Novel salt form of brexpiprazole-benzoic acid-dihydrate

Abstract

The invention relates to the technical field of crystal form drug molecules, and particularly provides a novel brexpiprazole-benzoic acid-dihydrate salt form as well as a preparation method and application thereof. The brexpiprazole-benzoic acid-dihydrate disclosed by the invention is radiated by Cu-K alpha, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at the positions of 8.2 + / -0.2 degrees, 8.4 + / -0.2 degrees, 8.9 + / -0.2 degrees, 13.7 + / -0.2 degrees, 14.8 + / -0.2 degrees and 16.4 + / -0.2 degrees. The purity of the prepared brexpiprazole-benzoic acid-crystal form is higher than 99.85%, and the brexpiprazole-benzoic acid-crystal form is high in solubility and good in stability. The method is simple in preparation process and has a relatively good industrial application prospect.

Description

Technical Field

[0001] This invention belongs to the field of crystal drug molecule technology, specifically relating to a new salt form of birepiperazole-benzoic acid-dihydrate, its preparation method, and its application. Background Technology

[0002] Brepiprazole, as shown in Formula 1, with the chemical name 7-(4-(4-(benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy)-1h-quinoline-2-one, is a white or off-white crystalline powder developed by Otsuka Pharmaceutical Co., Ltd. It is a dopamine D2 receptor partial agonist (improves positive and negative symptoms, cognitive impairment, and depressive symptoms), a 5-HT2A receptor antagonist (improves negative symptoms, cognitive impairment, symptoms of depression, and insomnia), an XL-adrenergic receptor antagonist (improves positive symptoms of schizophrenia), and a serotonin uptake / reuptake inhibitor (improves depressive symptoms); it is also a 5-HT1A partial agonist (with anti-anxiety and antidepressant activity) and a 5-HT7 antagonist. It was approved by the US FDA on July 11, 2015, for adjunctive treatment of schizophrenia and major depressive disorder.

[0003]

[0004] However, their inherent low water solubility (BCSII class) severely limits bioavailability, becoming a major challenge in formulation development. In recent years, research on improving the physicochemical properties of drugs through crystal engineering techniques has attracted much attention, among which the design of cocrystallization and solvates are effective strategies to improve solubility.

[0005] Existing literature indicates that the solubility of birepiperazole can be improved through hydrogen bond reconstruction with various carboxylic acids (such as malonic acid, succinic acid, and fumaric acid). For example, Rama et al. (Journal of Crystal Growth, 2020) reported a birepiperazole-fumaric acid cocrystal, but its solubility was only 2.6 times higher than that of the active pharmaceutical ingredient, which is insufficient to meet the requirements for high doses. In addition, Arabiani et al. (CrystEngComm, 2019) synthesized a birepiperazole-succinic acid cocrystal via a mechanochemical method, which improved the solubility by 1.59 times, but the improvement was limited. In the study of solvates, Zeidan et al. (Crystal Growth & Design, 2018) systematically characterized various crystal forms and solvates of buripiperazole (such as methanol solvate, toluene hemisolvate and dihydrate), and found that there is a monotonic relationship among its polymorphs. Among them, crystal form I is the most thermodynamically stable, but has low solubility. Although the dihydrate is stable in a water-containing environment, it is easily dehydrated and transformed into crystal form I in a low-humidity environment, resulting in a sudden change in solubility.

[0006] This invention provides a simple and easy-to-operate method for preparing a new salt form of high-purity birepiperazole-benzoic acid-dihydrate, as well as a product with good chemical stability and solubility, providing better drug application basis for the treatment of mental illness, thereby more effectively exerting the medicinal value of birepiperazole. Summary of the Invention

[0007] To address the shortcomings of existing technologies in terms of poor solubility and stability of bripiprazole crystals, this invention aims to provide a novel bripiprazole-benzoic acid-dihydrate salt with higher solubility and stability. Furthermore, this invention provides a simple, convenient, and high-yield method for preparing the novel bripiprazole-benzoic acid-dihydrate salt, suitable for industrial production.

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

[0009] On the one hand, the present invention provides a new salt form of bripiprazole-benzoic acid-dihydrate, which, when irradiated with Cu-Kα, exhibits characteristic peaks in its X-ray diffraction pattern (denoted as 2θ) at at least 8.2±0.2°, 8.4±0.2°, 8.9±0.2°, 13.7±0.2°, 14.8±0.2°, and 16.4±0.2°.

[0010] Preferably, the novel bripiprazole-benzoic acid-dihydrate salt form, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (denoted as 2θ) at at least 7.4±0.2°, 7.6±0.2°, 7.9±0.2°, 8.2±0.2°, 8.4±0.2°, 8.9±0.2°, 13.3±0.2°, 13.7±0.2°, 14.0±0.2°, 14.8±0.2°, 16.1±0.2°, 16.4±0.2°, 23.7±0.2°, 27.4±0.2°, 27.5±0.2°, and 28.7±0.2°.

[0011] Preferably, the novel salt form of bripiprazole-benzoic acid-dihydrate is obtained using 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 novel salt form of bripiprazole-benzoic acid-dihydrate has the molecular formula C. 32 H 37 N3O6S, crystallographic parameters: orthorhombic crystal system, space group Pbca, unit cell parameters: α = 90°, β = 90°, γ = 90°, unit cell volume

[0013] On the other hand, the present invention provides a method for preparing a new salt form of bripiprazole-benzoic acid-dihydrate, comprising the following steps:

[0014] Bripiperazole and benzoic acid were added to a mixed solvent, heated and stirred, filtered, cooled and allowed to stand to volatilize and crystallize, and then filtered and dried to obtain a new salt form of bripiprazole-benzoic acid-dihydrate.

[0015] Preferably, the mixed solvent is a mixture of acetone, water, and other organic solvents, wherein the other organic solvents are selected from ethanol, acetonitrile, diethyl ether, methanol, and isopropanol.

[0016] More preferably, the mixed solvent is a mixture of acetone, water, and acetonitrile.

[0017] Preferably, in the mixed solvent, the volume ratio of acetone, water and other organic solvents is 1:1:1.5 to 1:1:3, more preferably 1:1:2.

[0018] Preferably, the mass-to-volume ratio of buriperazole to solvent is 18:1 to 3; more preferably 9:1; wherein the mass is in mg and the volume is in ml.

[0019] Preferably, the molar ratio of buriperazole to benzoic acid is 1:0.9 to 1.1, more preferably 1:1.05.

[0020] Preferably, the heating temperature is 30–50°C, and more preferably 40–45°C.

[0021] The cooling crystallization temperature is 0–20°C, preferably 5–8°C.

[0022] The crystallization time is 24 to 60 hours.

[0023] The drying temperature is 50-65℃, and the drying time is 8-10 hours.

[0024] The raw material birepiperazole used in the preparation method can be prepared according to any method in the prior art or purchased from commercially available products.

[0025] Finally, the present invention provides a pharmaceutical composition containing the novel birepiperazole-benzoic acid-dihydrate salt form described in this invention and other pharmaceutically feasible components.

[0026] Preferably, the other pharmaceutically feasible components may be co-operable active pharmaceutical ingredients and / or pharmaceutically acceptable excipients.

[0027] Confirmation of crystal structure

[0028] The X-ray crystal data for the bripiprazole-benzoic acid-dihydrate salt type test described in this invention were collected on a Rigaku XtaLABSynergy instrument in Japan at a test temperature of 293(2) K. Cu-Ka radiation was used, and data were collected in an ω-scan manner with Lp correction. The structure was resolved using a direct method, and all non-hydrogen atoms were identified using the difference Fourier method. All hydrogen atoms on carbon and nitrogen were obtained through theoretical hydrogenation. The structure was refined using the least squares method.

[0029] The crystallographic data (as shown in Table 1) of the bripiprazole-benzoic acid-dihydrate salt form prepared in this invention were tested and analyzed. The crystal system is Orthorhombic, space group Pbca, and the cell parameters are: α = 90°, β = 90°, γ = 90°, unit cell volume

[0030] Table 1. Main crystallographic data of the new salt forms of bripiprazole-benzoic acid-dihydrate

[0031]

[0032]

[0033] The ORTEP diagram of the bripiprazole-benzoic acid-dihydrate salt form of this invention shows that this crystalline form contains one molecule of bripiprazole, one molecule of benzoic acid, and two molecules of water. The hydrogen atom bonded to the O4 atom of benzoic acid undergoes proton transfer and bonds to the N2 atom of bripiprazole to form a salt, as shown in the attached diagram. Figure 2 As shown. The hydrogen bond diagram of the repiperazole-benzoic acid-dihydrate 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.

[0034] Table 2 PXRD peaks of the new salt form of buripiperazole-benzoic acid-dihydrate

[0035]

[0036]

[0037] Compared with the prior art, the technical effects achieved by the present invention are as follows:

[0038] This invention provides a novel salt form of birepiperazole-benzoic acid-dihydrate for the first time. Its preparation method is simple, the crystallization process is easy to control, and it exhibits good reproducibility. It achieves a synergistic improvement in solubility and stability, breaking through the performance limits of existing binary systems, which helps to improve oral bioavailability and has strong pharmaceutical value. Attached Figure Description

[0039] Figure 1 The PXRD pattern is for the new salt form of birepiperazole-benzoic acid-dihydrate.

[0040] Figure 2 ORTEP diagram of the new salt form of birepiperazole-benzoic acid-dihydrate.

[0041] Figure 3 Hydrogen bond diagram for the new salt form of birepiperazole-benzoic acid-dihydrate.

[0042] Figure 4 The image shows the PXRD pattern of the crystal form in Comparative Example 1. Detailed Implementation

[0043] The present invention will be further illustrated below through embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the invention and not for limiting the invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention are all within the scope of protection of the present invention.

[0044] Example 1

[0045] 439.2 mg of biriperazole and 129.9 mg of benzoic acid were added to a mixed solvent of 12.2 mL acetone, 12.2 mL purified water and 24.4 mL acetonitrile. The mixture was heated and stirred at 40 °C until completely dissolved. After filtration, the mixture was allowed to stand at 5 °C to volatilize and crystallize. After filtration, the mixture was dried at 50 °C for 8 h to obtain biriperazole-benzoic acid-dihydrate. The yield was 98.4% and the purity was 99.98%.

[0046] Example 2

[0047] 435.6 mg of biriperazole and 110.4 mg of benzoic acid were added to a mixed solvent of 6.9 mL acetone, 6.9 mL purified water and 10.4 mL ethanol. The mixture was heated and stirred at 45 °C until completely dissolved. After filtration, the mixture was allowed to stand at 8 °C to evaporate and crystallize. After filtration, the mixture was dried at 50 °C for 8 h to obtain biriperazole-benzoic acid-dihydrate. Yield: 98.0%, purity: 99.97%.

[0048] Example 3

[0049] 430.7 mg of biriperazole and 133.4 mg of benzoic acid were added to a mixed solvent of 14.5 mL acetone, 14.5 mL purified water and 42.8 mL isopropanol. The mixture was heated and stirred at 50 °C until completely dissolved. After filtration, the solution was allowed to stand at 20 °C to evaporate and crystallize, yielding biriperazole-benzoic acid-dihydrate with a yield of 96.4% and a purity of 99.95%.

[0050] Example 4

[0051] 439.1 mg of biriperazole and 129.8 mg of benzoic acid were added to a mixed solvent of 12.2 mL acetone, 12.2 mL purified water and 24.4 mL isopropanol. The mixture was heated and stirred at 30 °C until completely dissolved. After filtration, the mixture was allowed to stand at 0 °C to evaporate and crystallize, yielding biriperazole-benzoic acid-dihydrate. The purity was 99.96%.

[0052] Comparative Example 1

[0053] Bripiperazole and benzoic acid were added to a ball mill, and ethanol was added dropwise to form an adduct. The material was then removed and dried in a forced-air oven to obtain bripiprazole-benzoate, with a yield of 78.4% and a purity of 99.87%.

[0054] Comparative Example 2

[0055] 40 mg of buriperazole was dissolved in an appropriate amount of ethanol and heated until completely dissolved. The hot mixture was filtered, and the supernatant was allowed to stand and crystallize to obtain buriperazole crystal form I, with a yield of 82.3% and a purity of 99.77%.

[0056] Comparative Example 3

[0057] 100 mg of biriperazole and 26.77 mg of fumaric acid were placed in a clean round-bottom flask at a stoichiometric ratio of 1:1, followed by the addition of 3 mL of ethanol. The resulting clear solution was stirred for approximately 2–3 hours. The clear solution was then filtered through 0.45 μm filter paper and allowed to stand for slow crystallization. After 2–3 days, white crystalline powder appeared in the solution. Filtration yielded a biriperazole-fumaric acid eutectic, with a yield of 90.7% and a purity of 99.91%.

[0058] Verification Experiment

[0059] Stability test

[0060] The crystal forms obtained in Example 1 and Comparative Examples 1-3 were placed in open environments under high temperature test (60℃), high humidity test (25℃, relative humidity 92.5%) and strong light irradiation test (illuminance 4500±500lx) conditions. Samples were taken after 5 days and 10 days and the results are shown in Table 3 below.

[0061] Table 3. Stability test results of biriperazole crystals under light, high temperature and high humidity conditions.

[0062]

[0063] Experiments showed that the purity of the new bripiprazole-benzoic acid-dihydrate salt form prepared by this invention did not change significantly under light, high temperature and high humidity conditions. However, the purity of the crystal forms in Comparative Examples 1-3 decreased significantly under the same experimental conditions, and the impurity content increased significantly. This indicates that the crystal form prepared by this invention has good chemical stability.

[0064] Solubility test

[0065] Test method: Water, 0.01 mol / L hydrochloric acid solution, and pH 6.8 PBS buffer were used as media. Excess amounts of the solutions from Examples 1 and Comparative Examples 1-3 were added to the above media, and the mixtures were stirred at 37°C for 24 hours. Samples were taken three times, filtered, and a suitable amount of the filtrate was diluted. The solubility in each medium was determined by HPLC. Specific test results are shown in Table 4.

[0066] Table 4. Solubility of birepiperazole crystals in different media (μg / ml)

[0067]

[0068]

[0069] Solubility tests showed that the solubility of the new bripiprazole-benzoic acid-dihydrate salt was significantly improved in water, 0.01 mol / L hydrochloric acid, and pH 6.8 PBS buffer. Similar solubility test results were observed in Examples 1-4.

Claims

1. A novel salt form of brexpiprazole-benzoic acid-dihydrate, characterized by, The X-ray diffraction spectrum of the crystal form, using Cu-Ka radiation, has characteristic peaks at at least 8.2±0.2°, 8.4±0.2°, 8.9±0.2°, 13.7±0.2°, 14.8±0.2°, 16.4±0.2°.

2. The novel salt form of brexpiprazole-benzoic acid-dihydrate according to claim 1, which is brexpiprazole-benzoic acid-dihydrate monohydrate. The X-ray diffraction spectrum of the crystal form, using Cu-Ka radiation, has characteristic peaks at at least 7.4±0.2°, 7.6±0.2°, 7.9±0.2°, 8.2±0.2°, 8.4±0.2°, 8.9±0.2°, 13.3±0.2°, 13.7±0.2°, 14.0±0.2°, 14.8±0.2°, 16.1±0.2°, 16.4±0.2°, 23.7±0.2°, 27.4±0.2°, 27.5±0.2°, 28.7±0.2°.

3. The novel salt form of brexpiprazole-benzoic acid-dihydrate according to claim 1, which is brexpiprazole-benzoic acid-dihydrate monohydrate. The crystallographic parameters of the crystal form are: orthorhombic system, space group Pbca, cell parameters are: α = 90°, β = 90°, γ = 90°, cell volume 4. The novel salt form of brexpiprazole-benzoic acid-dihydrate according to claim 1, which is brexpiprazole-benzoic acid-dihydrate monohydrate. The crystal form has characteristic peaks corresponding to the X-ray powder diffraction pattern shown in Figure 1 using Cu-Ka radiation.

5. A process for the preparation of a new salt form of brexpiprazole-benzoic acid-dihydrate according to any one of claims 1 to 4, characterized by, The method comprises the following steps: adding brexpiprazole and benzoic acid into a mixed solvent, heating and stirring, filtering, cooling and standing to volatilize and crystallize, filtering and drying to obtain brexpiprazole-benzoic acid-dihydrate crystal.

6. The method of claim 5, wherein the preparation of the new salt form of brexpiprazole-benzoic acid-dihydrate is characterized by, The mixed solvent is a mixed solvent of acetone, water and another organic solvent selected from one of ethanol, acetonitrile, diethyl ether, methanol and isopropanol; in the mixed solvent, the volume ratio of acetone, water and another organic solvent is 1:1:1.5-1:1:

3.

7. The method for preparing the new salt form of bripiprazole-benzoic acid-dihydrate as described in claim 5, characterized in that, The mass-volume ratio of brexpiprazole to the mixed solvent is 18:1-3; preferably 9:1; the mass is in mg and the volume is in ml.

8. The method of claim 5, wherein the preparation of the new salt form of brexpiprazole-benzoic acid-dihydrate is characterized by, The molar ratio of brexpiprazole to benzoic acid is 1:0.9-1.

1.

9. The method of claim 5, wherein the preparation of the new salt form of brexpiprazole-benzoic acid-dihydrate is characterized by, The heating temperature is 30-50℃; the cooling and crystallization temperature is 5-8℃.

10. A pharmaceutical composition, characterized by, The composition comprises the brexpiprazole-benzoic acid-dihydrate new salt form of any one of claims 1-4 and other pharmaceutically acceptable components.

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