New long-rod-shaped crystal habit compound of Nicodil and preparation method of new long-rod-shaped crystal habit compound

Abstract

The invention provides a long rod-like new crystal habit compound of Nicodil and a preparation method of the long rod-like new crystal habit compound. The preparation method specifically comprises the following steps: (1) mixing a Nicodil raw material medicine with a solvent, heating and dissolving to obtain a mixed solution; (2) dropwise adding a poor solvent into the mixed solution while keeping the temperature, cooling in a gradient manner, and keeping the temperature for crystallization; and (3) filtering the obtained reaction system, leaching the obtained filter cake with a reagent, and drying to obtain the nicodil new crystal habit compound. The nicodil new crystal habit compound prepared by the method is obviously different from needle-shaped crystalline powder and sheet-shaped crystalline powder in the prior art. The Nicodil new crystal habit compound obtained by the invention is a white long rod-like crystal, has the characteristics of small particle size, large specific surface area, high density, good solubility and the like, and has obvious advantages in the aspects of being convenient to produce and operate, improving the bioavailability of a preparation and the like. Moreover, the preparation process is simple to operate, low in energy consumption, safe and environment-friendly in production process and suitable for large-scale industrial production of pharmaceutical enterprises.

Description

Technical Field

[0001] The invention belongs to the technical field of Nicorandil, and particularly relates to a new long rod-shaped crystal habit compound of Nicorandil and a preparation method thereof. Background Art

[0002] Nicorandil is a vasodilator developed by Chugi Co., Ltd. of Japan. Its chemical name is ethoxynicotinamide nitrate. It belongs to the nitrate ester compound. It is a compound formed by connecting the partial structure of N-(2-hydroxyethyl) nicotinamide vitamin and organic nitrate. It is also an ATP-sensitive potassium channel opener. Nicorandil was launched in Japan in 1984. With the long-term clinical application of Nicorandil, its clinical efficacy in coronary heart disease and angina pectoris has been increasingly recognized. In my country, with the acceleration of population aging, the improvement of people's living standards, the accelerated pace of life, and the development of dietary habits towards high fever and high fat, cardiovascular diseases such as hypertension, hyperlipidemia, heart failure, and stroke in the population have gradually become one of the serious diseases that endanger human health and life. Nicorandil, which is used to treat coronary heart disease and angina pectoris, has a very broad application prospect because it contains nitrate groups in its structure, which can dilate both arterial and venous blood vessels. The structural formula of Nicorandil is shown below.

[0003]

[0004] Crystal habit refers to the external morphology of a crystal, that is, the macroscopic shape of the crystal particles. The crystal habit of a crystal is affected by many factors, including the internal structure of the crystal, crystallization conditions (such as temperature, pressure, solvent, etc.). Different crystal habits may affect the physical properties (such as hardness, melting point, conductivity, etc.) and chemical properties (such as reactivity, solubility, etc.) of the crystal. In existing public literature and patents, there are mainly the following methods for the crystallization method and crystallization solvent of Nicorandil:

[0005] (1) References: Xing Weifan, Zhang Xiaolian, Jiang Kailing, et al., Synthesis of a new antihypertensive drug, Yanlangdingde, Pharmaceutical Industry, 1983, 11: 2-3

[0006] This route uses fuming nitric acid and N-(2-hydroxyethyl) nicotinamide to nitrate in an ice-water bath to synthesize crude nicotinamide, which is then recrystallized from 95% ethanol to obtain the refined product. This route uses 95% ethanol to purify the nicotinamide in the form of white needle-shaped crystals.

[0007] (2) Reference: CN103370301 B

[0008] This route uses propionic acid as solvent, 65% nitric acid as nitrating agent, and the synthesized nicorandil salt system is introduced into 24% ammonia water for crystallization. The obtained nicorandil is white needle-shaped crystals.

[0009] (3) References: Jiao Jianyu, Huang Qingyun, et al., Process Improvement of Antianginal Drug Nicotinamide, Chinese Journal of Medicinal Chemistry, 1990, 1: 95-96

[0010] This route uses fuming nitric acid and N-(2-hydroxyethyl) nicotinamide to synthesize nicorandil nitrate, adjusts the pH with sodium carbonate in ice water to precipitate crude nicorandil, and then purifies it with a mixed solvent of ethanol and water to obtain white needle-shaped crystals of nicorandil.

[0011] It can be seen from the above-mentioned prior art that the products obtained by the current refining process are all needle-shaped crystals. The crystals of this crystal habit have low density and float on the upper layer of the crystal system, making it difficult to discharge the material and bringing great inconvenience to production. In addition, the solubility of the crystals of this crystal habit is poor.

[0012] In summary, how to provide a new crystal habit compound of Nicorandil and a preparation method thereof is an urgent problem to be solved by those skilled in the art. Summary of the invention

[0013] The object of the present invention is to provide a method for preparing a long rod-shaped new crystal habit compound of nicorandil, comprising recrystallizing with a mixed solvent of ethyl acetate and purified water. The nicorandil prepared by the method is a white powdery solid with a high density, can be evenly dispersed in a crystal system under stirring conditions, and is easy to discharge. In addition, the obtained nicorandil has a small particle size, is easy to sieve, has a large specific surface area, and has good solubility. Through XRD and electron microscope detection, the nicorandil provided by the present invention and the nicorandil crystallized from other documents are crystals of the same crystal form with different crystal habits, which provides a new possibility for improving production operability and improving the bioavailability of the preparation.

[0014] To achieve the above object, the present invention provides a method for preparing a long rod-shaped new crystal habit compound of Nicorandil, comprising the following steps:

[0015] (1) mixing the nicorandil raw material with a solvent, and heating to dissolve the mixture to obtain a mixed solution;

[0016] (2) adding a poor solvent dropwise to the mixed solution obtained in step (1), gradually reducing the temperature, and maintaining the temperature to allow crystallization;

[0017] (3) filtering the reaction system obtained in step (2), rinsing the filter cake obtained with a reagent, and drying the filter cake to obtain a new crystalline compound of Nicorandil.

[0018] In a preferred embodiment, in step (1), the solvent is ethyl acetate. The present invention has found through extensive research that ethyl acetate has moderate solubility and can dissolve Nicorandil at a slightly elevated temperature, thereby satisfying the requirement of changing crystal habit and ensuring a high yield.

[0019] In a preferred embodiment, in step (1), the mass ratio of the Nicorandil API to the solvent is 1:(3-7); preferably, the mass ratio of the Nicorandil API to the solvent is 1:5. The experimental results of the present invention show that the nicorandil crystallization yield decreases with the increase of the amount of ethyl acetate used, so the above mass ratio is limited.

[0020] In a preferred embodiment, in step (1), the heating and dissolving temperature is 30-40°C. The present invention has found in experiments that the nitrate structure of Nicorandil is prone to hydrolysis under high temperature and high humidity conditions, so the higher the temperature, the more favorable it is. The present invention limits the above reaction temperature while ensuring clear dissolution.

[0021] In a preferred embodiment, in step (2), the poor solvent is purified water.

[0022] In a preferred embodiment, in step (2), the mass ratio of the poor solvent to nicorandil is (3-7):1; preferably, the mass ratio of the poor solvent to nicorandil is 5:1.

[0023] In a preferred embodiment, in step (2), the poor solvent is added dropwise at a temperature of 30 to 40°C.

[0024] In a preferred embodiment, in step (2), the gradient cooling is: cooling to -5 to 5°C at a rate of 0.5 to 2°C / min; preferably, the gradient cooling is: cooling to -2 to 2°C at a rate of 1 to 1.5°C / min. The present invention has found in experiments that too slow cooling is not conducive to production operations, and too fast cooling rates will lead to larger crystal particle sizes. Moreover, since the crystal growth rate is faster than the impurity diffusion rate, rapid cooling may cause more impurities to be captured on the crystal surface, affecting product quality. The use of gradient cooling in the aforementioned range helps keep impurities away from growing crystals and improves crystal purity.

[0025] In a preferred embodiment, in step (2), the temperature of the heat preservation crystallization is -5 to 5°C; and the time of the heat preservation crystallization is 1 to 3 hours.

[0026] In a preferred embodiment, in step (2), during the heat preservation and crystallization, stirring is performed at 100 to 300 rpm.

[0027] In a preferred embodiment, in step (3), the elution reagent is ethyl acetate.

[0028] In a preferred embodiment, in step (3), the drying conditions may be conventional devices and conditions known to those skilled in the art, and are not limited here, such as drying at 30-40° C. for 2-8 hours.

[0029] Another object of the present invention is to provide a new crystal habit compound of Nicorandil prepared by any of the above methods. Nicorandil prepared by the scheme of the present invention is a white powder, and XRD X-ray powder diffraction light represented by 2θ shows obvious diffraction peaks at 9.16°, 10.61°, 19.63°, 20.57°, 23.33°, 26.45°, and 29.10°. The morphology under an electron microscope is mainly a long rod-shaped crystal habit with a particle size of 1 to 2 microns, which is significantly different from the plate-like crystal habit with a particle size of 10 to 20 microns prepared in the prior art.

[0030] Compared with the prior art, the technical solution of the present invention has the following advantages:

[0031] In the present invention, only ethyl acetate and purified water are used as crystallization solvents, the process flow is simple and easy to operate, there are no special requirements for equipment and energy consumption, and the production process is safe and environmentally friendly, and is suitable for large-scale industrial production in pharmaceutical companies.

[0032] The nicorandil new crystal compound prepared by the method provided by the present invention has small particle size, large specific surface area and high density, and has obvious advantages in terms of facilitating production operation and improving bioavailability of preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] These and / or other aspects and advantages of the present invention will become more clear and easier to understand from the following detailed description of the embodiments of the present invention in conjunction with the accompanying drawings, in which:

[0034] Figure 1 The X-ray diffraction patterns of the Nicorandil crystal powders prepared in Example 1 of the present invention and Comparative Examples 1, 2 and 3 are compared.

[0035] Figure 2 This is an electron micrograph of the Nicorandil API used in Example 1 of the present invention;

[0036] Figure 3 This is an electron microscope image of the Nicorandil crystals prepared in Example 1 of the present invention;

[0037] Figure 4 This is an electron microscope image of the Nicorandil crystals prepared in Comparative Example 1 of the present invention;

[0038] Figure 5 The crystal solubility curves of the long rod-like crystal habit and the plate-like crystal habit crystals prepared in Example 1 of the present invention and Comparative Example 1 are compared. DETAILED DESCRIPTION

[0039] In order to enable those skilled in the art to better understand the present invention, the present invention is further described in detail below in conjunction with the accompanying drawings and specific implementation methods, but it should be understood that the protection scope of the present invention is not limited to the specific implementation methods.

[0040] The embodiment of the present invention provides a new long rod-shaped crystal habit compound of nicorandil and a preparation method thereof, thereby solving the problems that only needle-shaped nicorandil crystals can be prepared in the prior art, and the crystals have low density and poor solubility, which affect production operations and have low bioavailability.

[0041] The technical solution of the present application is described in detail below through specific embodiments:

[0042] Unless otherwise specified, the technical means used in the present invention are conventional means well known to those skilled in the art, and the various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods. The reagents used in the present invention are analytically pure unless otherwise specified. The Nicorandil API used in the present invention comes from a commercial batch of products from Henan Tianfang Pharmaceutical Co., Ltd. (Batch No.: 2305002).

[0043] Example 1

[0044] 20g of Nicorandil API (batch number: 2305002) was added to a 250ml reaction bottle, 100g of ethyl acetate was added, and the mixture was heated to 30°C for dissolution, 100g of purified water was added dropwise while keeping the temperature, the mixture was slowly cooled to 0°C at 1.5°C / min, and the mixture was stirred at 200 rpm for 2 hours, filtered, and the filter cake was rinsed once with 20g of ethyl acetate, and dried at 35°C for 6h to obtain 18.6g of a new crystalline compound of Nicorandil (batch number: Nicorandil NK231009), with a molar yield of 93%. The purity of the product was 99.96% after testing.

[0045] Comparative Example 1

[0046] 30 ml of fuming nitric acid was added to a 100 ml reaction bottle equipped with a magnetic bar, cooled to -10°C, and 10 g of N-(2-hydroxyethyl) nicotinamide was added in batches. After the addition, the reaction was carried out at 0°C for 1 hour, and the reaction system was poured into pre-cooled ether to precipitate the nitrate of Nicorandil. The solid was filtered and dissolved in purified water. Sodium carbonate solution was added to neutralize the solid. The crude Nicorandil was filtered to obtain the crude product. The crude product was recrystallized from ethanol to obtain a needle-shaped crystalline powder (batch number: Nicorandil NK231007).

[0047] Comparative Example 2

[0048] 30 g of glacial acetic acid was charged into a 100 ml three-necked reaction flask purged with nitrogen and equipped with an anchor-shaped magnetic stirrer, a temperature probe and a dropping funnel, followed by the addition of 6.8 g of 68% nitric acid. The system was kept at a constant temperature of 18°C, 20 g of acetic anhydride was added within about 20 minutes, and the temperature was carefully not to exceed 25°C. The system was stirred for about 30 minutes; then cooled to 15°C, and 5 g of N-(2-hydroxyethyl) nicotinamide was added in five equal portions of 1 g each, each with a 5-minute interval, and the temperature was restored to 15°C before each addition. The system was stirred at 22°C for 90 minutes, and the contents of the flask were slowly poured into 24% ammonia water (70 g), and the temperature was carefully not to exceed 35°C. The temperature was lowered to 5°C and maintained for about 60 minutes. The solid was separated by filtration, washed with 10 ml of water, and dried to obtain a needle-shaped crystalline powder (batch number: Nicorandil NK230104).

[0049] Comparative Example 3

[0050] Add 50 ml of fuming nitric acid to a 100 ml reaction bottle, cool to -5°C, and add 20 g of N-(2-hydroxyethyl) nicotinamide in batches. After the addition, react at 0°C for 1.5 h, pour the reaction system into ice water, add sodium carbonate solution to neutralize, precipitate solid, filter to obtain crude Nicorandil, and recrystallize the crude product with 40% ethanol to obtain needle-shaped crystalline powder (batch number: Nicorandil NK231008).

[0051] Application Examples

[0052] (1) The X-ray diffraction patterns of the nicorandil crystal powders obtained in Example 1 and Comparative Examples 1, 2, and 3 were compared. The results are as follows: Figure 1 As shown in the figure, it can be seen that: from the position of the diffraction peak, it can be judged that it is the same crystal form, but the different intensities of the diffraction peaks should be crystals with different crystal habits.

[0053] (2) The electron microscopic images of the Nicorandil API used in Example 1 and the Nicorandil crystalline powders prepared in Example 1 and Comparative Example 1 are as follows: Figure 2 , 3 , 4. It can be seen from the figure that the microscopic morphology of the Nicorandil API is a plate-like crystal, while the microscopic morphology of the Nicorandil crystals prepared by the scheme of the present invention is a long rod-like shape with a length of 5 to 30 microns and a diameter of 1 to 2 microns. Therefore, the crystal density is high and the specific surface area is larger. The Nicorandil crystals prepared in Comparative Example 1 are plate-like crystals with a particle size of 10 to 20 microns. Their low density makes them easy to suspend in the upper layer of the crystal system, causing difficulty in discharging. The crystal morphology obtained in Comparative Examples 2 and 3 is basically the same as that in Comparative Example 1, and they are all plate-like crystals with a particle size of 10 to 20 microns.

[0054] (3) The solubility of Nicorandil finished product was determined by one-way ANOVA. The results are as follows: Figure 5As shown in the figure, the solubility of Example 1 in acidic media with pH values ​​of 1.2, 4.0, and 6.8 is 50.8, 29.8, and 23.6 mg·mL, respectively. －1 The solubility of comparative example 1 in acidic media with pH values ​​of 1.2, 4.0, and 6.8 was 47.5, 28.6, and 22.9 mg·mL, respectively. －1 , the solubility of both of them decreased significantly with the increase of pH. However, the solubility of Example 1 was higher than that of Comparative Example 1 in different pH media, especially in the acidic medium of pH 1.2, the difference in solubility between the two was most obvious, and the solubility of Example 1 increased by 6.9% compared with Comparative Example 1, which provided a high reference value for the study of improving the bioavailability of Nicorandil preparations.

[0055] In summary, Example 1 transforms the plate-like crystal habit of Nicorandil ( Figure 2 ) transforms into a long rod-like crystal habit ( Figure 3 ), without affecting the product quality, the crystal habit transformation is achieved by a streamlined process, which has high practical value. The prepared long rod-shaped crystal habit is a white powder with the advantages of small particle size, high density, high solubility, etc. Compared with the previous plate-shaped crystal habit, the needle-shaped or flaky crystals save the screening and crushing process, and reduce the risk of product degradation caused by high temperature and friction during the crushing process. At the same time, its higher density can be evenly dispersed in the system under stirring, rather than floating on the surface of the solvent, solving the problem of difficult discharge. The new crystal habit preparation method provided by the present invention provides a broader research idea and higher practical significance for the research and utilization of Nicorandil.

[0056] The foregoing description of specific exemplary embodiments of the present invention is for the purpose of illustration and demonstration. These descriptions are not intended to limit the present invention to the precise form disclosed, and it is clear that many changes and variations can be made based on the above teachings. The purpose of selecting and describing the exemplary embodiments is to explain the specific principles of the present invention and its practical application, so that those skilled in the art can realize and utilize various different exemplary embodiments of the present invention and various different selections and changes. The scope of the present invention is intended to be limited by the claims and their equivalents.

Claims

1. A method for preparing a long rod-shaped new crystal habit compound of Nicorandil, characterized in that: The following steps are involved: (1) mixing the Nicorandil API with a solvent, and heating to dissolve the mixture to obtain a mixed solution; (2) adding a poor solvent dropwise to the mixed solution obtained in step (1), gradually reducing the temperature, and maintaining the temperature to allow crystallization; (3) filtering the reaction system obtained in step (2), rinsing the filter cake obtained with a reagent, and drying the filter cake to obtain a new crystalline compound of Nicorandil.

2. The method for preparing the long rod-shaped new crystal habit compound of Nicorandil according to claim 1, characterized in that: In step (1), the solvent is ethyl acetate.

3. The method for preparing the long rod-shaped new crystal habit compound of Nicorandil according to claim 1, characterized in that: In step (1), the mass ratio of the Nicorandil API to the solvent is 1:(3-7).

4. The method for preparing the long rod-shaped new crystal habit compound of Nicorandil according to claim 1, characterized in that: In step (1), the heating and dissolving temperature is 30 to 40°C.

5. The method for preparing the long rod-shaped new crystal habit compound of Nicorandil according to claim 1, characterized in that: In step (2), the poor solvent is purified water.

6. The method for preparing the long rod-shaped new crystal habit compound of Nicorandil according to claim 1, characterized in that: In step (2), the mass ratio of the poor solvent to nicorandil is (3-7):

1.

7. The method for preparing the long rod-shaped new crystal habit compound of Nicorandil according to claim 1, characterized in that: In step (2), the gradient cooling is: cooling to -5 to 5°C at a rate of 0.5 to 2°C / min.

8. The method for preparing the long rod-shaped new crystal habit compound of Nicorandil according to claim 1, characterized in that: In step (2), the temperature of the heat preservation crystallization is -5 to 5°C; and the time of the heat preservation crystallization is 1 to 3 hours.

9. The method for preparing the long rod-shaped new crystal habit compound of Nicorandil according to claim 1, characterized in that: In step (3), the elution reagent is ethyl acetate.

10. The new nicorandil compound prepared by the method according to any one of claims 1 to 9, characterized in that: The new crystal habit compound is a white powder, and XRD shows X-ray powder diffraction light represented by 2θ, with obvious diffraction peaks at 9.16°, 10.61°, 19.63°, 20.57°, 23.33°, 26.45°, and 29.10°. The morphology under an electron microscope is mainly a long rod-shaped crystal habit with a particle size of 1 to 2 microns.

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