Production method and preservation method for reducing temperature sensitivity of Nicodil raw material medicine

Abstract

The invention relates to the technical field of pharmaceutical engineering, in particular to a production method and a preservation method for reducing temperature sensitivity of a Nicodil bulk drug. The method comprises the following steps: by taking ethanolamine and nicotinic acid as initial raw materials, carrying out nitration reaction on ethanolamine and fuming nitric acid to obtain a first intermediate; nicotinic acid and thionyl chloride are subjected to an acylation reaction to generate a dichloromethane solution in an intermediate state of nicotinic acid, and then the dichloromethane solution in the intermediate state of nicotinic acid and the first intermediate are subjected to an addition reaction to generate a crude nicorandil product; and refining the crude product of Nicodil with isopropanol to obtain a finished product of Nicodil, specifically comprising the following steps: adding the crude product of Nicodil and isopropanol in a reaction container according to a feeding mass ratio of 1: 6, heating to below 50 DEG C, stirring for dissolving, filtering, collecting filtrate, cooling to-10-0 DEG C, stirring for crystallization for 4-5 hours, filtering, collecting a filter cake, and drying to obtain the finished product of Nicodil. And drying the filter cake at 40-50 DEG C under reduced pressure for not less than 6 hours to obtain the finished product of Nicodil.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical engineering, and particularly relates to a production method and a preservation method for reducing the temperature sensitivity of nicorandil raw materials. Background Art

[0002] Nicorandil is widely used in the treatment of angina pectoris. The market application of nicorandil tablets began in the 1980s. Its mechanism of nitrogen-oxygen donor and vasodilatory effect are similar to those of nitrate drugs. For a long time, long-acting drugs such as isosorbide mononitrate have occupied a major position in the treatment of coronary heart disease. However, with the phenomena of low response or drug resistance of commonly used drugs such as nitrates, and the change of the market pattern of cardiovascular drugs, new opportunities have emerged in the market of nicorandil. Nicorandil is a nitroxy ester compound with a nitroxy group, which is extremely unstable in aqueous solution or under heating conditions and is prone to degradation. During the preparation of nicorandil, both the water content of the solvent and the increase in temperature can lead to the generation of impurities.

[0003] In the prior art, for example, the invention patent disclosed in the application number 202211433449.8 discloses that potassium nitrate and a small amount of concentrated nitric acid are added to acetone for dissolution, and acetic anhydride is added for dissolution to obtain System I; N-(2-hydroxyethyl)nicotinamide is added to acetone, and System I is added dropwise for heat preservation reaction. During the reaction process, the product nicorandil precipitates. After the reaction, the pH is adjusted, filtered, dried, and refined to obtain the nicorandil finished product. According to Example 1, the total yield of nicorandil is 94.61%. However, this method does not test the stability of the finished product under accelerated conditions. During the production of nicorandil, process impurities are introduced by the raw materials and the treatment methods of the production steps, and another part of the impurities are degradation impurities generated by the degradation of the finished product nicorandil under high temperature, high humidity, and light conditions. The prior art has not made improvements on how to reduce the sensitivity to the environment under the best preservation conditions of the nicorandil raw materials produced by its production method.

[0004] In addition, in the prior art, it is considered that the method of preparing nicorandil by nitration reaction using N-(2-hydroxyethyl)nicotinamide uses excessive nitric acid, which will cause nicorandil or its intermediate to be oxidized or turn the reaction to form other nitro derivatives. Therefore, the reaction yield is generally not high and the impurity content is high. Summary of the Invention

[0005] In view of the above technical problems, the first aspect of the present invention proposes a production method for reducing the temperature sensitivity of nicorandil raw materials. The synthesis route of the method is as follows:

[0006]

[0007] The impurity ethylene glycol in the ethanolamine (SM1) does not exceed 0.062% of the mass fraction of the ethanolamine, and the impurity diethanolamine does not exceed 0.10% of the mass fraction of the ethanolamine.

[0008] Furthermore, the method comprises the following steps:

[0009] S1 uses ethanolamine and nicotinic acid as starting materials, and ethanolamine undergoes nitration reaction with fuming nitric acid to obtain the first intermediate;

[0010] S2 nicotinic acid and thionyl chloride undergo an acylation reaction to generate an intermediate dichloromethane solution, and then the intermediate dichloromethane solution is subjected to an addition reaction with the first intermediate to generate a crude nicorandil;

[0011] S3 purifies the crude Nicorandil to obtain a finished Nicorandil product, which specifically comprises the following steps: adding the crude Nicorandil product and isopropanol in a ratio of 1:6 by mass to a reaction vessel, heating to below 50°C, stirring to dissolve, filtering, collecting the filtrate, cooling to -10-0°C, stirring to crystallize for 4-5h, filtering, collecting the filter cake, and drying the filter cake under reduced pressure at 40-50°C for not less than 6h to obtain the finished Nicorandil product.

[0012] Furthermore, the S1 specifically comprises: slowly adding a dichloromethane solution of ethanolamine to a mixed system of concentrated nitric acid and dichloromethane, carrying out a nitration reaction under the conditions of controlling the temperature at 10-30°C and the time at 0.5-1h, and after the nitration reaction is completed, adding acetic anhydride, and after a crystallization step, filtering the filter cake with dichloromethane, washing, and drying to obtain the first intermediate.

[0013] Further, S1 adds 9.3 kg of fuming nitric acid and 21 L of dichloromethane to a 100 L double-layer glass reactor, stirs evenly, controls the temperature to below 30° C., and slowly adds 3.0 kg of a dichloromethane solution of ethanolamine, wherein the ethanolamine is dissolved in 9 L of dichloromethane; after the addition is completed, controls the temperature to 10-30° C. and stirs to react for 0.5-1 h; after the reaction is completed, slowly adds 7.5 kg of acetic anhydride, controls the temperature to 10-30° C. and stirs to crystallize for 1-2 h, filters, washes the filter cake with an appropriate amount of dichloromethane, collects the filter cake, and dries under reduced pressure at 50-70° C. for not less than 6 h to obtain the first intermediate.

[0014] Furthermore, the addition reaction described in S3 is achieved by the following steps: adding 5.8 kg of nicotinic acid, 0.3 kg of dimethylformamide and 23 L of dichloromethane to a 50 L double-layer glass reactor, stirring evenly, slowly adding 8.4 kg of thionyl chloride, controlling the temperature to 30-40 ° C, reflux stirring and reacting for 4 hours, after the reaction is completed, the reaction solution is concentrated to dryness under reduced pressure below 40 ° C to obtain a nicotinic acid intermediate state, adding 33 L of dichloromethane and stirring and dispersing to obtain a dichloromethane solution of the nicotinic acid intermediate state.

[0015] Further, S3 specifically includes: mixing sodium carbonate, dichloromethane, and purified water with the first intermediate and stirring evenly, adding an intermediate dichloromethane solution, and performing an addition reaction under the conditions of temperature control at 10 - 20°C and stirring reaction for 1 h. After the addition reaction is completed, successively perform extraction, adjust the pH to 7.0 ± 0.5, control the temperature to 10 - 30°C, stir and crystallize for 1 h, then filter, wash the filter cake, and decompress and dry the filter cake at 40 - 50°C for not less than 8 h to obtain crude nicorandil.

[0016] On the other hand, the present invention proposes a preservation method for reducing the temperature sensitivity of nicorandil bulk drug. At an ambient temperature of 2 - 8°C, use a medicinal low-density polyethylene light-impermeable packaging material to hermetically package the nicorandil finished product prepared according to the above method.

[0017] Through accelerated test (25°C ± 2°C, 60% ± 5% RH) and long-term (5°C ± 3°C) stability investigation test, it is confirmed that the nicorandil bulk drug finished product prepared by the production method of the present invention can meet the quality standard regulations in all item inspection results after 3 months of accelerated and 6 months of long-term stability investigation. Hermetically preserved in a medicinal low-density polyethylene light-impermeable packaging material at 2 - 8°C, it can ensure a validity period of 24 months.

[0018] The present invention controls the quality of raw materials, reduces the impurities introduced by raw materials, and the yield is between 80 - 90%. The raw materials selected by the present invention have the following advantages: SM1 and SM2 are significant chemical structure fragments of nicorandil and can be identified by common analytical means such as HPLC and GC. SM1 and SM2 are commercially available chemicals, which have been industrially produced in China, can exist stably, can effectively control the quality and storage and transportation, and the possible degradation products and residual impurities have been reduced to an appropriate level without affecting the quality of subsequent products. There are 3 steps from SM1 and SM2 to the nicorandil finished product, including 2 reaction steps and 1 refining step. Each intermediate can exist stably and can obtain high-purity samples through simple purification methods (such as crystallization), and perfect quality control can be carried out. The 3 steps of synthesizing the nicorandil finished product from SM1 and SM2 do not involve the use of Class 1 solvents (solvents known to be carcinogenic and strongly suspected of being harmful to humans and the environment), and the reaction conditions are mild, meeting the requirements of green and safe production. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 : A production process flow chart of an embodiment;

[0020] Figure 2 : A production process flow chart of an embodiment;

[0021] Figure 3 : A production process flow chart of an embodiment;

[0022] Figure 4 : Process flow chart of a production process of an embodiment. Detailed implementation manners

[0023] The following embodiments further illustrate the content of the present invention, but should not be construed as limiting the present invention. Without departing from the spirit and essence of the present invention, modifications or substitutions made to the methods, steps or conditions of the present invention all fall within the scope of the present invention.

[0024] In the following embodiments, mainly based on the synthesis of nicorandil, ethanolamine (SM1) and nicotinic acid (SM2) are used as starting materials. SM1 undergoes a nitration reaction with fuming nitric acid to obtain a first intermediate; the intermediate state generated by the reaction of SM2 with thionyl chloride reacts with the first intermediate to generate a crude product, and the crude product is refined with isopropanol to obtain the finished product of nicorandil. The reaction route is as follows:

[0025]

[0026] It should be noted that the organic impurity situation of the raw material ethanolamine (SM1) is shown in Table 1-1, the inorganic impurity situation of the raw material nicotinic acid (SM2) is shown in Table 1-2, and the material quality control of other raw materials is in accordance with Table 2.

[0027] Table 1-1. Analysis table of organic impurity situation of ethanolamine (SM1)

[0028]

[0029] It should be noted that the boiling point of ethylene oxide is 10.7 °C and it is a gas at room temperature, and the boiling point of SM1 is 170.8 °C. Therefore, in the subsequent rectification and purification process of SM1, ethylene oxide will volatilize and be removed and will not remain in SM1. No organic solvent is used in the synthesis process of SM1, so there will be no residual organic solvent impurities.

[0030] Table 1-2. Analysis table of inorganic impurity situation of nicotinic acid (SM2)

[0031]

[0032] In the following embodiments, the quality of the materials needs to be controlled according to the standards in Table 2.

[0033] Table 2. Material control information

[0034]

[0035] Example 1 Synthesis of the first intermediate

[0036] The process flow of this example is as Figure 1, The materials are as follows in the table. Specifically: Add 9.3 kg of fuming nitric acid and 21 L of dichloromethane into a 100 L double-layer glass reactor, stir evenly, control the temperature below 30 °C, and slowly add a dichloromethane solution of 3.0 kg of ethanolamine (dissolve ethanolamine in 9 L of dichloromethane). After adding, control the temperature at 10 - 30 °C and stir for reaction for 0.5 - 1 h.

[0037] After the reaction is completed, slowly add 7.5 kg of acetic anhydride. After adding, control the temperature at 10 - 30 °C and stir for crystallization for 1 - 2 h, filter, wash the filter cake with an appropriate amount of dichloromethane, collect the filter cake, and dry it under reduced pressure at 50 - 70 °C for not less than 6 h to obtain the first intermediate.

[0038] Table 3. List of materials used in the synthesis of the first intermediate

[0039]

[0040] Yield range: 75 - 85%.

[0041] Synthesis of the crude product in Example 2

[0042] Use the first intermediate prepared in Example 1 and synthesize the crude product according to the process as Figure 2 . The materials are as follows in the table. Specifically, this example is divided into two steps:

[0043] Acylation reaction: Add 5.8 kg of nicotinic acid (SM2), 0.3 kg of dimethylformamide (DMF), and 23 L of dichloromethane into a 50 L double-layer glass reactor, stir evenly, slowly add 8.4 kg of thionyl chloride. After adding, control the temperature at 30 - 40 °C (reflux) and stir for reaction for 4 h. After the reaction is completed, concentrate the reaction solution under reduced pressure to dryness at a temperature below 40 °C to obtain the SM2 intermediate state, add 33 L of dichloromethane and stir to disperse it to obtain a dichloromethane solution of the SM2 intermediate state, and seal it for use.

[0044] Addition reaction: Add 6.5 kg of the first intermediate, 10.4 kg of sodium carbonate, 33 L of dichloromethane, and 65 L of purified water into a 150 L double-layer glass reactor, stir evenly, add the above-mentioned dichloromethane solution of the SM2 intermediate state. After adding, control the temperature at 10 - 20 °C and stir for reaction for 1 h. After the reaction is completed, let it stand for stratification, collect the organic phase, extract the aqueous phase with dichloromethane (13 L × 3), and combine the organic phases. Add 39 L of 1N hydrochloric acid solution to the organic phase, extract and stratify, and collect the aqueous phase. Add an appropriate amount of saturated sodium carbonate solution to the aqueous phase to adjust the pH to neutral (7.0 ± 0.5), control the temperature at 10 - 30 °C and stir for crystallization for 1 h, filter, wash the filter cake with an appropriate amount of purified water, collect the filter cake, and dry it under reduced pressure at 40 - 50 °C for not less than 8 h to obtain the crude product.

[0045] Table 4. List of materials used in the synthesis of the crude product

[0046]

[0047] The yield range of the crude product is 70 - 80%.

[0048] The crude product in Example 3 was refined to obtain the finished product.

[0049] According to the materials in the following table, based on the crude product prepared in Example 2, the finished product was obtained through the refining process as follows. Figure 3 The finished product was obtained.

[0050] Add 5.9 kg of the crude product and 35 L of isopropanol to a 100 L double - layer glass reactor. Heat up to below 50 °C, stir to dissolve, filter, collect the filtrate, cool down to - 10 - 0 °C, stir and crystallize for 4 - 5 h, filter, collect the filter cake, and dry under reduced pressure at 40 - 50 °C for not less than 6 h to obtain the finished product of nicorandil. The yield range is 80 - 90%.

[0051] Table 5. List of materials used for refining the crude product

[0052]

[0053] Storage of the finished product in Example 4

[0054] The finished product prepared in Example 3 was sealed and stored using a medicinal low - density polyethylene opaque packaging material. The storage condition was set at 2 - 8 °C, and the validity period was tentatively set at 24 months.

[0055] Test 1 Stability study test

[0056] According to the "Guidelines for Stability Testing of Drug Substances and Drug Products" (General Chapter 9001, Volume IV of the Chinese Pharmacopoeia 2020 Edition), the "Technical Guidelines for Stability Studies of Chemical Drugs (Drug Substances and Preparations) (Revised)" and other relevant guidelines, and with reference to the relevant regulations of the quality standard of nicorandil, the stability of this product was investigated for items such as appearance, pH value, clarity and color of the solution, related substances, moisture, bacterial endotoxin, microbial limit, and content determination.

[0057] Table 6. Information of test samples

[0058]

[0059]

[0060] Table 7. Detection indicators and detection methods for stability study

[0061]

[0062]

[0063] Table 8. Results of stability investigation

[0064]

[0065]

[0066] Conclusion of stability test: According to the nicorandil quality standard, accelerated (25°C ± 2°C, 60% ± 5% RH) and long-term (5°C ± 3°C) stability investigations were carried out on 3 batches of pilot-scale samples (batch numbers: 221001, 221002, 221003) and 3 batches of validation samples (batch numbers: 230501, 230502, 230503) produced; after 3 months of accelerated and 6 months of long-term stability investigations on the 3 pilot-scale batches, the test results of each item met the requirements of the quality standard; after 6 months of accelerated stability investigation on the 3 pilot-scale batches of samples, the contents of impurity C and total impurities exceeded the specified limits of the quality standard. After 1 month of accelerated stability investigation on the 3 validation batches of samples, the test results of each item met the requirements of the quality standard.

[0067] Test 2. Stress test

[0068] Taking batch number 221001 as the test sample, its stability under high temperature (40°C ± 2°C), light (4500 lx ± 500 lx, near-ultraviolet energy 0.84 w / m2, 25°C ± 2°C), and high humidity (90% ± 5% RH, 5°C ± 3°C) was investigated, and the results are shown in the following table. The specific impurity controlled under the related substances item in the quality standard is impurity C, and the control limit for the remaining known impurities as unknown impurities is 0.10%. All known impurities are listed in the stability investigation results this time to better show the growth trend of each impurity during stability.

[0069] Table 9-1. Results of high temperature stress test Batch number: 221001 Batch quantity: 5 kg Specification: Bulk drug

[0070]

[0071]

[0072] Table 9-2. Results of high humidity stress test Batch number: 221001 Batch quantity: 5 kg Specification: Bulk drug

[0073]

[0074]

[0075] Table 9-3. Results of light stress test Batch number: 221001 Batch quantity: 5 kg Specification: Bulk drug

[0076]

[0077]

[0078]

[0079] Table 9-4. Results of the batch light avoidance stress testBatch number: 221001Batch size: 5 kgSpecification: Bulk drug

[0080]

[0081]

[0082]

[0083] Although the present invention has been described in detail above with general descriptions, specific embodiments and experiments, some modifications or improvements can be made on the basis of the present invention, which are obvious to those skilled in the art. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection of the present invention.

Claims

1. A production method for reducing the temperature sensitivity of Nicorandil API, characterized in that: The synthetic route of the method is as follows: The impurity ethylene glycol in the ethanolamine (SM1) does not exceed 0.062% of the mass fraction of the ethanolamine, and the impurity diethanolamine does not exceed 0.10% of the mass fraction of the ethanolamine.

2. The method for reducing the temperature sensitivity of Nicorandil API according to claim 1, comprising the following steps: S1 uses ethanolamine and nicotinic acid as starting materials, and ethanolamine undergoes nitration reaction with fuming nitric acid to obtain the first intermediate; S2 nicotinic acid and thionyl chloride undergo an acylation reaction to generate an intermediate dichloromethane solution, and then the intermediate dichloromethane solution is subjected to an addition reaction with the first intermediate to generate a crude nicorandil; S3 purifies the crude Nicorandil to obtain a finished Nicorandil product, which specifically comprises the following steps: adding the crude Nicorandil product and isopropanol in a ratio of 1:6 by mass to a reaction vessel, heating to below 50°C, stirring to dissolve, filtering, collecting the filtrate, cooling to -10-0°C, stirring to crystallize for 4-5h, filtering, collecting the filter cake, and drying the filter cake under reduced pressure at 40-50°C for not less than 6h to obtain the finished Nicorandil product.

3. The method for reducing the temperature sensitivity of Nicorandil API according to claim 2, characterized in that: The S1 specifically comprises: slowly adding a dichloromethane solution of ethanolamine to a mixed system of concentrated nitric acid and dichloromethane, and performing a nitration reaction under the conditions of controlling the temperature at 10-30°C and the time at 0.5-1h. After the nitration reaction is completed, acetic anhydride is added, and after a crystallization step, the filter cake is filtered through dichloromethane, washed, and dried to obtain the first intermediate.

4. The method for reducing the temperature sensitivity of Nicorandil API according to claim 2, characterized in that: S1: Add 9.3 kg of fuming nitric acid and 21 L of dichloromethane to a 100 L double-layer glass reactor, stir evenly, control the temperature to below 30°C, slowly add 3.0 kg of dichloromethane solution of ethanolamine, wherein the ethanolamine is dissolved in 9 L of dichloromethane; after the addition, control the temperature to 10-30°C and stir to react for 0.5-1 h; after the reaction is completed, slowly add 7.5 kg of acetic anhydride, after the addition, control the temperature to 10-30°C and stir to crystallize for 1-2 h, filter, wash the filter cake with an appropriate amount of dichloromethane, collect the filter cake, and dry under reduced pressure at 50-70°C for not less than 6 h to obtain the first intermediate.

5. The method for reducing the temperature sensitivity of Nicorandil API according to claim 4, characterized in that: The addition reaction in S3 is achieved by the following steps: add 5.8kg nicotinic acid, 0.3kg dimethylformamide and 23L dichloromethane into a 50L double-layer glass reactor, stir evenly, slowly add 8.4kg thionyl chloride, control the temperature to 30-40°C, reflux and stir for 4h, after the reaction is completed, concentrate the reaction solution to dryness under reduced pressure below 40°C to obtain a nicotinic acid intermediate, add 33L dichloromethane, stir and disperse, and obtain a dichloromethane solution of the nicotinic acid intermediate.

6. The method for reducing the temperature sensitivity of Nicorandil API according to claim 2, characterized in that: S3 specifically comprises: mixing sodium carbonate, dichloromethane and purified water with the first intermediate and stirring evenly, adding the intermediate dichloromethane solution, and performing an addition reaction under the conditions of controlling the temperature at 10-20° C. and stirring for 1 hour. After the addition reaction is completed, extracting, adjusting the pH to 7.0±0.5, controlling the temperature at 10-30° C. and stirring for crystallization for 1 hour, filtering, washing the filter cake, and drying the filter cake under reduced pressure at 40-50° C. for not less than 8 hours to obtain a crude Nicorandil product.

7. The method for reducing the temperature sensitivity of Nicorandil API according to claim 2, characterized in that: The mass ratio of ethanolamine, fuming nitric acid and acetic anhydride in S1 is 3:9.3:7.

5.

8. The method for reducing the temperature sensitivity of Nicorandil API according to claim 2, characterized in that: In the acylation reaction described in S2, the mass ratio of nicotinic acid, thionyl chloride and DMF is 5.8:8.4:0.

3.

9. The method for reducing the temperature sensitivity of Nicorandil API according to claim 2, characterized in that: In the addition reaction described in S2, the mass ratio of the first intermediate and sodium carbonate is 6.5:10.

4.

10. A storage method for reducing the temperature sensitivity of Nicorandil API, characterized in that: The nicorandil product prepared according to any one of claims 1 to 9 is sealed and packaged using a pharmaceutical low-density polyethylene light-proof packaging material at an ambient temperature of 2-8°C.

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