A new crystalline form of cariprazine

Abstract

This invention belongs to the technical field of medicinal chemistry, specifically relating to a novel crystal form of cariprazine, specifically the cariprazine-4-hydroxybenzoic acid-methanol-hemihydrate crystal form and its preparation method. The novel cariprazine-fumaric acid crystal form provided by this invention comprises a basic unit of one molecule of cariprazine, one molecule of 4-hydroxybenzoic acid, one molecule of methanol, and 0.5 molecules of water. Its preparation method is simple to operate, the crystallization process is easy to control, and it has good reproducibility. The formation of a eutectic significantly enhances the solubility of cariprazine, exhibiting strong pharmaceutical value.

Description

Technical Field

[0001] This invention belongs to the technical field of medicinal chemistry, specifically relating to a new crystal form of cariprazine, specifically the crystal form of cariprazine-4-hydroxybenzoic acid solvate and its preparation method and application. Background Technology

[0002] Cariprazine, chemically named N'-[trans-4-[2-[4-(2,3-dichlorophenyl)-1-piperazinyl]ethyl]cyclohexyl]-N,N-dimethylurea(I), is a novel atypical antipsychotic drug that antagonizes dopamine D3, dopamine D2, and serotonin 2B receptors. It can be used to treat schizophrenia and type I bipolar disorder. Its structural formula is as follows: .

[0003] Currently, the product on the market is cariprazine hydrochloride capsules. This product is an oral preparation that needs to be administered daily to maintain its blood drug concentration. However, due to the need for frequent administration, patients have poor medication adherence.

[0004] Patent CN101679315A discloses various salts of caliprazine, including monohydrochloride, dihydrochloride, monohydrobromide, maleate, and methanesulfonate. Patent CN105218484A discloses caliprazine tartrate and provides the solubilities of caliprazine tartrate, caliprazine hydrochloride, caliprazine maleate, caliprazine benzenesulfonate, and caliprazine phosphate, all greater than 3 mg / mL. Patent WO2020056929A discloses a new crystal form of caliprazine hydrochloride, mentioning caliprazine hydrochloride. The salts rapidly dissociate into a free base in a pH 6.5 buffer solution.

[0005] During the research process, the inventors discovered that the stability of cariprasin hydrochloride aqueous solution is not ideal. It will dissociate under weakly acidic to alkaline conditions, thus posing a risk of dissociation in the suspension aqueous solution. This can easily cause changes in the properties and quality of the product, leading to changes in drug dissolution and absorption, affecting the efficacy of the drug and the safety of patients. Therefore, it is not suitable for use in long-acting sustained-release formulations.

[0006] Given the shortcomings of existing technologies, finding pharmaceutical salts and their crystal forms of cariprazine with low solubility, suitable for long-acting administration, high stability, good clinical efficacy, and / or suitable for commercialization is a pressing technical problem that needs to be solved in this field. Summary of the Invention

[0007] The purpose of this invention is to address the shortcomings of existing technologies by providing a caliprazine drug cocrystal and its preparation method, thereby solving the problems mentioned in the background section. This invention aims to provide a novel crystalline form of caliprazine with low hygroscopicity, namely, a novel crystalline form of caliprazine-4-hydroxybenzoic acid-methanol-hemihydrate. Furthermore, this invention provides a method for preparing caliprazine-4-hydroxybenzoic acid-methanol-hemihydrate, which is simple, convenient, and suitable for industrial production.

[0008] The specific technical content of this invention is as follows:

[0009] On one hand, the present invention provides a cariprazine-4-hydroxybenzoic acid-methanol-hemihydrate, characterized in that, using Cu-Kα radiation, the X-ray diffraction pattern represented by 2θ has characteristic peaks at least at 4.6±0.2°, 4.8±0.2°, 7.8±0.2°, 15.2±0.2°, and 19.1±0.2°.

[0010] Preferably, the carilarazine-4-hydroxybenzoic acid-methanol-hemihydrate, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (denoted as 2θ) at at least 4.6±0.2°, 4.8±0.2°, 7.8±0.2°, 14.4±0.2°, 14.9±0.2°, 15.2±0.2°, 18.3±0.2°, 19.1±0.2°, 20.0±0.2°, 20.7±0.2°, 21.5±0.2°, 24.0±0.2°, 24.2±0.2°, 28.9±0.2°, 30.2±0.2°, 35.5±0.2°, and 36.7±0.2°.

[0011] Preferably, the caliradin-4-hydroxybenzoic acid-methanol-hemihydrate is subjected to Cu-Kα radiation, and its characteristic peaks conform to the following... Figure 1 The X-ray powder diffraction pattern shown is shown.

[0012] Preferably, the carilarazine-4-hydroxybenzoic acid-methanol-hemihydrate has the molecular formula C 36 H 49 Cl2N4O 8.5 The crystallographic parameters are: triclinic crystal system, space group P-1, cell parameters: a=9.4813(2)Å, b=11.7145(2)Å, c=18.3188(4)Å, α=107.539(2)°, β=97.450(2)°, γ=99.460(2)°, cell volume V=1878.62(7)Å. 3 On the other hand, the present invention provides a method for preparing cariprazine-4-hydroxybenzoic acid-methanol-hemihydrate, comprising the following steps: Caliprazine and 4-hydroxybenzoic acid crystals were dissolved in a mixed solvent, heated and stirred, filtered, cooled and allowed to stand to volatilize and crystallize, and then filtered and dried to obtain caliprazine-4-hydroxybenzoic acid-methanol-hemihydrate.

[0013] Preferably, the mixed solvent is selected from a mixture of methanol, water and acetone, ethanol, n-butanol, trifluoroethanol and isopropanol, and particularly preferably a mixture of methanol, water and acetone in a volume ratio of 4:1:4.

[0014] Preferably, the mass-to-volume ratio of carilarazine to organic solvent is 1:0.09~0.18; more preferably 1:0.12.

[0015] Preferably, the molar ratio of cariprazine to 4-hydroxybenzoic acid is 1:1.2-1.5, more preferably 1:1.3.

[0016] Preferably, the heating temperature is 60~75℃, more preferably 70℃.

[0017] The cooling crystallization temperature is -5~10℃, preferably 0℃.

[0018] The crystallization time is 96-120 hours.

[0019] The drying temperature is 20~30℃, and the drying time is 48~72 hours.

[0020] The raw material cariprazine used in the preparation method can be prepared according to any method in the prior art or purchased from commercially available products.

[0021] Finally, the present invention provides a pharmaceutical composition comprising the cariprazine-4-hydroxybenzoic acid-methanol-hemihydrate of the present invention and other pharmaceutically feasible components.

[0022] Preferably, the other pharmaceutically feasible components may be co-operable active pharmaceutical ingredients and / or pharmaceutically acceptable excipients.

[0023] Confirmation of crystal structure

[0024] The X-ray crystal data for the test of carcalirazine-4-hydroxybenzoic acid-methanol-hemihydrate described in this invention were collected on a Rigaku XtaLAB Synergy instrument in Japan. The test temperature was 293(2) K, Cu-Ka radiation was used, and data were collected and processed in ω-scan mode. L p-correction. The structure was analyzed using the direct method, and all non-hydrogen atoms were identified using the difference Fourier method. All hydrogen atoms on carbon and nitrogen were obtained by theoretical hydrogenation. The structure was then refined using the least squares method.

[0025] The crystallographic data (as shown in Table 1) of the calilazine-4-hydroxybenzoic acid-methanol-hemihydrate crystal form prepared in this invention were tested and analyzed. The crystal system is triclinic, space group is P-1, and the cell parameters are: a=9.4813(2)Å, b=11.7145(2)Å, c=18.3188(4)Å, α=107.539(2)°, β=97.450(2)°, γ=99.460(2)°, and the cell volume V=1878.62(7)Å. 3 .

[0026] Table 1. Main crystallographic data of caliraline-4-hydroxybenzoic acid crystal forms

[0027] The ORTEP diagram of the caliprazine-4-hydroxybenzoic acid-methanol-hemihydrate of the present invention shows that this crystalline form contains one molecule of caliprazine, one molecule of 4-hydroxybenzoic acid, one molecule of methanol, and half a molecule of water, as shown in the attached diagram. Figure 2 As shown. The hydrogen bond diagram of the caliradin-4-hydroxybenzoic acid-methanol-hemihydrate of the present invention is attached. Figure 3 As shown. Based on the above crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Kα) are detailed in the appendix. Figure 1 And Table 2.

[0028] Table 2. PXRD peaks of caliraline-4-hydroxybenzoic acid crystal forms

[0029] Compared with the prior art, the technical effects achieved by the present invention are as follows: This invention provides for the first time a caraliprazine-4-hydroxybenzoic acid-methanol hemihydrate crystal form, the preparation method of which is simple to operate, the crystallization process is easy to control, and the reproducibility is good. The formation of a eutectic between the two significantly enhances the solubility of caraliprazine, giving it strong pharmaceutical value. Attached Figure Description

[0030] Figure 1 PXRD pattern of carilarazine-4-hydroxybenzoic acid-methanol-hemihydrate.

[0031] Figure 2 ORTEP diagram of cariprazine-4-hydroxybenzoic acid-methanol-hemihydrate.

[0032] Figure 3 Hydrogen bond diagram of carilarazine-4-hydroxybenzoic acid-methanol-hemihydrate. Detailed Implementation

[0033] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection claimed by the present invention.

[0034] Example 1

[0035] Cariprazine (427.4 mg, 1.0 mmol) and 4-hydroxybenzoic acid (179.5 mg, 1.3 mmol) were dissolved in a mixed solvent of methanol (24 mL), water (6 mL), and acetone (24 mL). The solution was heated in a water bath at 70 °C and stirred until completely dissolved. The solution was filtered and allowed to stand at room temperature to evaporate and crystallize, yielding cariprazine-4-hydroxybenzoic acid-methanol-hemihydrate. The yield was 98.8% and the purity was 99.96%.

[0036] Example 2

[0037] Cariprazine (427.4 mg, 1.0 mmol) and 4-hydroxybenzoic acid (165.7 mg, 1.2 mmol) were dissolved in a mixed solvent of methanol (17 mL), water (4 mL), and ethanol (17 mL). The solution was heated in a water bath at 60 °C and stirred until completely dissolved. The solution was filtered and allowed to stand at room temperature to evaporate and crystallize, yielding cariprazine-4-hydroxybenzoic acid-methanol-hemihydrate. The yield was 96.8% and the purity was 99.71%.

[0038] Example 3

[0039] Cariprazine (427.4 mg, 1.0 mmol) and 4-hydroxybenzoic acid (207.3 mg, 1.5 mmol) were dissolved in a mixed solvent of methanol (34 mL), water (8.5 mL), and n-butanol (34 mL). The solution was heated in a water bath at 75 °C and stirred until completely dissolved. The solution was filtered and allowed to stand at room temperature to evaporate and crystallize, yielding cariprazine-4-hydroxybenzoic acid-methanol-hemihydrate. The yield was 97.2% and the purity was 99.62%.

[0040] Example 4

[0041] Cariprazine (427.4 mg, 1.0 mmol) and 4-hydroxybenzoic acid (138.1 mg, 1.0 mmol) were dissolved in a mixed solvent of methanol (15 mL), water (3.5 mL), and acetone (15 mL). The solution was heated and stirred in a water bath at 55 °C until completely dissolved. The solution was filtered and allowed to stand at room temperature to evaporate and crystallize, yielding cariprazine-4-hydroxybenzoic acid-methanol-hemihydrate. The yield was 85.8% and the purity was 98.89%.

[0042] Example 5

[0043] Cariprazine (427.4 mg, 1.0 mmol) and 4-hydroxybenzoic acid (234.8 mg, 1.7 mmol) were dissolved in a mixed solvent of methanol (38 mL), water (9.5 mL), and acetone (38 mL). The solution was heated and stirred in a water bath at 55 °C until completely dissolved. The solution was filtered and allowed to stand at room temperature to evaporate and crystallize, yielding cariprazine-4-hydroxybenzoic acid-methanol-hemihydrate. The yield was 88.9% and the purity was 98.21%.

[0044] Comparative Example 1

[0045] Preparation of crystal form A of caliraline bis(1-hydroxy-2-naphthoic acid) hydrate

[0046] Take 1g of cariprazine free base and 0.85g of 1-hydroxy-2-naphthoic acid, add 20mL of ethanol:water = 1:1 mixed reagent, stir at 70℃ for 2 hours, turn off the heating and continue stirring for 3 hours, filter, dry under reduced pressure overnight at 40℃, and obtain 1.63g of cariprazine bis-1-hydroxy-2-naphthoic acid salt crystal form A, with a yield of 88% and an HPLC purity of 99.44%.

[0047] Comparative Example 2

[0048] Crystal form A of caliradin mono-1-hydroxy-2-naphthoic acid dihydrate

[0049] 100g of cariprazine free base and 43g of 1-hydroxy-2-naphthoic acid were added to 1000mL of ethanol:water = 1:1 mixture. The mixture was stirred and dissolved at 70℃, and the temperature was lowered to precipitate the precipitate. The stirring was continued for 5 hours, and the mixture was filtered and dried under reduced pressure overnight at 40℃ to obtain 13.6g of cariprazine mono-1-hydroxy-2-naphthoic acid dihydrate crystal form A, with a yield of 95% and an HPLC purity of 99.59%.

[0050] Verification test

[0051] 1. Stability test

[0052] The novel crystal form of cariprazine-4-hydroxybenzoic acid-methanol-hemihydrate prepared in Example 1 and the cariprazine bis-hydroxy-2-naphthoic acid salt hydrate prepared in Comparative Example 1 were placed under high temperature (60°C), high humidity (25°C / 90%RH), accelerated (40°C / 75%RH), and light (1.2×106 Lux·hr) conditions. Samples were taken at 0 days and 10 days for HPLC or XRPD detection.

[0053] Table 3 Results related to substances

[0054] Table 4 Crystal form stability results

[0055] The results of related substance testing are shown in Table 3. The changes in related substances of the cariprazine solvate of the present invention after 10 days of storage under high temperature, high humidity and accelerated conditions are all within 0.1%. The results of crystal form stability are shown in Table 4. It shows that compared with the known crystal form A of cariprazine bis-hydroxy-2-naphthoic acid salt hydrate and cariprazine mono-hydroxy-2-naphthoic acid salt dihydrate, the new crystal form of cariprazine of the present invention has better crystal form stability. After 10 days of storage under various conditions, the crystal form did not change and the crystallinity did not change significantly. Examples 1-5 also have similar stability.

[0056] 2. Comparison of solubility at different pH levels

[0057] The cariprazine-4-hydroxybenzoic acid-methanol-hemihydrate compound prepared in Example 1, the crystal form A of liprazine bis-hydroxy-2-naphthoic acid hydrate prepared in the comparative example, and the crystal form A of liprazine mono-hydroxy-2-naphthoic acid dihydrate were respectively added to the media with different pH values ​​described below. The media were shaken at 37°C for 24 hours, filtered through a 0.45 μm aqueous filter membrane, and the filtrates were collected. Solubility was determined using high-performance liquid chromatography (HPLC). 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. The results are shown in Table 5.

[0058] Table 5 Solubility Results

[0059] Solubility test results show that the carrillazine crystal form prepared by this invention exhibits significantly improved solubility compared to the preferred crystal form disclosed in the prior art. Further investigation revealed similar solubility test results for Examples 1-5.

[0060] 3. Solution stability experiment

[0061] 1. Experimental Materials: The cariprazine crystal form obtained in the examples and Comparative Example 1 were prepared into salt suspensions in aqueous solution using the same conventional process in the art. In vitro dissolution was tested, and the formulations are as follows:

[0062] Table 6. Formulation Prescriptions

[0063] Preparation process:

[0064] (1) Weigh out the prescribed amount of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol and about 60% of the total amount of water for injection, and stir to dissolve and disperse them.

[0065] (2) Add the prescribed amount of cariprazine crystal form to obtain a coarse particle suspension aqueous solution;

[0066] (3) The coarse particle suspension aqueous solutions obtained in Example 1 and Comparative Example 1 were respectively ground and dispersed using a ball mill;

[0067] (4) Add the prescribed amount of sodium carboxymethyl cellulose to the above suspension, stir until completely dispersed, and make up to a final volume to obtain a suspension with pH 7.4 ± 0.2;

[0068] The aqueous suspensions of cariprazine-fumaric acid solvate prepared in Example 1, as well as the aqueous suspensions of cariprazine bis(1-hydroxy-2-naphthoic acid) hydrate (crystal form A) and cariprazine mono(1-hydroxy-2-naphthoic acid) dihydrate (crystal form A) prepared in Comparative Example 1, were analyzed for related substances at 60°C for 10 days. The results are shown in the table below:

[0069] Table 7. Related to the suspensions in each example.

[0070] According to the results in the table above, among the suspensions of the same formulation, the suspension of cariprazine-4-hydroxybenzoic acid-methanol-hemihydrate is more stable than the suspensions of cariprazine dihydroxynaphthyl acid salt A and cariprazine mono-1-hydroxy-2-naphthyl acid salt dihydrate A.

[0071] 4. In vitro dissolution simulation experiment

[0072] Cariprazine-4-hydroxybenzoic acid-methanol-hemihydrate prepared in Examples 1-5 and cariprazine dihydroxynaphthalate crystal form A prepared in Comparative Example 1 were respectively added to a phosphate buffer solution at pH 7.4 and shaken at 37°C. The solubility was measured at 1, 3, 5, 7 and 24 hours.

[0073] Table 8 Results of in vitro dissolution simulation experiments

[0074] The results are shown in Table 8. The results show that the cariprazine-4-hydroxybenzoic acid-methanol-hemihydrate sample prepared by the present invention has a higher dissolution rate than cariprazine dihydroxynaphthalate crystal form A and the sample under the same conditions, indicating that the crystal form compound is more suitable for pharmaceutical use.

Claims

1. A novel crystalline form of cariprazine, characterized in that, The molar ratio of cariprazine, 4-hydroxybenzoic acid, methanol, and water in the crystal unit structure is 1:1:1:0.

5.

2. The novel crystalline form of cariprazine according to claim 1, characterized in that, Using Cu-K α Radiation, at 2 θ The X-ray powder diffraction, expressed in terms of angle, has characteristic diffraction peaks at 4.6±0.2°, 4.8±0.2°, 7.8±0.2°, 15.2±0.2°, and 19.1±0.2°.

3. The novel crystalline form of cariprazine according to claim 1, characterized in that, Using Cu-K α Radiation, at 2 θ The X-ray powder diffraction, expressed in angles, shows diffraction peaks at 4.6±0.2°, 4.8±0.2°, 7.8±0.2°, 14.4±0.2°, 14.9±0.2°, 15.2±0.2°, 18.3±0.2°, 19.1±0.2°, 20.0±0.2°, 20.7±0.2°, 21.5±0.2°, 24.0±0.2°, 24.2±0.2°, 28.9±0.2°, 30.2±0.2°, 35.5±0.2°, and 36.7±0.2°.

4. The novel crystalline form of cariprazine according to claim 1, characterized in that, The crystal form has an X-ray powder diffraction pattern as shown in Figure 1.

5. The novel crystalline form of cariprazine according to claim 1, characterized in that, The crystal form described has the molecular formula C. 36 H 49 Cl2N4O 8.5 The crystallographic parameters are: triclinic crystal system, space group P-1, cell parameters are: a=9.4813(2)Å, b=11.7145(2)Å, c=18.3188(4)Å, α=107.539(2)°, β=97.450(2)°, γ=99.460(2)°, cell volume V=1878.62(7)Å.

6. A method for preparing a novel crystalline form of carrillazine according to any one of claims 1-5, characterized in that, The preparation method includes the following steps: dissolving cariprazine and 4-hydroxybenzoic acid crystals in a mixed solvent, heating and stirring, filtering, cooling and allowing to stand to volatilize and crystallize, filtering and drying to obtain cariprazine-4-hydroxybenzoic acid-methanol-hemihydrate.

7. The preparation method according to claim 6, characterized in that, The mixed solvent is selected from a mixture of methanol, water and acetone, ethanol, n-butanol, trifluoroethanol and isopropanol, with a volume ratio of 4:1:

4.

8. The preparation method according to claim 6, characterized in that, The mass-to-volume ratio of carilarazine to organic solvent is 6-11:

1.

9. The preparation method according to claim 6, characterized in that, The molar ratio of cariprazine to 4-hydroxybenzoic acid is 1:1.2-1.

5.

10. The preparation method according to claim 6, characterized in that, The heating temperature is 60~75℃.

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