Crystalline form of brexpiprazole-maleic acid-methanol

Abstract

The invention relates to the technical field of crystal form medicine molecules, and particularly discloses a brexpiprazole-maleic acid-methanol crystal form as well as a preparation method and application thereof. According to the brexpiprazole-maleic acid-methanol crystal form disclosed by the invention, Cu-K alpha radiation is used, and an X-ray diffraction pattern represented by 2 theta has characteristic peaks at least at 16.3 + / -0.2 degrees, 21.9 + / -0.2 degrees, 22.2 + / -0.2 degrees, 24.1 + / -0.2 degrees and 27.3 + / -0.2 degrees. The purity of the prepared brexpiprazole-maleic acid-methanol crystal form is higher than 99.9%, and the brexpiprazole-maleic acid-methanol 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 birepiperazole-maleic acid-methanol crystal form, 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] Formula 1

[0005] However, its inherent low water solubility (BCS Class II) severely limits bioavailability, becoming a major challenge in formulation development. In recent years, research on improving the physicochemical properties of drugs through crystal engineering technology has attracted much attention, among which the design of crystal forms and solvates is an effective strategy to improve solubility.

[0006] Existing literature indicates that birepiperazole can improve its solubility by forming crystal forms 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-malonic acid crystal form with a triclinic crystal system (space group P-1), exhibiting a 1.37-fold increase in solubility compared to the active pharmaceutical ingredient. Furthermore, Arabiani et al. (CrystEngComm, 2019) synthesized a birepiperazole-succinic acid crystal form via a mechanochemical method, significantly increasing the dissolution rate and further validating the potential of crystal form technology in improving drug performance. In the study of solvates, Zeidan et al. (Crystal Growth & Design, 2018) systematically characterized various crystal forms and solvates of burepiperazole (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 and is widely used in formulations, but crystal form I has low solubility. Although the dihydrate is stable in an aqueous environment, it is easily dehydrated and transformed into crystal form I in a low humidity environment, resulting in a sudden change in solubility.

[0007] This invention provides a simple and easy-to-operate method for preparing high-purity birepiperazole-maleic acid-methanol crystal form, 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

[0008] To address the shortcomings of existing bripiprazole crystals, such as poor solubility and stability, this invention aims to provide a new crystalline form of bripiprazole with higher solubility and stability, namely the bripiprazole-maleic acid-methanol crystal form. Furthermore, this invention provides a simple, convenient, high-yield method for preparing the bripiprazole-maleic acid-methanol crystal form, suitable for industrial production.

[0009] The specific technical content of this invention is as follows:

[0010] On one hand, the present invention provides a breviperazole-maleic acid-methanol crystal form, characterized in that, using Cu-Kα radiation, the X-ray diffraction pattern represented by 2θ has characteristic peaks at least at 16.3±0.2°, 21.9±0.2°, 22.2±0.2°, 24.1±0.2°, and 27.3±0.2°.

[0011] Preferably, the breviperazole-maleic acid-methanol crystal form, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (expressed as 2θ) at at least 8.1±0.2°, 8.6±0.2°, 10.6±0.2°, 11.1±0.2°, 16.3±0.2°, 16.7±0.2°, 18.9±0.2°, 21.9±0.2°, 22.2±0.2°, 23.9±0.2°, 24.1±0.2°, and 27.3±0.2°.

[0012] Preferably, the bripiprazole-maleic acid-methanol crystal form 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.

[0013] Preferably, the breviperazole-maleic acid-methanol crystal form has the molecular formula C2. 30 H 35 N3O7S has the following crystallographic parameters: monoclinic system, space group P21 / c, cell parameters: a=24.0071(6)Å, b=11.2840(4)Å, c=11.1025(2)Å, α=90°, β=101.1570(10)°, γ=90°, and cell volume V=2950.78(14)Å. 3 .

[0014] On the other hand, the present invention provides a method for preparing bripiprazole-maleic acid-methanol crystal form, comprising the following steps:

[0015] Buripiperazole and maleic acid 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 the buripiperazole-maleic acid-methanol crystal form.

[0016] Preferably, the mixed solvent is a mixture of methanol and other solvents, wherein the other solvents are selected from ethanol, acetonitrile, acetone, and isopropanol.

[0017] More preferably, the mixed solvent is a mixture of methanol and acetone, or a mixture of methanol and ethanol.

[0018] Preferably, in the mixed solvent, the volume ratio of methanol to other organic solvents is 1:1 to 3, more preferably 1:1.5 to 2.5.

[0019] Preferably, the mass-to-volume ratio of burepiperazole to organic solvent is 1.1:1~3, more preferably 1.1:1.5~2.5; wherein the mass is expressed in mg and the volume in ml.

[0020] Preferably, the molar ratio of buriperazole to maleic acid is 1:0.9 to 1.1, more preferably 1:1.

[0021] Preferably, the heating temperature is 40~60℃, more preferably 50~55℃.

[0022] The cooling and crystallization temperature is 0~30℃, preferably 8~15℃.

[0023] The crystallization time is 8 to 60 hours.

[0024] The drying temperature is 50~65℃, and the drying time is 8~10 hours.

[0025] 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.

[0026] Finally, the present invention provides a pharmaceutical composition comprising the birepiperazole-maleic acid-methanol crystal form described herein and other pharmaceutically feasible components.

[0027] Preferably, the other pharmaceutically feasible components may be co-operable active pharmaceutical ingredients and / or pharmaceutically acceptable excipients.

[0028] Confirmation of crystal structure

[0029] The X-ray crystal data for the crystal form test of bripiprazole-maleic acid-methanol 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 an ω-scan manner. 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.

[0030] The crystallographic data (as shown in Table 1) of the breviperazole-maleic acid-methanol crystal form prepared in this invention were tested and analyzed. The crystal system is monoclinic, space group is P21 / c, and the cell parameters are: a=24.0071(6) Å, b=11.2840(4) Å, c=11.1025(2) Å, α=90°, β=101.1570(10)°, γ=90°, and the cell volume V=2950.78(14) Å. 3 .

[0031] Table 1. Main crystallographic data of bripiprazole-maleic acid-methanol crystal forms

[0032] The ORTEP diagram of the bripiprazole-maleic acid-methanol crystal form of the present invention shows that this crystalline form contains one molecule of bripiprazole, one molecule of maleic acid, and one molecule of methanol, and there are no hydrogen bonds within the unit cell, as shown in the attached diagram. Figure 2As shown in the attached diagram. The hydrogen bonding diagram of the bripiprazole-maleic acid-methanol crystal form of the present invention shows hydrogen bonding forces existing between the unit cells. 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.

[0033] Table 2. PXRD peaks of the buripiperazole-maleic acid-methanol crystal form

[0034] Compared with the prior art, the technical effects achieved by the present invention are as follows:

[0035] By utilizing the dicarboxylic acid structure of maleic acid to provide a strong hydrogen bond network, the drug molecule arrangement is optimized, and the lattice energy is increased while enhancing the permeability of water molecules. The crystallization kinetics are regulated by the solvation effect of methanol to form a thermodynamically stable crystal form, avoiding the risk of phase transition of hydrates during storage or dissolution. This achieves a synergistic improvement in solubility and stability, breaks through the performance limit of existing binary systems, and provides a highly reproducible crystallization process for industrial production. Attached Figure Description

[0036] Figure 1 The PXRD pattern of the buripiperazole-maleic acid-methanol crystal form.

[0037] Figure 2 The ORTEP diagram shows the crystal form of buripiperazole-maleic acid-methanol.

[0038] Figure 3 The hydrogen bond diagram for the breviperazole-maleic acid-methanol crystal form.

[0039] Figure 4 This is a DSC-TGA image of the breviperazole-maleic acid-methanol crystal form. Detailed Implementation

[0040] 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.

[0041] Example 1

[0042] 43.57 mg of biriperazole and 11.66 mg of maleic acid were dissolved in a mixed solvent of 23.8 mL of methanol and 35.6 mL of acetone. The solution was heated and stirred in a water bath at 50 °C until completely dissolved. The solution was filtered, allowed to stand at 15 °C to volatilize and crystallize, filtered again, and dried at 50 °C for 8 h to obtain biriperazole-maleic acid-methanol. The yield was 98.2% and the purity was 99.93%.

[0043] Example 2

[0044] 43.38 mg of biriperazole and 11.61 mg of maleic acid were dissolved in a mixed solvent of 28 mL of methanol and 70.5 mL of isopropanol. The mixture was heated and stirred in a water bath at 55 °C until completely dissolved. After filtration, the mixture was allowed to stand at 8 °C to volatilize and crystallize. After filtration, the mixture was dried at 50 °C for 8 h to obtain biriperazole-maleic acid-methanol. The yield was 97.7% and the purity was 99.93%.

[0045] Example 3

[0046] 43.44 mg of biriperazole and 10.45 mg of maleic acid were dissolved in a mixed solvent of 17.4 mL of methanol and 26 mL of acetonitrile. The mixture was heated and stirred in a water bath at 40 °C until completely dissolved. The solution was filtered, allowed to stand at 0 °C to volatilize and crystallize, filtered again, and dried at 65 °C for 10 h to obtain biriperazole-maleic acid-methanol. The yield was 96.8% and the purity was 99.92%.

[0047] Example 4

[0048] 43.36 mg of biriperazole and 12.77 mg of maleic acid were dissolved in a mixed solvent of 3.6 mL of methanol and 10.8 mL of ethanol. The solution was heated and stirred in a water bath at 60 °C until completely dissolved. The solution was allowed to stand at 30 °C to volatilize and crystallize. The solution was filtered and dried at 50 °C for 8 h to obtain biriperazole-maleic acid-methanol. The yield was 97.5% and the purity was 99.90%.

[0049] Comparative Example 1

[0050] Referring to patent CN200680011923.0, a methanol solution of maleic acid was added to a methanol and dichloromethane solution of bripiprazole, and the solvent was evaporated under reduced pressure. The residue was recrystallized in 80% ethanol to obtain bripiprazole maleate, with a yield of 81.1% and a purity of 99.88%.

[0051] Comparative Example 2

[0052] 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%.

[0053] Comparative Example 3

[0054] 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%.

[0055] Verification Experiment

[0056] I. Stability Experiment

[0057] 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.

[0058] Table 3. Stability test results of crystal forms under light, high temperature and high humidity conditions.

[0059] Experiments showed that the purity of the bripiprazole-maleic acid-methanol crystal 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.

[0060] II. Solubility Test

[0061] Test method: Water, 0.01 mol / L hydrochloric acid solution, and pH 6.8 PBS buffer were used as media. Excess amounts of the crystal forms obtained in Example 1 and Comparative Examples 1-3 were added to the above media, and the mixtures were stirred at 37°C for 24 hours. Sampling was repeated three times, the solutions were filtered, and appropriate amounts of the filtrate were diluted. The solubility in each medium was determined by HPLC. Specific test results are shown in Table 4.

[0062] Table 4. Solubility of crystal forms in different media (μg / ml)

[0063] Solubility tests showed that the solubility of the bripiprazole-maleic acid-methanol crystal form 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 1-3.

Claims

1. A breviperazole-maleic acid-methanol crystal form, characterized in that, The crystal form, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (denoted as 2θ) at at least 16.3±0.2°, 21.9±0.2°, 22.2±0.2°, 24.1±0.2°, and 27.3±0.2°.

2. The bripiprazole-maleic acid-methanol crystal form according to claim 1, characterized in that, The crystal form, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (denoted as 2θ) at at least 8.1±0.2°, 8.6±0.2°, 10.6±0.2°, 11.1±0.2°, 16.3±0.2°, 16.7±0.2°, 18.9±0.2°, 21.9±0.2°, 22.2±0.2°, 23.9±0.2°, 24.1±0.2°, and 27.3±0.2°.

3. The bripiprazole-maleic acid-methanol crystal form according to claim 1, characterized in that, The crystallographic parameters of the crystal form are: monoclinic system, space group P2. 1 / c The unit cell parameters are: a=24.0071(6)Å, b=11.2840(4)Å, c=11.1025(2)Å, α=90°, β=101.1570(10)°, γ=90°, and the unit cell volume V=2950.78(14)Å. 3 .

4. The bripiprazole-maleic acid-methanol crystal form according to claim 1, characterized in that, The crystal form was subjected to Cu-Kα radiation, and its characteristic peaks corresponded to the X-ray powder diffraction pattern shown in Figure 1.

5. A method for preparing the bripiprazole-maleic acid-methanol crystal form as described in any one of claims 1-4, characterized in that, The method includes the following steps: dissolving buriperazole and maleic acid in a mixed solvent, heating and stirring, filtering, cooling and allowing to stand to volatilize and crystallize, filtering and drying to obtain buriperazole-maleic acid-methanol crystal form.

6. The method for preparing the bripiprazole-maleic acid-methanol crystal form according to claim 5, characterized in that, The mixed solvent is a mixture of methanol and other solvents; the other solvents are selected from ethanol, acetonitrile, acetone, and isopropanol; wherein the volume ratio of methanol to other solvents is 1:1 to 3, preferably 1:1.5 to 2.

5.

7. The method for preparing the bripiprazole-maleic acid-methanol crystal form according to claim 5, characterized in that, The mass-to-volume ratio of the buriperazole to the mixed solvent is 1.1:1~3, preferably 1.1:1.5~2.5; wherein the mass is expressed in mg and the volume in ml.

8. The method for preparing the bripiprazole-maleic acid-methanol crystal form according to claim 5, characterized in that, The molar ratio of buriperazole to maleic acid is 1:0.9 to 1.1, preferably 1:

1.

9. The method for preparing the bripiprazole-maleic acid-methanol crystal form according to claim 5, characterized in that, The heating temperature is 40~60℃, preferably 50~55℃; the cooling and crystallization temperature is 0~30℃, preferably 8~15℃.

10. A pharmaceutical composition, characterized in that, The composition comprises the birepiperazole-maleic acid-methanol crystal form as described in any one of claims 1 to 4, and other pharmaceutically acceptable components.

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