Novel crystal form of cariprazine and preparation method thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a novel crystal form of cariprazine, in particular to a crystal form of a cariprazine-fumaric acid-methanol-acetonitrile solvate as well as a preparation method and application thereof. The novel crystal form of cariprazine-fumaric acid provided by the invention contains basic units of one molecule of cariprazine, one molecule of fumaric acid, one molecule of methanol and one molecule of acetonitrile, the stability, solubility and the like are greatly improved, and the preparation method is simple to operate, good in reproducibility and suitable for industrial production.

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 cariprazine fumarate crystal form and its preparation method and application. Background Technology

[0002] Cariprazine (RGH188) is an atypical antipsychotic developed by Forest Lab in the United States. It is a partial agonist of dopamine D2 and D3 receptors. In September 2015, the FDA approved it for marketing in the United States under the brand name Vraylar, for the treatment of adult patients with schizophrenia and bipolar disorder. The structural formula of cariprazine 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] Chinese patent CN101679315A discloses various salts of caliprazine, including monohydrochloride, dihydrochloride, monohydrobromide, maleate, and methanesulfonate. Chinese 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] Currently marketed cariprazine drugs are available in solid API form as hydrochloride. The free base form of cariprazine has lower solubility. Utilizing this property, the free base can be used to develop long-acting injectable formulations and other pharmaceutical preparations. This invention provides a cariprazine-fumaric acid-methanol-acetonitrile solvate, a method that is simple, has high yield, is convenient, and suitable for industrial production. Summary of the Invention

[0006] The purpose of this invention is to address the shortcomings of existing technologies by providing a caliprazine-fumaric acid-methanol-acetonitrile solvate 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 the caliprazine-fumaric acid-methanol-acetonitrile solvate. Furthermore, this invention provides a simple, convenient method for preparing the caliprazine-fumaric acid-methanol-acetonitrile solvate, suitable for industrial production.

[0007] The specific technical content of this invention is as follows:

[0008] On one hand, the present invention provides a cariprazine-fumaric acid-methanol-acetonitrile solvate, characterized in that it uses Cu-Kα radiation to achieve a 2 θ The X-ray diffraction pattern shown has characteristic peaks at least at 7.9±0.2°, 12.3±0.2°, 16.6±0.2°, 20.3±0.2°, and 24.7±0.2°.

[0009] Preferably, the carilarazine-fumaric acid crystal form, when subjected to Cu-Kα radiation, exhibits an X-ray diffraction pattern expressed in 2θ at at least 5.7±0.2°, 7.9±0.2°, 12.3±0.2°, 12.8±0.2°, 16.6±0.2°, 16.8±0.2°, 17.5±0.2°, 18.4±0.2°, 19.2±0.2°, 19.9±0.2°, 20.3±0.2°, and 20°. Characteristic peaks are observed at 8±0.2°, 21.1±0.2°, 22.0±0.2°, 22.7±0.2°, 24.7±0.2°, 25.7±0.2°, 34.1±0.2°, 35.5±0.2°, 37.8±0.2°, 40.5±0.2°, and 45.0±0.2°.

[0010] Preferably, the carilarazine-fumaric acid eutectic 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.

[0011] Preferably, the caliradin-fumaric acid crystal form has the molecular formula C1. 28 H 42 Cl2N5O6 has the following crystallographic parameters: triclinic crystal system, space group P-1, cell parameters: a=11.8275(2)Å, b=11.9066(2)Å, c=12.6811(3)Å, α=101.272(2)°, β=104.565(2)°, γ=97.367(2)°, and cell volume V=1665.23(6)Å. 3 On the other hand, the present invention provides a method for preparing cariprazine-fumaric acid crystal form, comprising the following steps: Caliprazine and fumaric 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-fumaric acid crystals.

[0012] Preferably, the solvent is selected from methanol, acetonitrile and acetone, tetrahydrofuran, toluene, ethanol, and ethyl acetate. A mixed solvent of methanol, acetonitrile, and acetone is particularly preferred, with a volume ratio of 4.0~5.5:1.5~2.5:1, and more preferably 5:2:1.

[0013] Preferably, the mass-to-volume ratio of cariprazine to organic solvent is 1:0.07~0.15; more preferably 1.0:0.09.

[0014] Preferably, the molar ratio of cariprazine to fumaric acid is 1:1.1 to 1.7, more preferably 1:1.4.

[0015] Preferably, the heating temperature is 65~80℃, more preferably 70℃.

[0016] The cooling crystallization temperature is -5~5℃, preferably 0℃.

[0017] The crystallization time is 48-72 hours.

[0018] The drying temperature is 25-35℃, and the drying time is 24-36 hours.

[0019] 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.

[0020] Finally, the present invention provides a pharmaceutical composition containing the cariprazine-fumaric acid crystal form described herein and other pharmaceutically feasible components.

[0021] Preferably, the other pharmaceutically feasible components may be co-operable active pharmaceutical ingredients and / or pharmaceutically acceptable excipients.

[0022] Confirmation of crystal structure

[0023] The X-ray crystal data for the carilarazine-fumaric acid crystal form test described in this invention were collected using a Rigaku XtaLABSynergy instrument from Japan. The test temperature was 293(2) K, and Cu-Ka radiation was used. Data were collected and processed using an ω-scan method. 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.

[0024] The crystallographic data of the calirazine-fumaric acid crystal form prepared by the present invention (as shown in Table 1) are as follows: triclinic crystal system, space group P-1, cell parameters: a=11.8275(2)Å, b=11.9066(2)Å, c=12.6811(3)Å, α=101.272(2)°, β=104.565(2)°, γ=97.367(2)°, cell volume V=1665.23(6)Å3.

[0025] Table 1. Main crystallographic data of caliradin-fumaric acid-methanol-acetonitrile solvate

[0026] The ORTEP diagram of the caliprazine-fumaric acid-methanol-acetonitrile solvate of the present invention shows that the crystalline form contains one molecule of caliprazine, one molecule of fumaric acid, one molecule of methanol, and one molecule of acetonitrile, as shown in the attached diagram. Figure 2 As shown. The hydrogen bond diagram of the carilarazine-fumaric acid-methanol-acetonitrile solvate 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.

[0027] Table 2. PXRD peaks of caliraline-fumaric acid crystal form

[0028] Compared with the prior art, the technical effects achieved by the present invention are as follows:

[0029] This invention provides, for the first time, a cariprazine-fumaric acid-methanol-acetonitrile solvate, which has a simple preparation method, easy-to-control crystallization process, and good reproducibility. The formation of a eutectic between the two significantly enhances the solubility of cariprazine, demonstrating strong pharmaceutical value. Attached Figure Description

[0030] Figure 1 PXRD pattern of carilarazine-fumaric acid-methanol-acetonitrile solvate.

[0031] Figure 2 ORTEP diagram of cariprazine-fumaric acid-methanol-acetonitrile solvate.

[0032] Figure 3 Local ORTEP plot of cariprazine-fumaric acid-methanol-acetonitrile solvate.

[0033] Figure 4 Hydrogen bond diagram of carilarazine-fumaric acid-methanol-acetonitrile solvate. Detailed Implementation

[0034] 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.

[0035] Example 1

[0036] Cariprazine (427.41 mg, 1.0 mmol) and fumaric acid (162.5 mg, 1.4 mmol) were dissolved in a mixed solvent of methanol (25 mL), acetonitrile (10 mL), and acetone (5 mL). The mixture 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 a cariprazine-fumaric acid-methanol-acetonitrile solvate with a yield of 98.61% and a purity of 99.95%.

[0037] Example 2

[0038] Cariprazine (427.41 mg, 1.0 mmol) and fumaric acid (127.67 mg, 1.1 mmol) were dissolved in a mixed solvent of methanol (16 mL), acetonitrile (10 mL), and tetrahydrofuran (4 mL). The mixture was heated in a water bath at 65 °C and stirred until completely dissolved. The solution was filtered and allowed to stand at room temperature to evaporate and crystallize, yielding a cariprazine-fumaric acid-methanol-acetonitrile solvate with a yield of 96.56% and a purity of 99.71%.

[0039] Example 3

[0040] Cariprazine (427.41 mg, 1.0 mmol) and fumaric acid (197.32 mg, 1.7 mmol) were dissolved in a mixed solvent of methanol (38 mL), acetonitrile (20 mL), and toluene (7 mL). The mixture was heated in an 80°C water bath and stirred until completely dissolved. The solution was filtered and allowed to stand at room temperature to evaporate and crystallize, yielding a cariprazine-fumaric acid-methanol-acetonitrile solvate with a yield of 97.36% and a purity of 99.65%.

[0041] Example 4

[0042] Cariprazine (427.41 mg, 1.0 mmol) and fumaric acid (116.07 mg, 1.0 mmol) were dissolved in a mixed solvent of methanol (18 mL), acetonitrile (9 mL), and ethanol (5 mL). The mixture 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 a cariprazine-fumaric acid-methanol-acetonitrile solvate with a yield of 84.62% and a purity of 98.96%.

[0043] Example 5

[0044] Cariprazine (427.41 mg, 1.0 mmol) and fumaric acid (220.53 mg, 1.9 mmol) were dissolved in a mixed solvent of methanol (40 mL), acetonitrile (18 mL), and toluene (7 mL). The mixture was heated in a water bath at 85 °C and stirred until completely dissolved. The solution was filtered and allowed to stand at room temperature to evaporate and crystallize, yielding a cariprazine-fumaric acid-methanol-acetonitrile solvate with a yield of 89.66% and a purity of 98.05%.

[0045] Comparative Example 1

[0046] Preparation of Caliprazine bishydroxynaphthyl salt crystal form A

[0047] 4000 mg (9.36 mmol) of cariprazine was dissolved in 200 mL (5.4 mg / mL) of phosphoric acid solution to obtain solution A; 3634 mg (9.36 mmol) of dihydroxynaphthyl 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 over 30 minutes with stirring. The product was filtered to separate the product and washed with water. The product was dried under vacuum at 40 °C for 12 hours to obtain a light yellow solid. 2000 mg of this solid was added to 20 mL of methanol, and the mixture was stirred at room temperature for 24 hours to crystallize. The crystals were then filtered and dried under vacuum at 55 °C to obtain 1900 mg of cariprazine dihydroxynaphthyl acid salt crystal form A, with a yield of 95%.

[0048] Verification test

[0049] 1. Stability test

[0050] The novel crystalline form of cariprazine-fumaric acid-methanol-acetonitrile 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.

[0051] Table 3 Results related to substances

[0052] Table 4 Crystal form stability results

[0053] The results of related substance testing are shown in Table 3. The changes in related substances of the cariprazine solvate of the present invention were all within 0.1% after being placed under high temperature, high humidity and accelerated conditions for 10 days. The results of crystal form stability are shown in Table 4. It shows that compared with the known cariprazine dihydroxynaphthyl salt crystal form A, the new crystal form of cariprazine of the present invention has better crystal form stability. After being placed under various conditions for 10 days, the crystal form did not change and the crystallinity did not change significantly.

[0054] 2. In vitro dissolution simulation experiment

[0055] The cariprazine-fumaric acid-methanol-acetonitrile solvate prepared in Example 1 and the cariprazine dihydroxynaphthalate crystal form A prepared in the comparative example 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 by high-performance liquid chromatography (HPLC). pH 3, pH 4, pH 5, and pH 6 were acetic acid buffer solutions, and pH 7, pH 8, and pH 9 were phosphate buffer solutions. The results are shown in Table 5.

[0056] Table 5 Solubility Results

[0057] Solubility test results show that the cariprazine 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.

[0058] 3. Solution stability experiment

[0059] 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:

[0060] Table 6. Formulation Prescriptions

[0061] Preparation process:

[0062] (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.

[0063] (2) Add the prescribed amount of cariprazine crystal form to obtain a coarse particle suspension aqueous solution;

[0064] (3) The coarse particle suspension aqueous solutions obtained in Example 1 and Comparative Example 1 were respectively ground and dispersed using a ball mill;

[0065] (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;

[0066] The aqueous suspensions of caliprazine-fumaric acid solvates prepared in Example 1 and the aqueous suspensions of caliprazine dihydroxynaphthyl salt crystal form A prepared in Comparative Example 1 were tested for related substances at 60°C for 10 days. The results are shown in the table below:

[0067] Table 7. Related to the suspensions in each example.

[0068] According to the results in the table above, among the suspensions of the same formulation, the suspension of cariprazine-fumaric acid solvate crystal form is more stable than the suspension of cariprazine bishydroxynaphthenate crystal form A.

Claims

1. A novel crystalline form of cariprazine, characterized in that, The molar ratio of cariprazine, fumaric acid, methanol, and acetonitrile in the crystal unit structure is 1:1:1:

1.

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 5.7±0.2°, 7.9±0.2°, 12.3±0.2°, 16.6±0.2°, 20.3±0.2°, and 24.7±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 5.7±0.2°, 7.9±0.2°, 12.3±0.2°, 12.8±0.2°, 16.6±0.2°, 16.8±0.2°, 17.5±0.2°, 18.4±0.2°, 19.2±0.2°, 19.9±0.2°, 20.3±0.2°, 20.8±0.2°, 21.1±0.2°, 22.0±0.2°, 22.7±0.2°, 24.7±0.2°, 25.7±0.2°, 34.1±0.2°, 35.5±0.2°, 37.8±0.2°, 40.5±0.2°, and 45.0±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 C0. 28 H 42 Cl2N5O6 has the following crystallographic parameters: triclinic crystal system, space group P-1, cell parameters: a=11.8275(2)Å, b=11.9066(2)Å, c=12.6811(3)Å, α=101.272(2)°, β=104.565(2)°, γ=97.367(2)°, and cell volume V=1665.23(6)Å. 3 .

6. A method for preparing a novel crystalline form of cariprazine according to any one of claims 1-5, characterized in that, The preparation method includes the following steps: dissolving cariprazine and fumaric 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-fumaric acid solvate crystals.

7. The preparation method according to claim 6, characterized in that, The solvent is selected from methanol, acetonitrile and acetone, tetrahydrofuran, toluene, ethanol and ethyl acetate, with a volume ratio of 4.0~5.5:1.5~2.5:

1.

8. The preparation method according to claim 6, characterized in that, The mass-to-volume ratio of carilarazine to organic solvent is 1:0.07~0.

15.

9. The preparation method according to claim 6, characterized in that, The molar ratio of cariprazine to fumaric acid is 1:1.1 to 1.

7.

10. The preparation method according to claim 6, characterized in that, The heating temperature is 65~80℃.

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