Brucpiprazole-p-toluenesulfonic acid crystal form

Abstract

The invention relates to the technical field of crystal form medicine molecules, and particularly discloses a brexpiprazole-p-toluenesulfonic acid crystal form as well as a preparation method and application thereof. The brexpiprazole-p-toluenesulfonic acid-crystal form disclosed by the invention is radiated by Cu-K alpha, and an X-ray diffraction pattern represented by 2 theta has characteristic peaks at least at 3.2 + / -0.2 degrees, 6.3 + / -0.2 degrees, 9.4 + / -0.2 degrees, 18.6 + / -0.2 degrees and 28.0 + / -0.2 degrees. The purity of the prepared brexpiprazole-p-toluenesulfonic acid-crystal form is higher than 99.9%, and the brexpiprazole-p-toluenesulfonic acid-crystal form has high solubility and good 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-p-toluenesulfonic acid-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] However, as a typical BCSII drug, iripeprazole's inherent low water solubility severely restricts the improvement of its oral bioavailability, becoming a core bottleneck in the drug's formulation development and clinical application. In the field of drug physicochemical property optimization, crystal engineering technology has become a research hotspot in recent years due to its ability to precisely control drug crystal structure and improve key properties; among them, co-crystal design and solvate preparation are currently the mainstream and effective technical strategies for improving the solubility of poorly soluble drugs.

[0005] Current research has explored various methods for optimizing the crystal engineering of birepiperazole, but significant limitations remain. Regarding cocrystallization, literature confirms that birepiperazole can form cocrystallizations with various carboxylic acids, such as malonic acid, succinic acid, and fumaric acid, through hydrogen bonding to improve solubility. For example, the birepiperazole-fumaric acid cocrystallization reported by Rama's team (Journal of Crystal Growth, 2020) only improved solubility by 2.6 times compared to the active pharmaceutical ingredient, which is insufficient to meet the needs of high-dose clinical use. Arabiani et al. (CrystEngComm, 2019) further synthesized a birepiperazole-succinic acid cocrystallization via mechanochemical methods, but the solubility improvement was only 1.59 times, failing to meet expectations. In the field of solvates research, Zeidan's team (Crystal Growth & Design, 2018) systematically characterized various crystal forms and solvates of birepiperazole (including methanol solvate, toluene hemisolvent, and dihydrate), and found that there is a monotonic stability relationship among its polymorphs. Among them, crystal form I has the best thermodynamic stability, but its solubility is extremely low. Although the dihydrate has a certain stability in a water-containing environment, it has a humidity sensitivity defect. In a low humidity environment, it is easy to dehydrate and transform into crystal form I, which leads to a sudden change in drug solubility and seriously affects the stability of formulation quality.

[0006] To address the shortcomings of the existing technologies, this invention proposes an innovative solution: providing a simple and highly controllable preparation method that can efficiently synthesize high-purity buripiperazole-p-toluenesulfonic acid-crystal form; overcoming the limitations of existing crystal engineering schemes, maximizing the pharmaceutical value of buripiperazole, and providing key technical support for its formulation optimization and clinical application upgrade. Summary of the Invention

[0007] 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: bripiprazole-p-toluenesulfonic acid-crystal form. Furthermore, this invention provides a simple, convenient, high-yield method for preparing the bripiprazole-p-toluenesulfonic acid-crystal form, suitable for industrial production.

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

[0009] The invention is characterized by using Cu-Kα radiation, and the X-ray diffraction pattern, expressed in 2θ, has characteristic peaks at at least 3.2±0.2°, 6.3±0.2°, 9.4±0.2°, 18.6±0.2°, and 28.0±0.2°.

[0010] Preferably, the bripiprazole-p-toluenesulfonic acid-crystal type, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (expressed as 2θ) at at least 3.2±0.2°, 6.3±0.2°, 9.4±0.2°, 12.4±0.2°, 15.5±0.2°, 16.7±0.2°, 18.4±0.2°, 18.6±0.2°, 21.8±0.2°, 24.9±0.2°, 25.7±0.2°, 28.0±0.2°, 31.2±0.2°, 34.4±0.2°, and 40.9±0.2°.

[0011] Preferably, the buripiperazole-p-toluenesulfonic acid-crystal type 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 buripiperazole-p-toluenesulfonic acid-crystal form has the molecular formula C1. 128 H 156 N 12 O 28 S8, crystallographic parameters: monoclinic crystal system, space group P21 / c, unit cell parameters: α = 90°, β = 100.8040(10)°, γ = 90°, unit cell volume

[0013] On the other hand, the present invention provides a method for preparing bripiprazole-p-toluenesulfonic acid-crystal form, comprising the following steps:

[0014] Buripiperazole and p-toluenesulfonic 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 buripiperazole-p-toluenesulfonic acid-crystal form.

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

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

[0017] Preferably, in the mixed solvent, the volume ratio of ethanol to other organic solvents is 1:1 to 3, more preferably 1:1.5 to 2.5.

[0018] Preferably, the mass-to-volume ratio of burepiperazole to solvent is 1.1:1 to 3, more preferably 1.1:1.5 to 2.5; wherein the mass is expressed in mg and the volume in ml.

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

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

[0021] The cooling crystallization temperature is 0–30°C, and preferably, the cooling crystallization temperature is 8–15°C.

[0022] The crystallization time is 8 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 comprising the burepiperazole-p-toluenesulfonic acid-crystal form described herein 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-p-toluenesulfonic acid-crystal type test described in this invention were collected on a Rigaku XtaLAB Synergy 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 birepiperazole-p-toluenesulfonic acid-crystal form prepared in this invention were tested and analyzed. The crystal system is monoclinic, space group P21 / c, and the cell parameters are: α = 90°, β = 100.8040(10)°, γ = 90°, unit cell volume

[0030] Table 1. Major crystallographic data of buripiperazole-p-toluenesulfonic acid-crystal form

[0031]

[0032]

[0033] The ORTEP diagram of the bripiprazole-p-toluenesulfonic acid-crystal form of this invention shows that this crystalline form contains four molecules of bripiprazole, four molecules of p-toluenesulfonic acid, and eight molecules of water. The hydrogen atom attached to the sulfonyl group of the p-toluenesulfonic acid undergoes proton transfer and connects to the nitrogen atom on the adjacent bripiprazole to form a salt, as shown in the attached diagram. Figure 2 As shown. The hydrogen bond diagram of bripiprazole-p-toluenesulfonic acid-water 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 buripiperazole-p-toluenesulfonic acid-crystal type

[0035]

[0036]

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

[0038] This invention discloses for the first time a novel birepiperazole-p-toluenesulfonic acid-water salt form. The preparation method of this novel salt form is simple, the crystallization process is highly controllable and reproducible; more importantly, it achieves a synergistic effect of solubility and stability, effectively breaking through the performance bottleneck of existing binary salt systems, and can significantly improve oral bioavailability, demonstrating extremely high drug development potential and application value in the field of drug research and development. Attached Figure Description

[0039] Figure 1 The PXRD pattern of birepiperazole-p-toluenesulfonic acid-crystal form is shown.

[0040] Figure 2 ORTEP diagram of buripiperazole-p-toluenesulfonic acid-crystal form.

[0041] Figure 3 This is a hydrogen bond diagram of the buripiperazole-p-toluenesulfonic acid-crystal form.

[0042] Figure 4 The image shows the PXRD pattern of birepiperazole-p-toluenesulfonate. 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] 433.7 mg of biriperazole and 172.3 mg of p-toluenesulfonic acid were dissolved in a mixed solvent of 236 mL of ethanol and 355 mL of acetonitrile. The solution was heated and stirred at 40 °C until completely dissolved. The solution was filtered, allowed to stand at 15 °C to evaporate and crystallize, filtered again, and dried at 50 °C for 10 h to obtain biriperazole-p-toluenesulfonic acid-water. Yield: 97.5%, purity: 99.95%.

[0046] Example 2

[0047] 385 mg of biriperazole and 153 mg of p-toluenesulfonic acid were dissolved in a mixed solvent of 250 mL of ethanol and 625 mL of acetonitrile. The mixture was heated and stirred at 45 °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 65 °C for 8 h to obtain biriperazole-p-toluenesulfonic acid-water. Yield: 97.6%, Purity: 99.94%.

[0048] Example 3

[0049] 439.1 mg of biriperazole and 156.9 mg of p-toluenesulfonic acid were dissolved in a mixed solvent of 200 mL of ethanol and 200 mL of acetone. The solution was heated and stirred at 30 °C until completely dissolved. The solution was filtered, allowed to stand at 0 °C to evaporate and crystallize, filtered again, and dried at 65 °C for 8 h to obtain biriperazole-p-toluenesulfonic acid-water. Yield: 96.6%, purity: 99.90%.

[0050] Example 4

[0051] 435.6 mg of biriperazole and 190.3 mg of p-toluenesulfonic acid were dissolved in a mixed solvent of 297 mL of ethanol and 891 mL of isopropanol. The mixture was heated and stirred at 50 °C until completely dissolved. After filtration, the mixture was allowed to stand at 30 °C to evaporate and crystallize. After filtration, the mixture was dried at 50 °C for 10 h to obtain biriperazole-p-toluenesulfonic acid-water. Yield: 96.1%, Purity: 99.91%.

[0052] Comparative Example 1

[0053] Referring to patent CN200680011923.0, p-toluenesulfonic acid monohydrate was added to a methanol and dichloromethane solution containing bripiprazole, and the solvent was evaporated under reduced pressure. The residue was recrystallized in ethanol to obtain bripiprazole p-toluenesulfonate in the form of a white powder, with a yield of 85.2% 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] I. Stability Experiment

[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 bripiprazole-p-toluenesulfonic acid-crystal form under light, high temperature and high humidity conditions.

[0062]

[0063]

[0064] Experiments showed that the purity of the bripiprazole-p-toluenesulfonic acid-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.

[0065] II. Solubility Test

[0066] 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. Sampling was repeated three times, the solutions were 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.

[0067] Table 4. Solubility of crystal forms in different media (μg / ml)

[0068]

[0069] Solubility tests showed that the solubility of the birepiperazole-p-toluenesulfonic acid-crystal form in water, 0.01 mol / L hydrochloric acid, and pH 6.8 PBS buffer was significantly improved. Similar solubility test results were observed in Examples 1-3.

Claims

1. A crystalline form of brexpiprazole-p-toluenesulfonic acid hydrate, characterized by, The X-ray diffraction spectrum of the crystal form has characteristic peaks at at least 3.2±0.2°, 6.3±0.2°, 9.4±0.2°, 18.6±0.2°, 28.0±0.2°, using Cu-Kα radiation.

2. Brexpiprazole-p-toluenesulfonic acid-water crystalline form according to claim 1, characterized by, The X-ray diffraction spectrum of the crystal form has characteristic peaks at at least 3.2±0.2°, 6.3±0.2°, 9.4±0.2°, 12.4±0.2°, 15.5±0.2°, 16.7±0.2°, 18.4±0.2°, 18.6±0.2°, 21.8±0.2°, 24.9±0.2°, 25.7±0.2°, 28.0±0.2°, 31.2±0.2°, 34.4±0.2°, 40.9±0.2°, using Cu-Kα radiation.

3. Brexpiprazole-p-toluenesulfonic acid-water crystalline form according to claim 1, characterized by, The crystallographic parameters of said crystalline form are: monoclinic crystal system, space group P21 / c, with unit cell parameters: α = 90°, β = 100.8040(10)°, γ = 90°, with unit cell volume 4. Brexpiprazole-p-toluenesulfonic acid-water crystalline form according to claim 1, characterized by, The crystal form has characteristic peaks in accordance with the X-ray powder diffraction pattern shown in Figure 1, using Cu-Kα radiation.

5. A process for the preparation of brexpiprazole-p-toluenesulfonic acid-water crystalline form according to any one of claims 1 to 4, characterized by, The method comprises the following steps: dissolving brexpiprazole and p-toluenesulfonic acid in a mixed solvent, heating and stirring, filtering, standing and evaporating to crystallize at a reduced temperature, filtering and drying to obtain the brexpiprazole-p-toluenesulfonic acid-water crystal form.

6. The method for preparing bripiprazole-p-toluenesulfonic acid-crystal form according to claim 5, characterized in that, The mixed solvent is a mixed solvent of ethanol and another organic solvent, and the other organic solvent is selected from one of acetonitrile, acetone and isopropyl alcohol; in the mixed solvent, the volume ratio of ethanol to the other organic solvent is 1:1-3.

7. The method for preparing bripiprazole-p-toluenesulfonic acid-crystal form according to claim 5, characterized in that, The mass-volume ratio of brexpiprazole to the mixed solvent is 1.1:1-3; wherein the mass is in mg and the volume is in ml.

8. The method for preparing bripiprazole-p-toluenesulfonic acid-crystal form according to claim 5, characterized in that, The molar ratio of brexpiprazole to p-toluenesulfonic acid is 1:0.9-1.

1.

9. The method for preparing bripiprazole-p-toluenesulfonic acid-crystal form according to claim 5, characterized in that, The heating temperature is 30-50°C; and the temperature for crystallization at a reduced temperature is 0-30°C.

10. A pharmaceutical composition, characterized by, The composition comprises the brexpiprazole-p-toluenesulfonic acid-water crystal form according to any one of claims 1-4 and other pharmaceutically acceptable components.

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