRPD detection.

[0179] The results of the detection of related substances are shown in Table 1. When the crystalline form A of the calipradine mono-1-hydroxy-2-naphthoate dihydrate and the crystalline form A of the calipradine bis-1-hydroxy-2-naphthoate hydrate of the present invention were left for 10 days under high temperature, high humidity, and accelerated conditions, the change in related substances was within 0.3% in both cases, and the increase under high temperature conditions was even less compared to pamoate, similar to pamoate. The impurities increased only slightly upon light irradiation, and relatively good stability was maintained even with appropriate light-shielding measures. The crystal form stability results are shown in Table 2. Compared to the known crystal form I of caliprazine hydrochloride, crystal form A of the caliprazine bis-1-hydroxy-2-naphthoate hydrate of the present invention exhibits even better crystal form stability. After being left for 10 days under each condition, the crystal form did not change, and the crystallinity also remained clearly unchanged. Crystal form A of the caliprazine mono-1-hydroxy-2-naphthoate dihydrate of the present invention is relatively stable under high humidity, light irradiation, and accelerated conditions, and its crystal form does not change, but it is converted to crystal form C of caliprazine mono-1-hydroxy-2-naphthoate under high temperature conditions.

[0180] [Table 3]

[0181] [Table 4]

[0182] Example 10: Comparison of solubility at different pH levels Crystalline form A of caliprazine mono-1-hydroxy-2-naphthoate dihydrate produced in Example 1A, crystalline form C of caliprazine semi-mono-1-hydroxy-2-naphthoate produced in Example 4, crystalline form A of caliprazine bis-1-hydroxy-2-naphthoate hydrate produced in Example 5, amorphous caliprazine pamoate produced in Example 7, crystalline form I of caliprazine hydrochloride produced in Example 8, and commercially available caliprazine free base were each taken and added to the following media with different pH values, shaken for 24 hours at 37°C, filtered through a 0.45 μm aqueous filter membrane, collected the filtrate, and measured the solubility by high-performance liquid chromatography. Of these, pH 3, pH 4, pH 5, and pH 6 were acetic acid buffer solutions, and pH 7, pH 7.4, pH 8, and pH 9 were phosphate buffer solutions.

[0183] The results of the solubility test are shown in Table 3. The solubility of the caliprazine mono-1-hydroxy-2-naphthoate and its crystalline form, as well as the caliprazine bis-1-hydroxy-2-naphthoate produced in this invention, were all relatively low within the pH range of 3 to 9. Furthermore, the solubility within the pH range of 3 to 6 was significantly lower than that of the hydrochloride, and the solubility within the pH range of 7 to 9 was significantly lower than that of the pamoate. Due to the relatively low solubility, the release rate of the salt and crystalline forms could be minimally dependent on pH, thereby avoiding the influence of the drug release rate on the pH environment of different areas in the body, preventing the occurrence of rapid release phenomena or excessive increases in blood drug concentration in local areas of the body, and reducing differences in drug release between individuals. In addition, the crystalline form of caliprazine 1-hydroxy-2-naphthoate showed relatively good stability, making it suitable for long-acting formulations, reducing the number of administrations, improving patient compliance, and the market outlook was favorable.

[0184] [Table 5]

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

[0186] [Table 6]

[0187] Manufacturing process: (1) Weigh the Tween20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethylcellulose, and approximately 60% of the total amount of water for injection into the mixture, and dissolve and disperse them by stirring.

[0188] (2) Add the specified amount of caliprazine mono-1-hydroxy-2-naphthoate crystalline form C, selectively adjust the pH to 4.0-9.0 with sodium hydroxide or hydrochloric acid, bring to a final volume, and stir until completely dispersed to obtain the suspensions of Examples 11-14.

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

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

[0191] [Table 7]

[0192] Manufacturing process: (1) Weigh the Tween20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethylcellulose, and approximately 60% of the total amount of water for injection into the mixture, and dissolve and disperse them by stirring.

[0193] (2) Add the specified amount of caliprazine mono-1-hydroxy-2-naphthoate crystalline form C, selectively adjust the pH to 4.0-9.0 with sodium hydroxide or hydrochloric acid, bring to a final volume, and stir until completely dispersed to obtain the suspensions of Examples 15-19.

[0194] The formulation samples prepared in Examples 15-19 were each examined for needle penetration, suspendability, moisture content, sedimentation ratio, and redispersibility. It was found that all of the above suspension samples could pass through a 0.45 × 15 mm injection needle, indicating good suspendability. The sedimentation ratio of the samples in Examples 15-19 was greater than 0.9 for at least 10 minutes, indicating good redispersibility (they could be quickly dispersed when shaken after sedimentation). The drug samples in Examples 16-19 adhered little to the vial wall, indicating good moisture content.

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

[0196] [Table 8]

[0197] Manufacturing process: (1) Weigh the amounts of poloxamer 188, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethylcellulose, and approximately 60% of the total amount of water for injection into the mixture, and dissolve them by stirring to disperse.

[0198] (2) Add the specified amount of calipradine mono-1-hydroxy-2-naphthoate dihydrate crystalline form A or calipradine bis-1-hydroxy-2-naphthoate hydrate crystalline form A, selectively adjust the pH to 4.0-9.0 with sodium hydroxide or hydrochloric acid, bring to a final volume, and stir until completely dispersed to obtain the suspensions of Examples 20-25.

[0199] The formulation samples prepared in Examples 20-25 were each examined for needle penetration, suspension, moisture content, sedimentation ratio, and redispersibility. It was found that all of the above suspension samples could pass through a 0.45 × 15 mm injection needle, indicating good suspension properties, minimal drug adhesion to the vial wall, good moisture content, and that the sedimentation ratio of the samples in Examples 20-25 was greater than 0.9 for at least 10 minutes, indicating good redispersibility (they could be rapidly dispersed when shaken after sedimentation).

[0200] Examples 26-31: Aqueous suspensions of calyprazine mono-1-hydroxy-2-naphthoate in different doses of sodium carboxymethylcellulose.

[0201] [Table 9]

[0202] Manufacturing process: (1) Weigh the Tween20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethylcellulose, and approximately 60% of the total amount of water for injection into the mixture, and dissolve and disperse them by stirring.

[0203] (2) Add the specified amount of caliprazine mono-1-hydroxy-2-naphthoate crystalline form C, selectively adjust the pH to 4.0-9.0 with sodium hydroxide or hydrochloric acid, bring to a final volume, and stir until completely dispersed to obtain the suspensions of Examples 26-31.

[0204] The formulation samples prepared in Examples 26-31 were each examined for needle penetration, suspendability, sedimentation ratio, and redispersibility. It was found that all of the above suspension samples could pass through a 0.45 × 15 mm injection needle, indicating good suspendability. Furthermore, the sedimentation ratio of the samples from Examples 26-31 was greater than 0.9 for at least 10 minutes, indicating good redispersibility (they could be rapidly dispersed after shaking following sedimentation).

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

[0206] [Table 10]

[0207] Manufacturing process: (1) Weigh the Tween20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, PVP K30, and approximately 60% of the total amount of water for injection into the mixture, and dissolve and disperse them by stirring.

[0208] (2) Add the specified amount of caliprazine mono-1-hydroxy-2-naphthoate dihydrate crystalline form A, selectively adjust the pH to 4.0-9.0 with sodium hydroxide or hydrochloric acid, bring to a final volume, and stir until completely dispersed to obtain the suspensions of Examples 32 and 33.

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

[0210] Examples 34-37: Aqueous suspensions of caliprazine mono-1-hydroxy-2-naphthoates of different particle sizes

[0211] [Table 11]

[0212] Manufacturing process: (1) Weigh the Tween20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, and approximately 60% of the total amount of sterile water for injection, and dissolve them by stirring to disperse.

[0213] (2) Add the specified amount of caliprazine mono-1-hydroxy-2-naphthoate in crystalline form C to obtain a suspension aqueous solution of coarse particles.

[0214] (3) The suspension aqueous solutions of coarse particles obtained in Examples 34 to 37 were each ground and dispersed using a ball mill.

[0215] (4) Add the specified amount of sodium carboxymethylcellulose to each of the above suspensions, stir until completely dispersed, and adjust to the final volume to obtain the suspensions of Examples 34 to 37 with a pH of 7.4 ± 0.2.

[0216] (5) The particle size distribution of the samples from Examples 34 to 37 was measured using an OMEC LS-909 particle size analyzer, and the results are shown in the table below.

[0217] [Table 12]

[0218] The results in the table above show that even with the same composition of suspension solution, it is possible to produce suspension solutions with different particle sizes (Dv90) by controlling the grinding parameters.

[0219] Examples 38-40: Aqueous suspensions of different crystalline forms of caliprazine mono-1-hydroxy-2-naphthoates

[0220] [Table 13]

[0221] Manufacturing process: (1) Weigh the Tween20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethylcellulose, and approximately 60% of the total amount of water for injection into the mixture, and dissolve and disperse them by stirring.

[0222] (2) Add the above crystalline form of caliprazine mono-1-hydroxy-2-naphthoate in the specified amount, selectively adjust the pH to 4.0-9.0 with sodium hydroxide or hydrochloric acid, bring to a final volume, and stir until completely dispersed to obtain the suspensions of Examples 38-40.

[0223] The formulation samples prepared in Examples 38-40 were each examined for needle penetration, suspendability, sedimentation ratio, and redispersibility. It was found that all of the above suspension samples could pass through a 0.45 × 15 mm injection needle, indicating good suspendability. Furthermore, the sedimentation ratio of the samples from Examples 38-40 was greater than 0.9 for at least 10 minutes, indicating good redispersibility (they could be rapidly dispersed after shaking following sedimentation). Based on the results in the table above, we examined needle penetration, suspension properties, sedimentation ratio, and moisture content, and found that the same aqueous suspension formulation is applicable to any of the different crystalline forms of caliprazine mono-1-hydroxy-2-naphthoate.

[0224] Example 41: Stability of a caliprazine 1-hydroxy-2-naphthoate suspension aqueous solution at 60°C. Aqueous suspensions of calipradine mono-1-hydroxy-2-naphthoate dihydrate crystalline form A, prepared in Example 21, and aqueous suspensions of calipradine bis-1-hydroxy-2-naphthoate hydrate crystalline form A, prepared in Example 24, were taken, and the relevant substances were detected at 60°C on days 0, 5, and 10. The results are shown in the table below.

[0225] [Table 14]

[0226] From the results in the table above, it was found that, in suspension aqueous solutions of the same formulation, the suspension aqueous solution of calipradine mono-1-hydroxy-2-naphthoate dihydrate crystalline form A is more stable than the suspension aqueous solution of calipradine bis-1-hydroxy-2-naphthoate hydrate crystalline form A.

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

[0228] [Table 15]

[0229] Manufacturing process: (1) Weigh the Tween20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethylcellulose / PVPK30, and approximately 60% of the total volume of sterile water for injection, stir to dissolve and disperse, and then adjust the volume to 200 mL.

[0230] (2) Add the specified amount of caliprazine mono-1-hydroxy-2-naphthoate dihydrate in crystalline form A to obtain a suspension aqueous solution of coarse particles, and adjust the volume to 200 mL.

[0231] (3) The suspension aqueous solutions of coarse particles obtained in Examples 42 to 43 were each ground and dispersed using a ball mill.

[0232] (4) The particle size distribution of the samples from Examples 42 and 43 was measured using an OMEC LS-909 particle size analyzer, and the results are shown in the table below.

[0233] [Table 16]

[0234] The results in the table above show that by controlling the grinding parameters, it is possible to produce suspension aqueous solutions of particles with smaller particle sizes (Dv90).

[0235] Samples of the suspension prepared in the above examples were taken to assess stability under various conditions, including high temperature (60°C), light irradiation, accelerated storage (40°C / 75%RH), long-term storage (25°C / 60%RH), and low temperature (2-8°C). Data regarding content and particle size are shown in the table below.

[0236] [Table 17]

[0237] From the above data, the polishing samples with different formulations all showed good stability in terms of related substances, content, and particle size under different conditions. At the same time, the needle penetration and redispersibility of the above stable samples were all good, and no abnormalities were observed.

[0238] Example 44: Study of hydrochloride dissociation In Example 8, caliprazine hydrochloride crystalline form I was taken and added to corresponding aqueous media at pH 6, pH 7, pH 7.4, pH 8, and pH 9, respectively. The mixture was shaken for 4 hours at 37°C, centrifuged, and the residue was subjected to XRPD detection. The results showed that caliprazine hydrochloride crystalline form I was dissociated into caliprazine free base. A comparative result using pH 7.4 as an example is shown in Figure 16 (the rest are not shown). From this, it was found that caliprazine hydrochloride crystalline form I is unstable in solution, and that the change in crystalline form after administration alters the efficacy and reduces the safety of administration.

[0239] Examples 45-47: Pharmacokinetic studies of a suspension containing caliprazine 1-hydroxy-2-naphthoate in rats

[0240] [Table 18]

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

[0242] 1. Manufacturing process of the suspension injection solutions of Examples 45-46: (1) Weigh the amounts of poloxamer 188, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethylcellulose, and approximately 60% of the total amount of water for injection into the mixture, and dissolve them by stirring to disperse.

[0243] (2) The corresponding samples of calipradine mono-1-hydroxy-2-naphthoate dihydrate crystal form A or calipradine bis-1-hydroxy-2-naphthoate hydrate crystal form A were added in the specified amounts, stirred until completely dispersed, and then brought to a constant volume to obtain the suspension injection solutions of Examples 45-46 with a pH of 7.4 ± 0.2.

[0244] 2. Manufacturing process of the suspension injection solution of Example 47: (1) Weigh the Tween20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethylcellulose, and approximately 60% of the total amount of water for injection into the mixture, and dissolve and disperse them by stirring.

[0245] (2) Add the respective amounts of amorphous caliprazine pamoate, stir until completely dispersed, and adjust to the final volume to obtain the suspension injection solution of Example 47 with a pH of 7.4 ± 0.2.

[0246] 3. The particle size distribution of the samples from Examples 45-46 was measured using an OMEC LS-909 particle size analyzer, and the results are shown in the table below.

[0247]

Table 19

[0248] Example 48: Preparation of Oral Liquid of Hydrochloride Crystal Form I (1) An appropriate amount of the sample of cariprazine hydrochloride crystal form I obtained in Example 8 was taken and added to about 60% of the total volume of water for injection, and optionally 0.1% of Tween 20 and 0.35% of sodium carboxymethylcellulose were added, and stirred to disperse.

[0249] (2) It was adjusted to pH 5.0 - 5.5 with hydrochloric acid, made up to volume, and the final clear oral liquid of Example 48 was obtained.

[0250] Example 49: Pharmacokinetic Experiment Examples 45 - 48: Twelve male SD rats were divided into 4 groups. Among them, 3 groups were administered samples of cariprazine mono 1-hydroxy-2-naphthoate formulation (Example 45), cariprazine bis 1-hydroxy-2-naphthoate formulation (Example 46), and cariprazine pamoate formulation (Example 47) at a single dose of 9 mg / kg by intramuscular injection respectively. And plasma was collected at 0 h, 1 h, 3 h, 7 h, 24 h, 4 d, 7 d, 15 d, 20 d, 25 d, 30 d after administration. The 4th group was administered a sample of cariprazine hydrochloride crystal form I formulation (Example 48) at a single dose of 0.3 mg / kg by forced oral administration, and plasma was collected at 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h after administration. During the test, animals in the intramuscular injection group were allowed to freely ingest food and water, animals in the forced oral administration group were fasted overnight before administration, and resumed eating and drinking 4 hours after administration.

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

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

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

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

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

[0256] The in vivo pharmacokinetic parameters of the animals are shown in Tables 8 to 9, and the drug concentration-time curves are shown in Figures 20 to 21.

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

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

[0259] Furthermore, from the perspective of maintaining blood drug concentration, in Examples 42, 45, and 46, the concentration was maintained at approximately 1 ng / mL within 15-20 days after administration to the injection group, while in Example 47, it was maintained for only 11 days. This indicates that Examples 42, 45, and 46 exert their pharmacological effects in the body for an even longer period, demonstrating superior sustained-release effect compared to Example 47.

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

[0261] [Table 20]

[0262] [Table 21]

[0263]

Table 22

[0264]

Table 23

[0265]

Table 24

[0266]

Table 25

[0267] The above has been exemplarily described for the embodiments of the technical solution of the present invention. It should be understood that the claims of the present invention are not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the scope of not departing from the gist and principles of the present invention should all be included within the scope of the patent claims of this application.

Brief Description of the Drawings

[0268] [Figure 1] XRPD pattern of crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate. [Figure 2] DSC / TGA pattern of crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate. [Figure 3] 1H-NMR pattern of crystalline form A of cariprazine mono 1-hydroxy-2-naphthoate dihydrate. [Figure 4] XRPD pattern of crystalline form B of cariprazine mono 1-hydroxy-2-naphthoate. [Figure 5] DSC pattern of crystalline form B of cariprazine mono 1-hydroxy-2-naphthoate. [Figure 6]This is the 1H-NMR pattern of crystal form B of caliprazine mono-1-hydroxy-2-naphthoate. [Figure 7] This is the XRPD pattern of crystalline form C of caliprazine mono-1-hydroxy-2-naphthoate. [Figure 8] This is the DSC pattern of crystalline form C of caliprazine mono-1-hydroxy-2-naphthoate. [Figure 9] This is the 1H-NMR pattern of the crystalline form C of calipradine bis-1-hydroxy-2-naphthoate. [Figure 10] This is the XRPD pattern of crystalline form A of calipradine bis-1-hydroxy-2-naphthoate hydrate. [Figure 11] This is the DSC / TGA pattern of crystalline form A of calipradine bis-1-hydroxy-2-naphthoate hydrate. [Figure 12] This is the 1H-NMR pattern of crystal form A of calipradin bis-1-hydroxy-2-naphthoate hydrate. [Figure 13] This is the XRPD pattern of crystalline form H of caliprazine pamoate. [Figure 14] This is the amorphous XRPD pattern of caliprazine pamoate. [Figure 15] This is the XRPD pattern of crystalline form I of caliprazine hydrochloride. [Figure 16] This is an XRPD pattern overlay of the caliprazine hydrochloride dissociation study under pH 7.4 conditions in Example 44, where A is the free caliprazine base, B is the caliprazine hydrochloride crystalline form I, and C is the caliprazine hydrochloride crystalline form I sample after shaking in a pH 7.4 medium. [Figure 17] This figure shows the relationship between the average blood drug concentration of caliprazine in an oral liquid sample of the formulation of Example 48 of the present invention in rats and time. [Figure 18]This figure shows the relationship between the average blood drug concentration of caliprazine and time for injection samples of the formulations of Examples 45-47 of the present invention in rats. In this figure, ■ represents the crystalline form A of caliprazine mono-1-hydroxy-2-naphthoate dihydrate, ▲ represents the crystalline form A of caliprazine bis-1-hydroxy-2-naphthoate hydrate, and ◆ represents the amorphous form of caliprazine pamoate. [Figure 19] Figure 18 is a localized magnified view (a diagram showing the relationship between the average blood drug concentration of caliprazine and time from 0 to 24 hours, where ■ represents the crystalline form A of caliprazine mono-1-hydroxy-2-naphthoate dihydrate, ▲ represents the crystalline form A of caliprazine bis-1-hydroxy-2-naphthoate hydrate, and ◆ represents the amorphous form of caliprazine pamoate). [Figure 20] This figure shows the relationship between the average blood drug concentration of caliprazine and time in injection samples of the formulation of Example 42 of the present invention in rats of different sexes. In this figure, ■ represents the relationship in male rats with crystalline form A of caliprazine mono-1-hydroxy-2-naphthoate dihydrate, and ▲ represents the relationship in female rats with crystalline form A of caliprazine mono-1-hydroxy-2-naphthoate dihydrate. [Figure 21] Figure 18 shows localized emission diagrams (relationships between average blood drug concentration of caliprazine and time from 0 to 24 hours, where ■ represents the relationship of caliprazine mono-1-hydroxy-2-naphthoate dihydrate crystalline form A in male rats, and ▲ represents the relationship of caliprazine mono-1-hydroxy-2-naphthoate dihydrate crystalline form A in female rats). [Figure 22] This is the X-ray diffraction pattern of a single crystal of caliprazine mono-1-hydroxy-2-naphthoate dihydrate in crystal form A. [Figure 23] This is an elliptical diagram of the single-crystal molecular structure of caliprazine mono-1-hydroxy-2-naphthoate dihydrate. [Figure 24] This is a projection of the stacked unit cells along the b-axis of a single crystal of calipradine mono-1-hydroxy-2-naphthoate dihydrate.

Claims

1. A pharmaceutically acceptable salt crystal of caliprazine, At least one of the following forms (1) to (4) is selected: (1) The crystal form A of calipladine mono-1-hydroxy-2-naphthoate dihydrate has characteristic peaks in its X-ray powder diffraction pattern at 2θ values ​​of 12.7°±0.2°, 15.6°±0.2°, 17.3°±0.2°, 18.8°±0.2°, 19.7°±0.2°, 20.2°±0.2°, 20.7°±0.2°, and 24.3°±0.2°. (2) A single crystal of calipladine mono-1-hydroxy-2-naphthoate dihydrate in crystalline form A, whose X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 12.7°±0.2°, 15.7°±0.2°, 17.5°±0.2°, 19.0°±0.2°, 19.7°±0.2°, 20.3°±0.2°, 20.8°±0.2°, and 23.4°±0.2°. (3) The crystal form C of calipladine mono-1-hydroxy-2-naphthoate, whose X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 4.4°±0.2°, 12.8°±0.2°, 15.6°±0.2°, 17.8°±0.2°, 19.9°±0.2°, 20.2°±0.2°, 21.1°±0.2°, and 23.7°±0.2°. (4) The crystal form A of calipradine bis-1-hydroxy-2-naphthoate hydrate has characteristic peaks in its X-ray powder diffraction pattern at 2θ values ​​of 4.7°±0.2°, 9.4°±0.2°, 12.7°±0.2°, 17.1°±0.2°, 19.1°±0.2°, 20.1°±0.2°, 20.8°±0.2°, and 27.4°±0.2°. The aforementioned caliprazine mono-1-hydroxy-2-naphthoate is represented by the following formula (I), and the aforementioned caliprazine bis-1-hydroxy-2-naphthoate is represented by the following formula (II), and these are crystalline, pharmaceutically acceptable salts of caliprazine. 【Chemistry 1】

2. The X-ray powder diffraction pattern of crystalline form A of the aforementioned calipladine mono-1-hydroxy-2-naphthoate dihydrate has absorption peaks at 2θ values ​​of 4.4°±0.2°, 8.6°±0.2°, 9.7°±0.2°, 11.4°±0.2°, 12.7°±0.2°, 15.6°±0.2°, 16.5°±0.2°, 16.9°±0.2°, 17.3°±0.2°, 18.8°±0.2°, 19.7°±0.2°, 20.2°±0.2°, 20.7°±0.2°, 23.3°±0.2°, 24.3°±0.2°, 24.9°±0.2°, and 29.5°±0.2°. The X-ray diffraction patterns of the single crystal of crystal form A of the aforementioned calipladine mono-1-hydroxy-2-naphthoate dihydrate are as follows: 2θ values ​​of 11.5°±0.2°, 12.7°±0.2°, 15.7°±0.2°, 16.6°±0.2°, 16.9°±0.2°, 17.5°±0.2°, 18.1°±0.2°, 19.0°±0.2°, 19.7°±0.2°, 20.0°±0.2°, 20.3°±0.2°, 20.8°±0.2°, 21.3°±0.2°, 23.4°±0.2°, 23.6°± It has absorption peaks at 0.2°, 24.4°±0.2°, 24.9°±0.2°, and 29.6°±0.2°. The X-ray powder diffraction patterns of the crystalline form C of the aforementioned calipladine mono-1-hydroxy-2-naphthoate are as follows: 2θ values ​​of 4.4°±0.2°, 8.6°±0.2°, 9.7°±0.2°, 11.5°±0.2°, 12.8°±0.2°, 13.2°±0.2°, 15.6°±0.2°, 16.6°±0.2°, 17.8°±0.2°, 19.3°±0.2°, 19.9°±0.2°, 20.2°±0.2°, 21.1°±0.2°, 22.4°±0.2°, 23.7°±0.2°, 24.2°± It has characteristic peaks at 0.2° and 24.9°±0.2°. The X-ray powder diffraction pattern of crystalline form A of the aforementioned calipradin bis-1-hydroxy-2-naphthoate hydrate has characteristic peaks at 2θ values ​​of 4.7°±0.2°, 8.8°±0.2°, 9.4°±0.2°, 12.7°±0.2°, 16.5°±0.2°, 17.1°±0.2°, 18.4°±0.2°, 19.1°±0.2°, 19.9°±0.2°, 20.1°±0.2°, 20.8°±0.2°, 21.1°±0.2°, 21.9°±0.2°, 24.1°±0.2°, 24.8°±0.2°, 25.6°±0.2°, and 27.4°±0.2°. The pharmaceutically acceptable salt crystals according to claim 1.

3. The crystalline form A of the aforementioned caliprazine mono-1-hydroxy-2-naphthoate dihydrate has one selected from the following: The X-ray powder diffraction pattern shown in Figure 1, Table 1 The differential scanning calorimetry pattern shown in Figure 2, Table 2 Melting point of 101.3℃, The thermogravimetric analysis pattern shown in Figure 2, The crystalline form C of the aforementioned caliprazine mono-1-hydroxy-2-naphthoate has one selected from the following: The X-ray powder diffraction pattern shown in Figure 7, Table 3 The differential scanning calorimetry pattern shown in Figure 8, Table 4 Melting point of 103.4℃, The crystalline form A of the aforementioned calipradin bis-1-hydroxy-2-naphthoethate hydrate has one selected from the following: X-ray powder diffraction pattern shown in Figure 10, Table 5 The differential scanning calorimetry pattern shown in Figure 11, Table 6 Melting point of 86.3℃, The thermogravimetric analysis pattern shown in Figure 11, The pharmaceutically acceptable salt crystals according to claim 1.

4. A method for producing pharmaceutically acceptable salt crystals according to claim 1, 2, or 3, (1) A method for producing crystal form A of calipradine mono-1-hydroxy-2-naphthoate dihydrate (excluding single crystals of crystal form A), (a1) A step of mixing caliprazine and 1-hydroxy-2-naphthoic acid with a solvent in a molar ratio of 1:1, (a2) Stirring at 25-70°C to obtain crystal form A of calipladine mono-1-hydroxy-2-naphthoate dihydrate (excluding single crystals of crystal form A), The solvent is methanol, or a mixture of ethanol and water. The volume ratio of methanol or ethanol to water is 2:1 to 1:

2. The manufacturing method involves a mass-to-volume ratio of caliprazine to the total volume of the solvent system of 1 g: 5-30 mL. (2) A method for producing the crystalline form C of the caliprazine mono-1-hydroxy-2-naphthoate salt, (c1) A step of mixing caliprazine and 1-hydroxy-2-naphthoic acid with a solvent in a molar ratio of 1:1, (c2) Stirring at 25-70°C to obtain the crystalline form C of the calipladine mono-1-hydroxy-2-naphthoate, The aforementioned solvent is a mixture of acetone and water. The volume ratio of acetone to water is 2:1 to 1:

2. The manufacturing method involves a mass-to-volume ratio of caliprazine to the total volume of the solvent system of 1 g: 5-30 mL. (3) A method for producing the crystalline form A of the calipradin bis-1-hydroxy-2-naphthoate hydrate, The process includes the step of adding caliprazine and 1-hydroxy-2-naphthoic acid to a solvent in a molar ratio of 1:2, stirring at 25-70°C, and obtaining crystalline form A of the caliprazine bis-1-hydroxy-2-naphthoate hydrate. The solvent is methanol, or a mixture of ethanol and water. The volume ratio of methanol or ethanol to water is 1:

1. The manufacturing method involves a mass-to-volume ratio of caliprazine to the total volume of the solvent system of 1 g:20-40 mL. A manufacturing method that includes one selected from the following.

5. A combination of pharmaceutically acceptable salts of caliprazine, At least one of the pharmaceutically acceptable salt crystals described in claim 1, 2, or 3, A combination comprising, optionally present or absent, a pharmaceutically acceptable salt of a caliprazine other than the caliprazine mono-1-hydroxy-2-naphthoate and the caliprazine bis-1-hydroxy-2-naphthoate, or a combination of the caliprazine mono-1-hydroxy-2-naphthoate or a form of the caliprazine bis-1-hydroxy-2-naphthoate other than the aforementioned forms (1) to (4).

6. The combination of pharmaceutically acceptable salts of caliprazine according to claim 5, wherein the weight percentage content of the crystalline form of caliprazine mono-1-hydroxy-2-naphthoate or caliprazine bis-1-hydroxy-2-naphthoate in the total weight of the pharmaceutically acceptable salts of caliprazine in the above combination is greater than the content of the other pharmaceutically acceptable salts of caliprazine or the content of the crystalline form of caliprazine mono-1-hydroxy-2-naphthoate or caliprazine bis-1-hydroxy-2-naphthoate other than the above forms (1) to (4).

7. A pharmaceutical composition comprising pharmaceutically acceptable salt crystals according to claim 1, 2, or 3.

8. The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition comprises caliprazine solid particles having a particle size Dv(10) ≤ 30 microns, Dv(50) ≤ 50 microns and Dv(90) ≤ 100 microns, or Dv(90) ≤ 50 microns, wherein the caliprazine solid particles are one selected from the crystalline forms of caliprazine mono-1-hydroxy-2-naphthoate and caliprazine bis-1-hydroxy-2-naphthoate.

9. The aforementioned caliprazine pharmaceutical composition is (a) A crystal selected from at least one of the following: crystal form A of the caliprazine mono-1-hydroxy-2-naphthoate dihydrate, a single crystal of crystal form A of the caliprazine mono-1-hydroxy-2-naphthoate dihydrate, crystal form C of the caliprazine mono-1-hydroxy-2-naphthoate, and crystal form A of the caliprazine bis-1-hydroxy-2-naphthoate hydrate. (b) Sodium carboxymethylcellulose or PVP K30, (c) Tween20 or Poloxamer188, (d) Disodium hydrogen phosphate, (e) Sodium dihydrogen phosphate, and (f) Contains mannitol, Furthermore, the pharmaceutical composition of caliprazine may selectively contain a pH adjusting agent. The pharmaceutical composition according to claim 7, wherein the pH of the aforementioned caliprazine pharmaceutical composition is 4.0 to 9.

0.

10. The aforementioned caliprazine pharmaceutical composition further comprises one or more selected from suspending agents, wetting agents, osmotic pressure modifiers, solvents, and buffering agents. The suspending agent is one or more selected from carboxymethylcellulose sodium, methylcellulose, and polyvinylpyrrolidone. The aforementioned wetting agent is one or more selected from Tween20, Tween80, and Poloxamer 188. The osmotic pressure adjusting agent is one or more selected from sodium chloride, mannitol, and sucrose. The buffering agent is one or more selected from phosphoric acid, phosphate, quamous acid, sodium quamous acid, hydrochloric acid, and sodium hydroxide. The pharmaceutical composition according to claim 7, wherein the solvent is water.

11. The concentration range of the suspending agent is 0 to 10 mg / mL, or 3.5 to 7.5 mg / mL. The concentration range of the wetting agent is 0.2 to 10 mg / mL, or 1 to 5 mg / mL. The pharmaceutical composition according to claim 10, wherein the concentration range of the osmotic pressure adjusting agent is 20 to 30 mg / mL or 23 to 26 mg / mL.

12. The aforementioned pharmacopoeia composition of caliprazine is an aqueous suspension or an aqueous suspension flotation agent. The pharmaceutical composition according to claim 7, wherein the mass-volume concentration of the caliprazine solid particles is 30 mg / mL or more.

13. The aforementioned caliprazine pharmaceutical composition is an injectable preparation. The pharmaceutical composition according to claim 7, wherein the caliprazine injectable preparation has a mass-volume concentration of 30 mg / mL or more of caliprazine solid particles.

14. Use of the pharmaceutically acceptable salt crystals according to claim 1 in the manufacture of a drug for the treatment and / or prevention of cognitive impairment or mental disorder.

15. Use of a combination of pharmaceutically acceptable salts of caliprazine according to claim 5 in the manufacture of a drug for treating and / or preventing cognitive impairment or mental disorder.

16. Use of the pharmaceutical composition according to claim 7 in the manufacture of a drug for treating and / or preventing cognitive impairment or mental disorder.

17. Use of the pharmaceutically acceptable salt crystals according to claim 1 in the manufacture of a drug for the treatment and / or prevention of psychosis, bipolar disorder, or acute mania.

18. Use of a combination of pharmaceutically acceptable salts of caliprazine according to claim 5 in the manufacture of a drug for treating and / or preventing psychosis, bipolar disorder, or acute mania.

19. Use of the pharmaceutical composition according to claim 7 in the manufacture of a drug for treating and / or preventing psychosis, bipolar disorder, or acute mania.

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