Preparation and application of drug-drug cocrystal of dibazol hydrochloride and atenolol and pharmaceutical composition

Abstract

The application belongs to the technical field of pharmaceutical cocrystal and relates to preparation and application of a pharmaceutical-pharmaceutical cocrystal of dibazol hydrochloride and atenolol and a pharmaceutical composition. The preparation method comprises a cooling crystallization method, a suspension stirring method and a mechanical ball milling method. Compared with the prior art, the prepared dibazol hydrochloride-atenolol cocrystal has the advantages of simple preparation method, easy control, good reproducibility, stable cocrystal of dibazol hydrochloride and atenolol, high purity of crystal type (more than 99.9%), fast dissolution speed of cocrystal and potential for drug combination.

Description

Technical Field

[0001] This invention belongs to the field of drug cocrystal technology, and relates to a novel drug-drug cocrystal form of dibazol hydrochloride (2-benzylbenzimidazole hydrochloride) and atenolol, its preparation method and application, as well as a drug composition. Background Technology

[0002] Essential hypertension is one of the most common diseases worldwide and a major cause of serious cardiovascular and cerebrovascular diseases, as well as kidney diseases. Treating hypertension can significantly reduce premature cardiovascular disease and the persistently high mortality rate. The pathogenesis of hypertension is complex, resulting from the interaction of genetic and environmental factors, and approximately 50% of hypertensive patients present with refractory hypertension, posing a significant challenge to effective treatment. Existing medications for treating hypertension mainly include diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers, beta-blockers, and alpha-blockers. To enhance the therapeutic effect, the combination of antihypertensive drugs is a common clinical strategy; two drugs can be prescribed alone or as a fixed-dose combination. Two antihypertensive drugs with different mechanisms of action often have synergistic or at least additive effects, and reducing the dosage of each drug can reduce its adverse effects.

[0003] Drug-drug cocrystals refer to crystalline compositions formed by linking two drug molecules in a specific stoichiometric ratio through non-covalent bonds such as hydrogen bonds. Studies have shown that drug-drug cocrystals, when used in combination with other drugs, have potential advantages such as improved drug molecule stability or solubility, and therefore hold greater promise than compound preparations.

[0004]

[0005] Bendazol, chemically known as 2-benzylbenzimidazole (C... 14 H 12 Dibazol (N2) is soluble in ethanol, hot benzene, and glacial acetic acid, but has very poor solubility in water. Currently, the commercially available dibazol product is dibazol hydrochloride (C2). 14 H 12 Dibazol (N2·HCl) is a vasodilator antihypertensive drug that directly relaxes vascular smooth muscle to lower blood pressure. Dibazol has low solubility and high permeability, classifying it as a Class II compound in the biopharmaceutics classification system. Although its hydrochloride form—dibazol hydrochloride—is used to improve solubility, its solubility is still relatively poor. Atenolol is a β-receptor blocker widely used in the treatment of cardiovascular diseases, suitable for mild to moderate hypertension; its molecular formula is C2H2SO4. 14 H 22 N2O3. Atenolol has low solubility and poor permeability. Summary of the Invention

[0006] The purpose of this invention is to provide a drug-drug cocrystal of dibazol hydrochloride and atenolol, its preparation and application, and a pharmaceutical composition thereof. This invention utilizes cocrystalization technology to co-crystallize dibazol hydrochloride and atenolol, preparing a dibazol hydrochloride-atenolol cocrystal. Dibazol hydrochloride and atenolol have different mechanisms of action in treating hypertension, and the dibazol hydrochloride-atenolol cocrystal can improve the in-situ dissolution rate of dibazol hydrochloride and exhibits good stability, showing considerable application potential in combination drug therapy for hypertension.

[0007] The objective of this invention can be achieved through the following technical solutions:

[0008] In existing crystallization techniques, there are many types of solvents that can be used for crystallization, and there are countless mixed solvents of different types and proportions. However, it is impossible to predict the crystal form that will be crystallized before the crystallization experiment, especially for the formation of drug cocrystals. Through long-term experimental research on dibazol hydrochloride, this invention has finally discovered the solvent for preparing cocrystals and its preparation method.

[0009] A first aspect of the present invention provides a drug-drug co-crystal form of dibazol hydrochloride and atenolol, comprising dibazol hydrochloride and atenolol in a molar ratio of 2:1;

[0010] The drug-drug cocrystal of dibazol hydrochloride and atenolol, as measured by Cu Kα radiation, exhibits characteristic peaks at diffraction angles 2θ of 7.1°, 10.8°, 11.3°, 11.8°, 14.3°, 14.8°, 17.2°, 18.5°, 19.0°, 19.8°, 20.4°, 21.1°, 21.8°, 22.2°, 23.6°, 24.1°, 26.2°, 27.4°, 28.0°, and 29.0°.

[0011] Furthermore, the differential scanning calorimetry curve of this eutectic crystal form has an endothermic peak at 137±5℃.

[0012] A second aspect of the present invention provides a method for preparing a drug-drug cocrystal of dibazol hydrochloride and atenolol, comprising: mixing dibazol hydrochloride and atenolol in an organic solvent at 30-80°C, cooling to 5-35°C and stirring continuously, filtering, and drying at 30-80°C.

[0013] Furthermore, the ratio of the total mass of dibazol hydrochloride and atenolol to the volume of the organic solvent is 1 g: (3-25) mL; the organic solvent is one of water, alcohol, ethyl acetate, chloroform, acetonitrile, or acetone.

[0014] Furthermore, after cooling, the stirring time is continued for 1 to 10 hours.

[0015] A third aspect of the present invention provides a method for preparing a drug-drug cocrystal of dibazol hydrochloride and atenolol, comprising: mixing dibazol hydrochloride and atenolol in an organic solvent, continuously stirring at 15-60°C, filtering, and drying at 30-80°C.

[0016] Furthermore, the ratio of the total mass of dibazol hydrochloride and atenolol to the volume of the organic solvent is 1 g: (3-25) mL; the organic solvent is one of water, alcohol, ethyl acetate, chloroform, acetonitrile, or acetone.

[0017] A fourth aspect of the present invention provides a method for preparing a drug-drug cocrystal of dibazol hydrochloride and atenolol, comprising: mixing dibazol hydrochloride and atenolol in an organic solvent and mechanically ball milling.

[0018] Further, the ratio of the total mass of the dibazol-type drug and mandelic acid to the volume of the organic solvent is 1 g:(20-200) μL; the organic solvent is one of water, alcohol, ethyl acetate, acetonitrile or acetone; the mechanical ball milling conditions include a frequency of 1-10 times / second and a milling time of 10-100 min.

[0019] A fifth aspect of the invention provides a pharmaceutical composition comprising a drug-drug cocrystal of dibazol hydrochloride and atenolol, and a pharmaceutically acceptable excipient.

[0020] A sixth aspect of the present invention provides an application of a drug-drug cocrystal of dibazol hydrochloride and atenolol, comprising using the dibazol hydrochloride and atenolol drug-drug cocrystal to prepare a drug for the prevention or treatment of hypertension.

[0021] Compared with the prior art, the present invention has the following characteristics:

[0022] 1) The method for preparing the dibazol hydrochloride-atenolol eutectic obtained by the present invention is simple, easy to control, and has good reproducibility. It can obtain a stable dibazol hydrochloride-atenolol eutectic with high crystal purity, reaching over 99.9%, and good stability.

[0023] 2) Fast dissolution rate: The dissolution rate of dibazol hydrochloride-atenolol cocrystal is 3 times that of dibazol hydrochloride at 10 minutes, and reaches its maximum dissolution rate at 30 minutes, which is 5 times that of dibazol hydrochloride. Compared with dibazol hydrochloride salt, the dissolution rate is faster, which can help develop improved dibazol hydrochloride formulations with higher bioavailability and better efficacy.

[0024] 3) Potential for drug combination therapy: Dibazol hydrochloride and atenolol have synergistic antihypertensive effects, which could lead to the development of drug formulations with better efficacy for the treatment of hypertension. Attached Figure Description

[0025] Figure 1 The X-ray powder diffraction pattern of the dibazol-atenolol hydrochloride eutectic obtained in Example 1 is shown below.

[0026] Figure 2 The DSC image shows the crystal form of the dibazol-atenolol hydrochloride eutectic obtained in Example 1;

[0027] Figure 3 XRPD plot of the stability test of the dibazol-atenolol hydrochloride eutectic crystal form prepared in Example 1;

[0028] Figure 4 The dissolution curves of dibazolium hydrochloride and dibazolium hydrochloride-atenolol eutectic in Example 6 are shown. Detailed Implementation

[0029] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments.

[0030] A method for preparing a drug-drug cocrystal of dibazol hydrochloride and atenolol based on cooling crystallization includes the following steps:

[0031] 1) Dibazol hydrochloride and atenolol were mixed in an organic solvent at a molar ratio of 2:1 at 30–80°C to obtain a clear solution;

[0032] The ratio of the total mass of dibazol hydrochloride and atenolol to the volume of organic solvent is 1 g: (3-25) mL.

[0033] The organic solvent is one of water, an alcohol, ethyl acetate, chloroform, acetonitrile, or acetone. Preferably, the alcohol is ethanol or methanol. More preferably, the organic solvent is acetonitrile.

[0034] 2) Cool the clarified solution to 5–35°C, continue stirring, and maintain for 1–10 hours;

[0035] 3) Filtration, and drying of the filter cake at 30-80℃.

[0036] A method for preparing a drug-drug cocrystal of dibazol hydrochloride and atenolol based on suspension stirring includes the following steps:

[0037] 1) Mix dibazol hydrochloride and atenolol in an organic solvent at a molar ratio of 2:1;

[0038] The ratio of the total mass of dibazol hydrochloride and atenolol to the volume of organic solvent is 1 g: (3-25) mL.

[0039] The organic solvent is one of water, an alcohol, ethyl acetate, chloroform, acetonitrile, or acetone. Preferably, the alcohol is ethanol or methanol. More preferably, the organic solvent is acetonitrile.

[0040] 2) Stir continuously at 15–60℃ for 2–48 hours;

[0041] 3) Filtration, and drying of the filter cake at 30-80℃.

[0042] A method for preparing dibazol hydrochloride and atenolol drug-drug cocrystal based on mechanical ball milling includes: mixing dibazol hydrochloride and atenolol, adding an organic solvent, and performing liquid-phase assisted mechanical ball milling in a vibratory ball mill for a period of time to obtain dibazol hydrochloride-atenolol drug-drug cocrystal.

[0043] The ratio of the total mass of dibazolium-based drugs and mandelic acid to the volume of organic solvent is 1 g:(20-200) μL; the organic solvent is one of water, alcohol, ethyl acetate, acetonitrile, or acetone; preferably, the alcohol is ethanol or methanol. More preferably, the organic solvent is acetonitrile; the mechanical ball milling conditions include a frequency of 1-10 times / second and a milling time of 10-100 min.

[0044] A pharmaceutical composition comprising a drug-drug cocrystal of dibazol hydrochloride and atenolol, and a pharmaceutically acceptable excipient.

[0045] An application of a drug-drug cocrystal of dibazol hydrochloride and atenolol includes using the dibazol hydrochloride and atenolol drug-drug cocrystal to prepare a drug for the prevention or treatment of hypertension.

[0046] The following embodiments are implemented based on the above-described technical solution of the present invention, and provide detailed implementation methods and specific operation processes. However, the scope of protection of the present invention is not limited to the following embodiments.

[0047] Example 1: Preparation of dibazol hydrochloride-atenolol eutectic crystal form

[0048] 26.6 g atenolol and 48.9 g dibazol hydrochloride were dispersed in 350 mL of methanol to form a supersaturated solution. After stirring at room temperature for 48 hours, the mixture was filtered, the crystals were collected, and dried at 50 °C to obtain a solid, which is the dibazol hydrochloride-atenolol eutectic. Figure 1 The X-ray powder diffraction pattern features shown, and Figure 2 The DSC spectral characteristics of the dibazol-atenolol hydrochloride eutectic crystal form are shown.

[0049] Among them, such as Figure 1 The X-ray powder diffraction pattern of the dibazol-atenolol hydrochloride eutectic crystal form shown is obtained using Cu Kα rays. The X-ray powder diffraction pattern exhibits characteristic peaks at diffraction angles 2θ (°, ±0.2): 7.1°, 10.8°, 11.3°, 11.8°, 14.3°, 14.8°, 17.2°, 18.5°, 19.0°, 19.8°, 20.4°, 21.1°, 21.8°, 22.2°, 23.6°, 24.1°, 26.2°, 27.4°, 28.0°, and 29.0°. Specifically, the characteristic peaks of the crystal form at diffraction angle 2θ are shown in Table 1, where the error range of 2θ values ​​is ±0.2°.

[0050] Table 1

[0051]

[0052]

[0053] like Figure 2 The DSC chromatogram of the dibazol-atenolol hydrochloride eutectic crystal form shown in the figure has an endothermic peak at 137±5℃.

[0054] Example 2: Preparation of dibazol hydrochloride-atenolol eutectic crystal form

[0055] 13.3 g atenolol and 24.5 g dibazol hydrochloride were dispersed in 200 mL of acetonitrile solvent and heated to 50 °C to dissolve completely. The mixture was then cooled at a rate of 0.5 °C / min until it reached 10 °C. After stirring for 3 hours, the mixture was filtered, the crystals were collected, and dried at 40 °C to obtain a solid, which is the dibazol hydrochloride-atenolol eutectic.

[0056] Example 3: Preparation of dibazol hydrochloride-atenolol eutectic crystal form

[0057] 48.94 mg of dibazol hydrochloride and 26.63 mg of atenolol were placed in the adapter of a ball mill at a molar ratio of 2:1. Three 4 mm zirconia grinding balls were added, and 20 μL of methanol was added. The mixture was thoroughly ground and mixed in the ball mill for 1 hour. The sample was then collected, which is the dibazol hydrochloride-atenolol eutectic.

[0058] Example 4: Stability test of dibazol hydrochloride-atenolol eutectic

[0059] The dibazol-atenolol hydrochloride cocrystal from Example 1 was placed at 40°C / 75% RH for one month, and samples were taken for X-ray powder diffraction characterization. The results showed that the dibazol-atenolol hydrochloride cocrystal, after being placed at 40°C / 75% RH for one month, exhibited the following XRPD pattern (…). Figure 3 The only changes were in peak intensity and peak width. The drug molecules did not transform into single molecules, nor did they dissociate or degrade. This indicates that the dibazol hydrochloride-atenol eutectic can exist stably under these conditions and has a certain degree of chemical stability.

[0060] Example 5: Hygroscopicity test of dibazol hydrochloride-atenolol eutectic

[0061] Dibazol-Atenolol hydrochloride eutectic and its single drug (dibazol hydrochloride and atenolol) were placed at 40℃ / 75%RH, and the total mass change was measured at 1, 2, 3, 5, 10, and 15 days (Table 1). The hygroscopicity was calculated using the formula (Formula 1). The calculated hygroscopicity over the statistical period showed a maximum value of 0.79%, and remained below 1% for 15 days, indicating that it is stable at 40℃ / 75%RH and meets pharmacopoeia requirements, making it suitable for pharmaceutical use.

[0062] Table 2. Mass (mg) changes of dibazol hydrochloride, atenolol, and their eutectic under specific conditions.

[0063]

[0064]

[0065] Moisture absorption rate = (m1-m0) / m0*100% Formula 1

[0066] m1 is the mass after placement, and m0 is the initial mass.

[0067] Example 6: In-situ dissolution rate detection of dibazol hydrochloride-atenolol eutectic

[0068] This study selected the dibazol hydrochloride-atenol eutectic prepared in Example 1 for dissolution testing, comparing it with the dissolution of dibazol hydrochloride raw material. The chromatographic conditions in this example were: ODS column (250 mm × 4.6 mm, 5 μm); mobile phase: triethylamine-water-methanol (0.5:19.5:80, V / V / V); column temperature: 26 °C; flow rate: 1.0 mL / min; detection wavelength: 275 nm; injection volume: 20 μL.

[0069] The experimental steps are as follows:

[0070] 1) Preparation of standard solutions: Accurately weigh 1.0 g of dibazol hydrochloride as a reference standard, add 200 ml of dilute hydrochloric acid to dissolve it completely, and take 2.0, 4.0, 8.0, 12.0, 16.0, 20.0 and 24.0 ml of the solution and add it to a 25 ml volumetric flask to make up to volume. After detection by high performance liquid chromatography, a standard curve of dibazol hydrochloride can be plotted based on the known concentration and peak area.

[0071] 2) Referring to the General Rules for Dissolution and Release Determination in Chinese Pharmacopoeia 2020 Edition 0931, take an excess of dibazol hydrochloride into a dissolution vessel that meets the requirements, and then add an appropriate amount (10 ml) of 0.1N dilute hydrochloric acid solution to the dissolution vessel, using 10 ml of 0.1N hydrochloric acid solution as the dissolution medium.

[0072] 3) Take an excess of the eutectic sample (the eutectic sample obtained in Example 1) into a dissolution cup that meets the requirements, and then add an appropriate amount (10 ml) of 0.1N dilute hydrochloric acid solution into the dissolution cup, using 10 ml of 0.1N hydrochloric acid solution as the dissolution medium;

[0073] 4) Immediately place the dissolving cup into a pre-set temperature of 37°C and a speed of 100 rpm constant temperature shaking box (turn on the magnetic stirrer, keep the speed constant, and start the timer at the same time);

[0074] 5) After shaking, take 0.5 ml of the solution, filter it through a 0.22 μm filter membrane, and analyze the solution concentration by high performance liquid chromatography. Immediately after sampling, add an equal amount of dissolution medium and continue stirring.

[0075] The sampling time was 5, 10, 15, 20, 30, 45, 60, 90 and 120 min, and the dissolution curves of dibazol hydrochloride and dibazol hydrochloride-atenolol eutectic were plotted.

[0076] like Figure 4 As shown in the results, the dissolution rate of dibazol hydrochloride in the dibazol-atenolol cocrystal was greater than that of the active pharmaceutical ingredient. At 10 minutes, the dissolution rate was 3 times that of dibazol hydrochloride, and at 30 minutes, the dissolution rate reached its maximum, which was 5 times that of dibazol hydrochloride. The dissolution rate was faster than that of dibazol hydrochloride salt.

[0077] The eutectic forms of dibazolium hydrochloride and atenolol were obtained through different methods in the above embodiments. The inherent dissolution rate of the above eutectic of the present invention was studied.

[0078] This invention provides a novel drug-drug cocrystal of dibazol hydrochloride (2-benzylbenzimidazole hydrochloride) and atenolol, its preparation method, and its applications. The cocrystal was characterized using X-ray powder diffraction and differential scanning calorimetry. The newly prepared cocrystal was found to have a faster dissolution rate compared to dibazol hydrochloride and shows potential for combined drug use. The preparation method of the cocrystal is simple, easy to control, and has good reproducibility, yielding stable dibazol hydrochloride and atenolol cocrystals.

[0079] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. A drug-drug co-crystal form of dibazol hydrochloride and atenolol, characterized in that, Including dibazol hydrochloride and atenolol in a molar ratio of 2:1; The drug-drug cocrystal of dibazol hydrochloride and atenolol, as measured by Cu Kα rays, exhibits characteristic peaks at diffraction angles 2θ of 7.1°, 10.8°, 11.3°, 11.8°, 14.3°, 14.8°, 17.2°, 18.5°, 19.0°, 19.8°, 20.4°, 21.1°, 21.8°, 22.2°, 23.6°, 24.1°, 26.2°, 27.4°, 28.0°, and 29.0°.

2. The drug-drug co-crystal form of dibazol hydrochloride and atenolol according to claim 1, characterized in that, The differential scanning calorimetry curve of this eutectic crystal form has an endothermic peak at 137±5℃.

3. A method for preparing the drug-drug co-crystal form of dibazol hydrochloride and atenolol as described in claim 1 or 2, characterized in that, The method includes: mixing dibazol hydrochloride and atenolol in acetonitrile at 30-80°C, cooling to 5-35°C and stirring continuously, filtering, and drying at 30-80°C.

4. The method for preparing the dibazol hydrochloride and atenolol drug-drug cocrystal according to claim 3, characterized in that, The ratio of the total mass of dibazol hydrochloride and atenolol to the volume of acetonitrile is 1 g: (3~25) mL.

5. A method for preparing a drug-drug cocrystal of dibazol hydrochloride and atenolol as described in claim 1 or 2, characterized in that, The method includes: mixing dibazol hydrochloride and atenolol in acetonitrile, stirring continuously at 15~60℃, filtering, and drying at 30~80℃.

6. The method for preparing the dibazol hydrochloride and atenolol drug-drug cocrystal according to claim 5, characterized in that, The ratio of the total mass of dibazol hydrochloride and atenolol to the volume of acetonitrile is 1 g: (3~25) mL.

7. A method for preparing a drug-drug cocrystal of dibazol hydrochloride and atenolol as described in claim 1 or 2, characterized in that, The method includes: mixing dibazol hydrochloride and atenolol in methanol and mechanically ball milling them.

8. The method for preparing the dibazol hydrochloride and atenolol drug-drug cocrystal according to claim 7, characterized in that, The ratio of the total mass of the dibazol-type drug and atenolol to the volume of methanol is 1 g:(20~200) μL; the mechanical ball milling conditions are a grinding frequency of 1-10 times / second and a grinding time of 10-100 min.

9. A pharmaceutical composition, characterized in that, Includes the dibazol hydrochloride and atenolol drug-drug cocrystal as described in claim 1 or 2, and pharmaceutically acceptable excipients.

10. The use of a drug-drug cocrystal of dibazol hydrochloride and atenolol as described in claim 1 or 2 in the preparation of a medicament for treating hypertension.

Images