Novel crystal form of piveronium bromide and preparation method thereof

Abstract

The invention relates to a novel crystal form A of piveronium bromide and a preparation method thereof. An X-ray powder diffraction pattern of the compound has characteristic peaks at diffraction angles of 5.5 degrees, 11.5 degrees, 14.2 degrees, 15.2 degrees, 16.2 degrees, 18.2 degrees, 20.1 degrees, 22.8 degrees, 24.9 degrees, 26.7 degrees and 28.4 degrees (2 theta + / -0.2 degrees); the preparation method of the crystal form A is simple, convenient, good in reproducibility and suitable for industrial large-scale production; and the crystal form A has good stability and low hygroscopicity, is beneficial to long-term storage, can be better applied to preparation of pharmaceutical preparations, and has very high medicinal value.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical chemistry and chemical technology, in particular to a novel crystalline form of pinaverium bromide and a method for preparing the same. BACKGROUND

[0002] Pinaverium bromide is developed by the French pharmaceutical company, Sanofi, and is a calcium antagonist with high selectivity in spasmolytic action on the gastrointestinal tract. Pinaverium bromide tablets improve smooth muscle function by regulating calcium ion channels and can be used to relieve symptoms of discomfort caused by gastrointestinal dysfunction, irritable bowel syndrome, functional dyspepsia, etc. Its chemical name is 4-[(2-bromo-4,5-dimethoxyphenyl) methyl]-4-[2-[2(6,6-dimethylbicyclo[3,1,1]hept-2-yl) ethoxy] ethyl] morpholine bromide, and the specific structural formula is as follows: . SUMMARY

[0003] Pinaverium bromide is a quaternary ammonium salt compound, which is not easily absorbed orally, thus limiting its absorption through the intestinal mucosa. After oral administration, less than 10% of the dose enters the blood, of which 95%-98% is bound to proteins.

[0004] Generally, when a drug exists in various forms including amorphous form, one or more crystalline forms, etc., factors such as solubility, dissolution characteristics, and bioavailability can vary depending on the form.

[0005] In addition, when selecting from various crystalline forms or between crystalline forms and amorphous forms, the amorphous form has the advantages of increasing drug efficacy and showing rapid efficacy due to its generally high solubility. However, the amorphous form has the disadvantages of short shelf life and difficulty in adjusting the release rate and blood concentration of the drug due to its instability. In contrast, the crystalline form, although having lower solubility and corresponding lower bioavailability, has the advantages of high stability and facilitating the preparation of a long-acting release formulation. Therefore, the crystalline form has higher stability and lower solubility than the amorphous form, and it is often difficult to choose between the stability and solubility of a drug. When stability is given the highest priority, it is necessary to sacrifice solubility, and when solubility is considered first, stability can be sacrificed. The pinaverium bromide crystal form A of the present application has high stability and good solubility, further improving the pharmaceutical value of the drug.

[0006] The present application provides a stable solid form of pinaverium bromide, the inventors accidentally found that the crystalline form shows good stability, and does not change the physicochemical properties under the conditions of long-term high temperature, high humidity and light, has low hygroscopicity, is beneficial to be formulated and long-term storage, and overcomes the defect that amorphous drugs are unstable due to the influence of external factors; meanwhile, the present application also provides a method for preparing pinaverium bromide form A, which is simple in steps, easy to operate and suitable for industrial large-scale production.

[0007] The present application provides a pinaverium bromide form A which is easy to prepare and has excellent stability, has Figure 1 X-ray powder diffraction pattern as shown in the present application. Its characteristics are that the characteristic peaks are at diffraction angles of 5.5°, 11.5°, 14.2°, 15.2°, 16.2°, 18.2°, 20.1°, 22.8°, 24.9°, 26.7°, 28.4° (2θ±0.2°) in the X-ray powder diffraction pattern. The X-ray powder diffraction instrument is a Japanese Shimadzu XRD6000 polycrystalline X-ray diffractometer, and the detection conditions are as follows: CuKα radiation, tube flow 30 mA, tube pressure 40 kv, scanning range 5-50 degrees, scanning speed 4 degrees, step length 0.02 degrees.

[0008] The pinaverium bromide form A provided by the present application has Figure 2 an infrared spectrum (IR) as shown in the present application. Its characteristics are that the characteristic absorption peaks are at 1120 cm -1 , 1172 cm -1 , 1217 cm -1 , 1242 cm -1 , 1265 cm -1 , 1458 cm -1 , 1516 cm -1 , 2873 cm -1 and 2941 cm -1 .

[0009] The pinaverium bromide form A provided by the present application has Figure 3 a thermogram formed by DSC (differential scanning calorimetry) as shown in the present application. Its characteristics are that when measured by differential scanning calorimetry, the form A has an absorption peak at 168℃-172℃.

[0010] On the other hand, the present application provides a method for preparing pinaverium bromide form A, which comprises: suspending pinaverium bromide compound in any form in ethyl acetate, acetonitrile, tetrahydrofuran or methyl tert-butyl ether; heating and stirring for 1 hour to 24 hours; and cooling to room temperature, and stirring for 1 hour to 48 hours to mature the crystal.

[0011] The step of heating and stirring can be performed by raising the temperature to 50 to 80°C.

[0012] The present application provides another method for preparing the crystalline form A of pinaverium bromide: dissolving a pinaverium bromide compound in any form in a good solvent; adding an anti-solvent to the resulting solution to crystallize the compound; and stirring for 6 to 24 hours at room temperature to mature the crystals.

[0013] The good solvent can be methanol or dichloromethane, and the anti-solvent is preferably methyl tert-butyl ether, but is not limited thereto. The use amount of methanol or dichloromethane and methyl tert-butyl ether was investigated, and the optimal ratio in the preparation process was obtained. When the volume ratio of methanol or dichloromethane to methyl tert-butyl ether is 1:10, the obtained pinaverium bromide crystalline form is optimal.

[0014] The term "anti-solvent" used herein refers to a solvent that exhibits low solubility or insolubility to the target compound, and the target compound can be precipitated by adding the anti-solvent to a solution in which the target compound is dissolved. Therefore, in the method for preparing the crystalline form A of the present application, the crystallization of the compound can be achieved by adding an appropriate anti-solvent to a solution in which the compound has been dissolved, taking into account the type of solvent and the solubility of the compound in the solvent, etc. The resulting crystals can have the X-ray powder diffraction pattern, DSC endothermic peak, and IR characteristic absorption peak described above.

[0015] In addition, the present application also removes impurities, residual solvents, etc. by filtration or drying, thereby improving the purity of the product.

[0016] The crystalline form A provided by the present application has excellent stability and good solubility in stability tests and solubility tests.

[0017] Beneficial effects: The pinaverium bromide crystalline form A provided by the present application has basically unchanged appearance, optical purity, and related substance items under long-term high temperature, high humidity, and light conditions, has low hygroscopicity, has excellent stability, is conducive to being formulated, and is conducive to long-term storage of the compound. In terms of solubility, the crystalline form A is comparable to the amorphous non-crystalline compound; on the basis of excellent stability, the crystalline form A also has good solubility, which is conducive to improving the bioavailability of the drug. BRIEF DESCRIPTION OF DRAWINGS

[0018] Figure 1 An X-ray diffraction pattern of the pinaverium bromide crystalline form A according to an exemplary embodiment of the present application is shown.

[0019] Figure 2 An IR spectrum of the pinaverium bromide crystalline form A according to an exemplary embodiment of the present application is shown.

[0020] Figure 3A thermogram of crystalline form A of pinaverium bromide according to an exemplary embodiment of the present application is shown, which was formed by DSC (Differential Scanning Calorimetry).

[0021] The present application is further illustrated by the following examples and experimental examples, and various alternatives and modifications will be apparent to those skilled in the art in view of the foregoing description and accompanying examples. Such alternatives, modifications and variations are intended to fall within the scope of the present application. DETAILED DESCRIPTION

[0022] Example 1: Preparation of crystalline form A using ethyl acetate Pinaverium bromide 10.0 g was weighed into a 250 mL round bottom flask, 100 mL of ethyl acetate was added, and the suspension was heated to reflux. The suspension was stirred at reflux temperature for 3 hours, and then slowly cooled to room temperature. The crystals were matured by stirring the suspension for 1 hour, and the resulting solid was filtered. The harvested solid was dried at 50 °C under normal pressure for 24 h to obtain 9.12 g of the target compound, i.e., crystalline form A of pinaverium bromide (yield: 91.2 %).

[0023] Example 2: Preparation of crystalline form A using acetonitrile Pinaverium bromide 10.0 g was weighed into a 250 mL round bottom flask, 100 mL of acetonitrile was added, and the solid was dissolved, and a white solid was precipitated. The suspension was stirred at reflux temperature for 3 hours, and then slowly cooled to room temperature. The crystals were matured by stirring the suspension for 1 hour, and the resulting solid was filtered. The harvested solid was dried at 50 °C under normal pressure for 24 h to obtain 5.86 g of the target compound, i.e., crystalline form A of pinaverium bromide (yield: 58.5 %).

[0024] Example 3: Preparation of crystalline form A using tetrahydrofuran Pinaverium bromide 10.0 g was weighed into a 250 mL round bottom flask, 100 mL of tetrahydrofuran was added, and the suspension was heated to reflux. The suspension was stirred at reflux temperature for 3 hours, and then slowly cooled to room temperature. The crystals were matured by stirring the suspension for 1 hour, and the resulting solid was filtered. The harvested solid was dried at 50 °C under normal pressure for 24 h to obtain 9.13 g of the target compound, i.e., crystalline form A of pinaverium bromide (yield: 91.3 %).

[0025] Example 4: Preparation of crystalline form A using methyl tert-butyl ether Pinaverium bromide 10.0 g was weighed into a 250 mL round bottom flask, 100 mL of methyl tert-butyl ether was added, and the suspension was heated to reflux. The suspension was stirred at reflux temperature for 3 hours, and then slowly cooled to room temperature. The crystals were matured by stirring the suspension for 1 hour, and the resulting solid was filtered. The harvested solid was dried at 50 °C under normal pressure for 24 h to obtain 9.65 g of the target compound, i.e., crystalline form A of pinaverium bromide (yield: 96.5 %).

[0026] Example 5: Preparation of crystal form A using methanol and methyl tert-butyl ether 10.0 g of pinaverium bromide was weighed into a 250 mL round-bottom flask, and 10 mL of methanol was added. The mixture was heated to dissolve the solid. 100 mL of methyl tert-butyl ether was added dropwise to the solution, and the mixture was stirred at 80 °C for 3 hours, resulting in the precipitation of a white solid. The solution was then slowly cooled to room temperature. The crystals were allowed to mature by stirring the suspension for 1 hour, and the resulting solid was filtered. The harvested solid was dried at 50 °C under normal pressure for 24 hours to obtain 9.45 g of the target compound, i.e., pinaverium bromide in crystal form A (yield: 94.5%).

[0027] Example 6: Preparation of crystal form A using dichloromethane and methyl tert-butyl ether 10.0 g of pinaverium bromide was weighed into a 250 mL round-bottom flask, and 10 mL of dichloromethane was added. The mixture was heated to dissolve the solid. 100 mL of methyl tert-butyl ether was added dropwise to the solution, and the mixture was stirred at 60 °C for 3 hours, resulting in the precipitation of a white solid. The solution was then slowly cooled to room temperature. The crystals were allowed to mature by stirring the suspension for 1 hour, and the resulting solid was filtered. The harvested solid was dried at 50 °C under normal pressure for 24 hours to obtain 9.7 g of the target compound, i.e., pinaverium bromide in crystal form A (yield: 97%).

[0028] Experimental Example 1: X-ray diffraction pattern analysis of crystal form A X-ray diffraction patterns of pinaverium bromide crystal form A prepared in Examples 1 to 6 were analyzed using a Shimadzu XRD6000 polymorph X-ray diffractometer (Japan). The results are as follows: Figure 1 As shown. Characteristic peaks were determined in its X-ray diffraction pattern at at least 5.5°, 11.5°, 14.2°, 15.2°, 16.2°, 18.2°, 20.1°, 22.8°, 24.9°, 26.7°, and 28.4° (2θ ± 0.2°). Figure 1 ).

[0029] Experimental Example 2: IR spectrum analysis of crystal form A The pinaverium bromide crystal form A prepared in Examples 1 to 6 was subjected to IR spectral analysis. Fourier transform infrared spectroscopy (Bruker) was used for spectral measurements and analysis, and the results are as follows: Figure 2 As shown. From Figure 2 As can be seen from the data, the crystal form A of the pinaverium bromide compound prepared in Examples 1 to 6 of the present invention is confirmed to be at 1120 cm⁻¹ in the IR spectrum. -1 1172 cm -1 1217 cm -1 1242 cm -1 1265 cm -1 1458 cm -1 1516 cm -1, 2873 cm -1 and 2941 cm -1 with characteristic absorption peaks.

[0030] Experimental Example 3: Differential Scanning Calorimetry of Form A Differential scanning calorimetry (DSC) was performed on the crystalline form A of the pinaverium bromide compound prepared in Examples 1 to 6. The results of analyzing the DSC thermogram are shown in Table 4. Figure 3 From the results, it can be confirmed that the crystalline form A of the pinaverium bromide compound prepared in Examples 1 to 6 of the present application has an endothermic peak at a temperature of 168 to 172°C.

[0031] From the above Experimental Examples 1 to 3, it can be confirmed that the crystalline form A of the pinaverium bromide compound prepared in Examples 1 to 6 has the same characteristics. Therefore, in the following examples, the pinaverium bromide crystalline form A prepared in Example 1 was used representatively to perform further experiments.

[0032] Experimental Example 4: In order to examine the stability of the pinaverium bromide crystalline form A prepared in Example 1 under high temperature, high humidity, and light conditions, the compound was exposed to given test conditions, and changes in appearance, optical isomer, and related substance content were measured. In addition, changes in color were observed with the naked eye, and the results are shown in Tables 1 to 3 below.

[0033] Table 1 Changes in appearance and impurity content of Form A under high temperature (60±2°C) Period Initial stage After 4 weeks Appearance White powder White powder Optical isomer content 3.46% 3.47% Maximum single impurity content 0.06% 0.05% Total impurity content 0.24% 0.23% .

[0034] Table 2 Changes in appearance and impurity content of Form A under light (4500 Lx±500 Lx) Period Initial stage After 4 weeks Appearance White powder White powder Optical isomer content 3.46% 3.50% Maximum single impurity content 0.06% 0.05% Total impurity content 0.24% 0.25% .

[0035] Table 3 Changes in appearance and impurity content of Form A under high humidity (25°C, RH 90%±5%) Period Initial stage After 4 weeks Appearance White powder White powder Optical isomer content 3.46% 3.51% Maximum single impurity content 0.06% 0.05% Total impurity content 0.24% 0.23% .

[0036] As shown in Tables 1 to 3, no significant changes were observed in appearance, optical purity, and related substances (non-optical purity) after the crystalline form A was exposed to high temperature, high humidity, and light conditions for 4 weeks, indicating that the pinaverium bromide crystalline form A has excellent stability.

[0037] Experimental Example 5: Hygroscopicity test of Form A Compounds with low hygroscopicity are advantageous in the preparation of formulations and also for storage. Furthermore, compounds with high hygroscopicity are difficult to formulate, and even if formulation is achieved successfully, reproducible results are difficult to obtain. The experiments were carried out in accordance with the corresponding guidelines of the Chinese Pharmacopoeia, and the results are shown in the following table: Sample Sample weight (g) Sample weight (g) after examination Hygroscopicity Sample 1 0.93799 0.93842 0.05% Sample 2 0.89153 0.89154 0 .

[0038] The results show that the crystalline form A of pinaverium bromide of the present application has low hygroscopicity, and is advantageous for long-term storage and for the preparation of pharmaceutical formulations.

[0039] Experimental Example 6: Solubility test of crystalline form A The sample of crystalline form A of pinaverium bromide obtained in Example 1 and the amorphous form were each taken in an amount of 5 mg and placed in a test tube. At room temperature, 1 ml of purified water was added each time and shaken for 3 minutes each time until the solution was clear and completely dissolved. The solubility was calculated, and the results are as follows: Sample Solubility mg / mL Sample 1 of Form A 2.10 Sample 2 of Form A 2.12 Amorphous 2.05 The results show that the crystalline form A of pinaverium bromide of the present application has solubility not inferior to the amorphous form.

Claims

1. A crystal form A of a compound represented by the following chemical formula, pinaverium bromide, has the following crystal form in its X-ray powder diffraction pattern: at diffraction angles of 5.5°, 11.5°, 14.2°, 15.2°, 16.2°, 18.2°, 20.1°, 22.8°, 24.9°, 26.7°, and 28.4° (2... θ It has a characteristic peak at ±0.2°, and its chemical formula is as follows: 。 2. The pinaverium bromide crystal form A according to claim 1, characterized in that, In the infrared spectrum, at 1120 cm⁻¹ -1 1172 cm -1 1217 cm -1 1242 cm -1 1265 cm -1 1458 cm -1 1516 cm -1 2873 cm -1 and 2941cm -1 It has a characteristic absorption peak.

3. The pinaverium bromide crystal form A according to claim 1, characterized in that, When measured using differential scanning calorimetry, crystal form A exhibits an endothermic peak at 168℃-172℃.

4. The preparation method of the pinaverium bromide crystal form A according to claim 1 comprises: suspending any form of pinaverium bromide compound in a solvent, wherein the solvent is selected from acetonitrile, C1-4 alkyl acetate, tetrahydrofuran, di(C1-4 alkyl) ether, (C1-4 alkyl)(C1-4 alkyl) ether, and C1-4 alkyl ether; heating and stirring for 1 hour to 24 hours; and cooling the reaction system to room temperature, and then stirring for 1 hour to 48 hours to mature the crystals; and separating to obtain crystal form A.

5. The method according to claim 4, wherein the solvent is acetonitrile, methyl acetate, ethyl acetate, tetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether, or a mixture thereof.

6. The method according to claim 4, wherein, The heating process involves raising the temperature to 50-120°C.

7. The method for preparing pinaverium bromide crystal form A according to claim 1 comprises: dissolving pinaverium bromide compound in any form in a good solvent selected from C1-4 alcohols, C1-4 dichloroalkanes, chloroform, and mixtures thereof; adding an antisolvent to the resulting solution to crystallize the compound; and stirring at room temperature for 1 hour to 24 hours to mature the crystals; and separating to obtain crystal form A.

8. The method according to claim 7, wherein, The good solvent is methanol, ethanol, isopropanol, n-propanol, dichloromethane, chloroform, or a mixture thereof.

9. The method according to claim 7, wherein, The antisolvent is ethyl acetate, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, or a mixture thereof.

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