Bevantolol hydrochloride crystal form and preparation method thereof

Abstract

The invention provides a bevantolol hydrochloride crystal form and a preparation method thereof, in an X-ray powder diffraction pattern of the bevantolol hydrochloride crystal form, at least characteristic diffraction peaks exist at positions with diffraction angles 2 theta + / -0.2 degrees of 4.9 degrees, 9.9 degrees, 14.9 degrees, 17.6 degrees, 23.1 degrees, 23.5 degrees and 24.3 degrees; the preparation method of the bevantolol hydrochloride crystal form comprises the following steps: adding a bevantolol hydrochloride raw material and a solvent into a container, and heating, stirring and raising the temperature until reflux and dissolution are clear; cooling to a preset temperature, preserving heat, stirring, crystallizing, and filtering to obtain a filter cake; and leaching the filter cake and drying to obtain the bevantolol hydrochloride crystal form. The bevantolol hydrochloride crystal form and the preparation method thereof are simple and convenient, the preparation conditions are mild, the prepared bevantolol hydrochloride crystal form is high in yield, strong in stability and convenient to store for a long time, and the dissolution rate is high after the bevantolol hydrochloride crystal form is prepared into tablets.

Description

Technical Field

[0001] The present application relates to the field of medical technology, and in particular to a bevanolol hydrochloride crystal form and a preparation method thereof. Background Art

[0002] Hypertension affects more than one-third of adults worldwide, more than half of whom are unaware of their condition, and nearly 80% of patients do not receive adequate treatment. Hypertension can lead to many health problems, including stroke, heart failure, heart attack, and kidney damage.

[0003] The chemical name of bevanolol hydrochloride is 1-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-3-(3-methylphenoxy)-2-propanol hydrochloride, and its structural formula is Bevanolol hydrochloride is a β1 adrenergic receptor antagonist that has been shown to be as effective as other β-blockers for the treatment of angina and hypertension. Animal experiments on the mechanism of action have confirmed that in addition to having antagonist activity on β1 receptors, it also has agonist and antagonist effects on some α1 receptors. This product has the characteristics of rapid onset and long-lasting effect, and can effectively control the patient's morning blood pressure rise. In the process of lowering blood pressure, it has the advantages of stable effect, good tolerance, and few adverse reactions, and it is safer. This product belongs to the fourth generation of lol antihypertensive drugs. Compared with the second and third generation β-blockers, it has less effect on patients' blood sugar, blood lipids, and uric acid levels.

[0004] After oral administration of solid preparations, drug absorption depends on the dissolution or release of the drug from the preparation, the dissolution of the drug under physiological conditions, and the penetration of the gastrointestinal tract. Since the dissolution and dissolution of the drug have an important influence on absorption, in vitro dissolution tests have the potential to predict its in vivo behavior. Dissolution refers to the rate and extent of dissolution of a drug from a solid preparation such as a tablet in a specified solvent. Under the condition of meeting the quality standards, the higher the solubility, the better the in vivo dissolution behavior, the better the drug absorption, and the higher the efficacy. The dissolution of tablets currently produced using bevanolol hydrochloride raw materials is relatively low. Therefore, there is an urgent need for a bevanolol hydrochloride product that can improve the solubility. Summary of the invention

[0005] In view of this, the purpose of the present application is to provide a bevanolol hydrochloride crystal form and a preparation method thereof.

[0006] Based on the above-mentioned purpose, the first aspect of the present application provides a bevanolol hydrochloride crystal form, in the X-ray powder diffraction pattern of the bevanolol hydrochloride crystal form, at least including characteristic diffraction peaks at diffraction angles 2θ±0.2° of 4.9°, 9.9°, 14.9°, 17.6°, 23.1°, 23.5° and 24.3°.

[0007] The second aspect of the present application provides a method for preparing the bevanolol hydrochloride crystal form as described in the first aspect above, comprising: adding bevanolol hydrochloride raw materials and a solvent into a container, heating and stirring to reflux and dissolve; cooling to a preset temperature and keeping the temperature and stirring to crystallize, filtering to obtain a filter cake; rinsing the filter cake and drying to obtain the bevanolol hydrochloride crystal form.

[0008] Furthermore, the addition ratio of the bevanolol hydrochloride raw material and the solvent is 10g:(60mL-200mL).

[0009] Furthermore, the addition ratio of the bevanolol hydrochloride raw material and the solvent is 10g:130mL.

[0010] Furthermore, the solvent is one or more of alcohols, esters, acetonitrile, DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide) and water.

[0011] Furthermore, the alcohol is one or more of methanol, ethanol, propanol, isopropanol and n-butanol, and the ester is ethyl acetate and / or isopropyl acetate.

[0012] Furthermore, the temperature of the reflux solution is 60°C-125°C.

[0013] Furthermore, the preset temperature is 10°C-30°C.

[0014] Furthermore, the time of heat preservation and stirring is 0.5h-6h.

[0015] Furthermore, the drying is forced air drying or vacuum drying, and the drying temperature is 40°C-60°C.

[0016] As can be seen from the above, the bevanolol hydrochloride crystal form and the preparation method thereof provided by the present application, in the X-ray powder diffraction pattern of the bevanolol hydrochloride crystal form, at least include characteristic diffraction peaks at positions where the diffraction angles 2θ±0.2° are 4.9°, 9.9°, 14.9°, 17.6°, 23.1°, 23.5° and 24.3°. After testing, the bevanolol hydrochloride crystal form has strong stability and is convenient for long-term storage. After being prepared into a preparation tablet, the solubility reaches more than 92%; the preparation method of the bevanolol hydrochloride crystal form comprises: adding bevanolol hydrochloride raw materials and solvents in a container, heating and stirring to reflux and dissolve; cooling to a preset temperature and keeping warm and stirring to crystallize, filtering to obtain a filter cake; eluting the filter cake and drying to obtain the bevanolol hydrochloride crystal form. The method is simple and convenient, with mild conditions and high yield. The bevanolol hydrochloride crystal form and the preparation method thereof are simple and convenient, and the preparation conditions are mild. The prepared bevanolol hydrochloride crystal form has a high yield and strong stability and is convenient for long-term storage. The bevanolol hydrochloride crystal form has high solubility after being prepared into tablets. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] In order to more clearly illustrate the technical solutions in the present application or related technologies, the drawings required for use in the embodiments or related technical descriptions are briefly introduced below. Obviously, the drawings described below are only embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work.

[0018] Figure 1 Schematic diagram of a process for preparing a bevanolol hydrochloride crystal form in an embodiment of the present application;

[0019] Figure 2 is the X-ray powder diffraction pattern of the bevanolol hydrochloride crystal form in Example 1 of the present application;

[0020] Figure 3 This is a DSC curve diagram of the bevanolol hydrochloride crystal form in Example 1 of the present application;

[0021] Figure 4 is the X-ray powder diffraction pattern of the bevanolol hydrochloride crystal form in Example 2 of the present application;

[0022] Figure 5 is the X-ray powder diffraction pattern of the bevanolol hydrochloride crystal form in Example 3 of the present application;

[0023] Figure 6 is the X-ray powder diffraction pattern of the bevanolol hydrochloride crystal form in Example 4 of the present application;

[0024] Figure 7 is the X-ray powder diffraction pattern of the bevanolol hydrochloride crystal form in Example 5 of the present application;

[0025] Figure 8 This is the X-ray powder diffraction pattern of the bevanolol hydrochloride crystal form in Example 6 of the present application. DETAILED DESCRIPTION

[0026] In order to make the objectives, technical solutions and advantages of the present disclosure more clearly understood, the present disclosure is further described in detail below in conjunction with specific embodiments.

[0027] It should be noted that, unless otherwise defined, the technical terms used in the following examples have the same meanings as those generally understood by those skilled in the art to which the present invention belongs. The test reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental methods, unless otherwise specified, are all conventional methods.

[0028] Hypertension affects more than one-third of adults worldwide, more than half of whom are unaware of it, and nearly 80% of patients do not receive adequate treatment or treatment that meets standards. Hypertension may cause many health problems, such as stroke, heart failure, heart attack, and kidney damage. Among them, more than 10 million people die each year from high systolic blood pressure. Nearly 30% of Chinese patients have hypertension, of which only about 39% receive treatment, and only 16% receive treatment that meets standards. Measuring blood pressure is currently the only way to diagnose hypertension. Adults should measure their blood pressure regularly, and if they feel they are at risk, they should seek medical attention as soon as possible.

[0029] The chemical name of bevanolol hydrochloride is 1-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-3-(3-methylphenoxy)-2-propanol hydrochloride, and its structural formula is The original manufacturer was Pfizer, and later it was researched and developed by Warner-Lambert. In 1987, Nycomed Pharma applied for listing in the Philippines for the treatment of hypertension and angina pectoris. In June 1995, it was produced and listed by Japan's Chemifa Co., Ltd., and subsequently registered and listed in South Korea, Germany and the Netherlands. Currently, imported drugs (trade name: Calvan) are on the market in China.

[0030] Bevanolol hydrochloride is a β1 adrenergic receptor antagonist that has been shown to be as effective as other β-blockers for the treatment of angina and hypertension. Animal experiments on the mechanism of action have confirmed that in addition to having antagonist activity on β1 receptors, it also has agonist and antagonist effects on some α1 receptors. This product has the characteristics of rapid onset and long-lasting effect, and can effectively control the patient's morning blood pressure rise. In the process of lowering blood pressure, it has the advantages of stable effect, good tolerance, and few adverse reactions, and it is safer. This product belongs to the fourth generation of lol antihypertensive drugs. Compared with the second and third generation β-blockers, it has less effect on patients' blood sugar, blood lipids, and uric acid levels.

[0031] After oral administration of solid preparations, drug absorption depends on the dissolution or release of the drug from the preparation, the dissolution of the drug under physiological conditions, and the penetration of the gastrointestinal tract. Since the dissolution and dissolution of the drug have an important influence on absorption, in vitro dissolution tests have the potential to predict its in vivo behavior. Dissolution refers to the rate and extent of dissolution of the drug from solid preparations such as tablets in a specified solvent. Under the condition of meeting the quality standards, the higher the solubility, the better the in vivo dissolution behavior, the better the drug absorption, and the higher the efficacy. The dissolution rate of bevanolol hydrochloride tablets is required to be above 80%. The dissolution rate of tablets currently produced with bevanolol hydrochloride raw materials is relatively low. Therefore, there is an urgent need for a bevanolol hydrochloride product that can improve the solubility.

[0032] Below, through specific embodiments and combined Figures 1 to 8 To describe the technical solution of this application in detail.

[0033] In some embodiments of the present application, a bevanolol hydrochloride crystal form is provided, and in the X-ray powder diffraction pattern of the bevanolol hydrochloride crystal form, characteristic diffraction peaks are at least included at positions where the diffraction angles 2θ±0.2° are 4.9°, 9.9°, 14.9°, 17.6°, 23.1°, 23.5° and 24.3°.

[0034] For example, in the X-ray powder diffraction spectrum of the bevanolol hydrochloride crystal form, characteristic diffraction peaks are present at positions where the diffraction angles 2θ are 4.9°, 9.9°, 14.9°, 17.6°, 23.1°, 23.5° and 24.3°. The bevanolol hydrochloride crystal form has strong stability and is convenient for long-term storage. After being prepared into a preparation tablet, the dissolution rate reaches more than 92%.

[0035] In some embodiments of the present application, a method for preparing a bevanolol hydrochloride crystalline form is provided, such as Figure 1 As shown, the following steps are included:

[0036] S1. Add bevanolol hydrochloride raw material and solvent into a container, and heat and stir to reflux and dissolve.

[0037] The bevantolol hydrochloride raw material is, for example, amorphous bevantol hydrochloride; the solvent is one or more of alcohols, esters, acetonitrile, DMF, DMSO and water, such as acetonitrile and water; the alcohol is one or more of methanol, ethanol, propanol, isopropanol and n-butanol, such as methanol and ethanol; the ester is ethyl acetate and / or isopropyl acetate, without specific limitation.

[0038] The addition ratio of bevanolol hydrochloride raw material and solvent is 10g:(60mL-200mL), for example, 10g:60mL, 10g:70mL, 10g:80mL, 10g:90mL, 10g:100mL, 10g:150mL, 10g:160mL, 10g:170mL, 10g:180mL, 10g:190mL or 10g:200mL, etc., without specific limitation.

[0039] The temperature of the reflux solution is 60°C-125°C, for example, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C or 125°C, etc., without specific limitation.

[0040] S2, cooling to a preset temperature and maintaining the temperature to stir and crystallize, and filtering to obtain a filter cake.

[0041] The preset temperature is 10°C-30°C, for example, 10°C, 15°C, 20°C, 25°C or 30°C, etc., and is not specifically limited. The time for heat preservation and stirring is 0.5h-6h, for example, 0.5h, 1h, 2h, 3h, 4h, 5h or 6h, etc., and is not specifically limited.

[0042] S3, eluting the filter cake and drying it to obtain the bevanolol hydrochloride crystal form.

[0043] The solvent in step S1 is used for elution; the drying is air drying or vacuum drying, and the drying temperature is 40°C-60°C, for example, 40°C, 45°C, 50°C, 55°C or 60°C, etc., without specific limitation.

[0044] The preparation method of the bevanolol hydrochloride crystal form is simple and convenient, the conditions are mild, the yield is high, the prepared bevanolol hydrochloride crystal form has strong stability, is convenient for long-term storage, and has high solubility after being prepared into tablets.

[0045] In some embodiments, the addition ratio of the bevanolol hydrochloride raw material and the solvent is 10 g:130 mL.

[0046] After testing, the bevanolol hydrochloride crystal prepared with an addition ratio of 10g:130mL had the highest yield, which could reach 98.9%, and the tablet solubility of the bevanolol hydrochloride crystal prepared was also the highest, which could reach 96%.

[0047] Example 1

[0048] In a 250mL three-necked flask, add 10.0g of bevanolol hydrochloride, 56mL of methanol and 4mL of purified water, heat to 60°C to reflux and dissolve, turn off the heating, cool to 28°C, keep stirring and crystallize for 2h, then filter and rinse, and dry the filter cake at 40°C to obtain 9.84g of white crystals, that is, the bevanolol hydrochloride crystal form is obtained, and the calculated yield is 98.4%.

[0049] The bevanolol hydrochloride crystal form was subjected to XRD test, and the test results were as follows: Figure 2 As shown in the spectrum, there are characteristic diffraction peaks at diffraction angles 2θ of 4.9°, 9.9°, 14.9°, 17.6°, 23.1°, 23.5° and 24.3°. The bevanolol hydrochloride crystal was subjected to DSC test, and the test results are as follows: Figure 3 As shown, its endothermic peak is at 142.27℃±3℃.

[0050] The bevanolol hydrochloride crystal obtained in Example 1 was prepared into tablets. The tablet preparation method included taking 5.00 g of the bevanolol hydrochloride crystal, passing it through a 100-mesh sieve, taking 8.80 g of cellulose, 9.78 g of magnesium stearate and 0.33 g of titanium oxide, respectively passing them through a 60-mesh sieve, and mixing them evenly; adding wetting agent water to the mixture to make a soft material, passing it through a 30-mesh sieve for granulation, and drying the wet granules at 60° C. until the weight loss was less than 3% (90° C., drying for 5 min); granulating, adding magnesium stearate (0.25 g, passed through a 60-mesh sieve in advance), mixing evenly, pressing into 100 tablets, and film coating.

[0051] The dissolution was determined by ultraviolet spectrophotometry, and 900 mL of water was selected as the dissolution medium. The basket method was used at 75 rpm. The dissolution of bevanolol hydrochloride in the tablets was determined to be 94% according to the spectrophotometric method (Part II IVA of the Chinese Pharmacopoeia 2020 Edition).

[0052] Example 2

[0053] In a 250mL three-necked flask, add 10.0g of bevanolol hydrochloride and 60mL of n-butanol, heat to 125°C to reflux and dissolve, turn off the heating, cool to 15°C, keep stirring and crystallize for 1h, then filter and rinse, and dry the filter cake under reduced pressure at 50°C to obtain 9.81g of white crystals, that is, the bevanolol hydrochloride crystalline form is obtained, and the calculated yield is 98.1%.

[0054] The bevanolol hydrochloride crystal form was subjected to XRD test, and the test results were as follows: Figure 4 As shown, there are characteristic diffraction peaks at diffraction angles 2θ of 4.9°, 9.8°, 14.9°, 17.6°, 23.0°, 23.5° and 24.2° in the spectrum.

[0055] The bevanolol hydrochloride crystalline tablets of Example 2 were prepared according to the tablet preparation method in Example 1.

[0056] The dissolution was determined by ultraviolet spectrophotometry, and 900 mL of water was selected as the dissolution medium. The basket method was used at 75 rpm. The dissolution of bevanolol hydrochloride in the tablet was determined to be 93% according to the spectrophotometric method (Part II IVA of the Chinese Pharmacopoeia 2020 Edition).

[0057] Example 3

[0058] In a 2L three-necked flask, add 50.0 g of bevanolol hydrochloride, 980 mL of propanol and 20 mL of purified water, heat to 125°C to reflux and dissolve, turn off the heating, cool naturally to 25°C, keep warm and stir to crystallize for 2.5 hours, then filter and rinse, and dry the filter cake at 50°C to obtain 42.6 g of white crystals, that is, the bevanolol hydrochloride crystal form is obtained, and the calculated yield is 85.2%.

[0059] The bevanolol hydrochloride crystal form was subjected to XRD test, and the test results were as follows: Figure 5 As shown, there are characteristic diffraction peaks at diffraction angles 2θ of 4.9°, 9.8°, 14.9°, 17.6°, 22.9°, 23.5° and 24.3° in the spectrum.

[0060] The bevanolol hydrochloride crystalline tablets of Example 3 were prepared according to the tablet preparation method in Example 1.

[0061] The dissolution was determined by ultraviolet spectrophotometry, 900 mL of water was selected as the dissolution medium, the basket method was used, and the speed was 75 rpm. The dissolution rate of bevanolol hydrochloride in the tablets was determined to be 95% according to the spectrophotometric method (Part II IVA of the Chinese Pharmacopoeia 2020 Edition).

[0062] Example 4

[0063] In a 2L three-necked flask, add 60.0g of bevanolol hydrochloride, 680mL of isopropanol and 20mL of purified water, heat to 80°C to reflux and dissolve, turn off the heating, cool naturally to 16°C, keep warm and stir to crystallize for 0.5h, then filter and rinse, and dry the filter cake at 45°C to obtain 58.82g of white crystals, that is, the bevanolol hydrochloride crystal form is obtained, and the calculated yield is 98.0%.

[0064] The bevanolol hydrochloride crystal form was subjected to XRD test, and the test results were as follows: Figure 6 As shown, there are characteristic diffraction peaks at diffraction angles 2θ of 4.8°, 9.8°, 14.7°, 17.5°, 23.1°, 23.5° and 24.3° in the spectrum.

[0065] The bevanolol hydrochloride crystal obtained in Example 4 was prepared into tablets. The tablet preparation method included taking 50.00 g of the bevanolol hydrochloride crystal, passing it through a 100-mesh sieve, taking 88.00 g of cellulose, 97.80 g of magnesium stearate and 3.25 g of titanium oxide, respectively passing them through a 60-mesh sieve, and mixing them evenly; adding wetting agent water to the mixture to make a soft material, passing it through a 30-mesh sieve for granulation, and drying the wet granules at 60° C. until the weight loss was less than 3% (90° C., drying for 5 min); granulating, adding magnesium stearate (2.50 g, passed through a 60-mesh sieve in advance), mixing evenly, pressing into 1000 tablets, and film coating.

[0066] The dissolution was determined by ultraviolet spectrophotometry, and 900 mL of water was selected as the dissolution medium. The basket method was used at 75 rpm. The dissolution of bevanolol hydrochloride in the tablets was determined to be 92% according to the spectrophotometric method (Part II IVA of the Chinese Pharmacopoeia 2020 Edition).

[0067] Example 5

[0068] In a 2L three-necked flask, add 60.0 g of bevanolol hydrochloride, 240 mL of ethyl acetate and 540 mL of ethanol, heat to 75°C to reflux and dissolve, turn off the heating, cool naturally to 25°C, keep warm and stir to crystallize for 6 hours, then filter and rinse, and dry the filter cake under reduced pressure at 60°C to obtain 59.38 g of white crystals, that is, the bevanolol hydrochloride crystal form is obtained, and the calculated yield is 98.9%.

[0069] The bevanolol hydrochloride crystal form was subjected to XRD test, and the test results were as follows: Figure 7 As shown, there are characteristic diffraction peaks at diffraction angles 2θ of 4.9°, 9.8°, 14.8°, 17.6°, 23.1°, 23.5° and 24.3° in the spectrum.

[0070] The bevanolol hydrochloride crystalline tablets of Example 5 were prepared according to the tablet preparation method in Example 4.

[0071] The dissolution was determined by ultraviolet spectrophotometry, and 900 mL of water was selected as the dissolution medium. The basket method was used at 75 rpm. The dissolution of bevanolol hydrochloride in the tablets was determined to be 96% according to the spectrophotometric method (Part II IVA of the Chinese Pharmacopoeia 2020 Edition).

[0072] Example 6

[0073] In a 50L reactor, add 2.0kg of bevanolol hydrochloride, 19L of isopropanol and 1L of purified water, heat to 65°C to reflux and dissolve, turn off the heating, cool naturally to 23°C, keep warm and stir to crystallize for 1h, then filter and rinse, and dry the filter cake under reduced pressure at 40°C to obtain 1.96kg of white crystals, that is, the bevanolol hydrochloride crystal form is obtained, and the calculated yield is 98.0%.

[0074] The bevanolol hydrochloride crystal form was subjected to XRD test, and the test results were as follows: Figure 8 As shown, there are characteristic diffraction peaks at diffraction angles 2θ of 4.9°, 9.9°, 14.9°, 17.5°, 23.1°, 23.5° and 24.3° in the spectrum.

[0075] The bevanolol hydrochloride crystalline tablets of Example 6 were prepared according to the tablet preparation method in Example 4.

[0076] The dissolution was determined by ultraviolet spectrophotometry, and 900 mL of water was selected as the dissolution medium. The basket method was used at 75 rpm. The dissolution of bevanolol hydrochloride in the tablets was determined to be 94% according to the spectrophotometric method (Part II IVA of the Chinese Pharmacopoeia 2020 Edition).

[0077] Comparative Example 1

[0078] Referring to the same tablet component ratio as in Example 1 to Example 6, a commercially available reference preparation of bevanolol hydrochloride tablets was obtained, with a specification of 50 mg, and a licensed manufacturer NIPPON CHEMIPHAR Co., Ltd. The dissolution was determined by ultraviolet spectrophotometry, and 900 mL of water was selected as the dissolution medium. The basket method was used at 75 rpm. The solubility of bevanolol hydrochloride in the tablet was determined to be 82% according to the spectrophotometric method (Chinese Pharmacopoeia 2020 Edition, Part II, IVA).

[0079] From the comparison of the data of the embodiment and the comparative example, it can be seen that the tablets prepared using the bevanolol hydrochloride crystal form having characteristic diffraction peaks at diffraction angles 2θ±0.2° of 4.9°, 9.9°, 14.9°, 17.6°, 23.1°, 23.5° and 24.3° have significantly higher solubility, and when the addition ratio of the bevanolol hydrochloride raw material and the solvent is 10 g: 130 mL (Example 5), the solubility is the highest.

[0080] In order to investigate the stability of the above-mentioned bevanolol hydrochloride crystal form, the bevanolol hydrochloride raw material and the prepared bevanolol hydrochloride crystal form in the embodiment were placed in a light box at 50°C, 4500±500LX for stability test, and the relevant substances were measured before the start of the test and on the 12th day and 30th day after the start of the test. The statistical results are shown in Table 1. It can be seen that the stability of the bevanolol hydrochloride crystal form in this embodiment is higher than the stability of the bevanolol hydrochloride raw material.

[0081] Table 1 Stability test table

[0082]

[0083]

[0084] Prepare several round-bottom flasks, each equipped with a magnetic stirrer. At room temperature, take 1 g of the bevanolol hydrochloride crystal form of Example 6, and perform a solubility test with 2.5 mL of solvent as one unit volume. Each time a unit volume is added, it is necessary to stir for 10 minutes, and observe whether it is dissolved. If it is not dissolved, continue to add a unit volume of solvent. After it is dissolved, the solubility is calculated according to the total amount of solvent added. The solubility data are shown in Table 2. It can be seen that the solubility of the bevanolol hydrochloride crystal form in this embodiment is good and meets the requirements of the preparation.

[0085] Table 2 Solubility test table

[0086] Solvents Solubility (mg / mL) water 50 Anhydrous ethanol 66 95% ethanol 57 Acetonitrile 9 Isopropyl alcohol 8

[0087] Those skilled in the art should understand that the discussion of any of the above embodiments is merely illustrative and is not intended to imply that the scope of the present disclosure (including the claims) is limited to these examples. Based on the concept of the present disclosure, the technical features in the above embodiments or different embodiments may be combined, the steps may be implemented in any order, and there are many other variations of the different aspects of the embodiments of the present disclosure as described above, which are not provided in detail for the sake of simplicity.

[0088] The embodiments of the present disclosure are intended to cover all such substitutions, modifications and variations that fall within the broad scope of the appended claims. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the embodiments of the present disclosure should be included in the scope of protection of the present disclosure.

Claims

1. A bevanolol hydrochloride crystal form, characterized in that: include: In the X-ray powder diffraction pattern of the bevanolol hydrochloride crystal form, characteristic diffraction peaks are at least included at positions where the diffraction angles 2θ±0.2° are 4.9°, 9.9°, 14.9°, 17.6°, 23.1°, 23.5° and 24.3°.

2. A method for preparing the bevanolol hydrochloride crystal form according to claim 1, characterized in that: include: Add bevanolol hydrochloride raw material and solvent into a container, heat and stir to raise the temperature to reflux and dissolve; Cool down to the preset temperature and keep warm, stir and crystallize, and filter to obtain a filter cake; The filter cake is rinsed and dried to obtain the bevanolol hydrochloride crystal form.

3. The preparation method of bevanolol hydrochloride crystal form according to claim 2, characterized in that, The addition ratio of the bevanolol hydrochloride raw material and the solvent is 10 g: (60 mL-200 mL).

4. The method for preparing the bevanolol hydrochloride crystal form according to claim 3, wherein The addition ratio of the bevanolol hydrochloride raw material and the solvent is 10 g:130 mL.

5. The method for preparing bevanolol hydrochloride crystal according to claim 2, characterized in that: The solvent is one or more of alcohols, esters, acetonitrile, DMF, DMSO and water.

6. The method for preparing the bevanolol hydrochloride crystal form according to claim 5, characterized in that: The alcohol is one or more of methanol, ethanol, propanol, isopropanol and n-butanol, and the ester is ethyl acetate and / or isopropyl acetate.

7. The method for preparing the bevanolol hydrochloride crystal form according to claim 2, characterized in that: The temperature of the reflux solution is 60°C-125°C.

8. The method for preparing the bevanolol hydrochloride crystal form according to claim 2, characterized in that: The preset temperature is 10°C-30°C.

9. The method for preparing the bevanolol hydrochloride crystal form according to claim 2, characterized in that: The time of heat preservation and stirring is 0.5h-6h.

10. The method for preparing the bevanolol hydrochloride crystal form according to claim 2, characterized in that: The drying is air-blast drying or vacuum drying, and the drying temperature is 40°C-60°C.

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