Method for preparing high-purity nifedipine

Abstract

The invention belongs to the technical field of pharmacy, and discloses a method for recovering nifedipine from nifedipine mother liquor and application. Carrying out reduced pressure distillation on the nifedipine mother liquor to recover part of ethanol, and then carrying out cooling crystallization, suction filtration and drying to obtain a nifedipine crude product; the method comprises the following steps: adding an ester solvent into a nifedipine crude product, heating, refluxing, dissolving, cooling until a large amount of solids are separated out, distilling under reduced pressure, reheating, cooling, crystallizing, carrying out suction filtration, and drying to obtain a nifedipine refined product. According to the method, the emission of three wastes is reduced, the treatment cost of the three wastes is reduced, the resource utilization rate is improved, green production is realized, and in addition, the nifedipine product recovered and produced by the method is good in purity and high in yield and can meet the drug registration requirements of most of countries.

Description

Technical Field

[0001] The invention relates to a method for preparing high-purity nifedipine by recovering nifedipine mother liquor, and belongs to the technical field of pharmaceuticals. Background Art

[0002] Nifedipine, chemical name is 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylic acid dimethyl ester, yellow crystalline powder, the structural formula is shown below. Nifedipine is a dihydropyridine calcium antagonist, which has the effect of inhibiting the influx of calcium ions, relaxing blood vessels and dilating coronary arteries, inhibiting vasospasm, and is used to prevent and treat angina pectoris caused by coronary heart disease, especially variant angina pectoris and angina pectoris caused by coronary artery spasm. Nifedipine is also used to treat patients with angina pectoris suffering from obstructive respiratory diseases. It not only has no adverse effects on respiratory function, but also has better efficacy than beta receptor antagonists. In addition, nifedipine is widely used in the treatment of hypertension in clinical practice. Nifedipine has significant clinical efficacy and has very good market application prospects.

[0003]

[0004] In order to reduce the discharge of three wastes, reduce the cost of three wastes treatment, improve resource utilization, and achieve green production, the mother liquor is usually recycled: first, the mother liquor solvent is recycled to achieve solvent recycling; second, the active ingredients in the mother liquor are recycled to improve atomic utilization. The solvent used in the purification method of the raw material drug nifedipine reported in patents CN102382040A, CN103204814A, CN108752263A, CN109232389A, CN111253304A, CN113234009A, CN113248421A, CN113582913A, CN114835633A and CN115353485A is a single alcohol solvent. Since these refining solvents are highly polar solvents, they have poor effects on removing small polar impurities in nifedipine. In addition, there is obvious enrichment of impurities in the recovered mother liquor of nifedipine. Therefore, there are still differences between the refining method of the raw material nifedipine and the refining method of nifedipine in the mother liquor. The high-purity nifedipine sample that meets the pharmacopoeia standards cannot be obtained by refining the nifedipine mother liquor using the methods reported in the above patents.

[0005] A method for recovering nifedipine mother liquor reported in patent CN115353485A is as follows: crystallize nifedipine methanol mother liquor to obtain a primary crude product; mix the primary crude product and ethyl acetate for pulping, and then perform a first solid-liquid separation to obtain a secondary crude product, and sequentially decolorize and recrystallize the secondary crude product from methanol. This method is for the recovery of nifedipine methanol mother liquor, and undergoes a three-step operation procedure of crystallization, pulping and recrystallization, with long operation steps and complicated procedures. However, for the removal of small polar impurities, the secondary crude product is pulped with ethyl acetate. Although the pulping operation can effectively remove small polar impurities adsorbed on the surface of nifedipine crystals, it has a poor effect on the removal of small polar impurities wrapped inside the crystals. Although methanol is further used for recrystallization, the purity of the prepared sample is still ≤99.8%. Generally, the higher the purity, the more stable it is during storage and transportation, and it is not easy to deteriorate or fail. The higher the purity of the drug, the higher the content of its active ingredient, so that it can more effectively exert its therapeutic effect, reduce the risk of side effects, and improve the safety of medication. The limit of organic impurities in APIs is usually 0.1%, but the limit of highly toxic genotoxic impurities is much lower than 0.1%, which may be only one part per million. Currently, the safety of genotoxic impurities is increasingly valued by the pharmaceutical industry. Drug regulatory agencies such as the FDA and EMA have established a series of testing standards and control measures.

[0006] In summary, the present invention has good purification effect, simple process operation, is suitable for large-scale industrial production, is green and environmentally friendly, can meet the drug registration requirements of almost all countries, and has great practical application value. Summary of the invention

[0007] Technical problem: The raw material nifedipine produces a mother liquor after refining. In order to improve the utilization efficiency of the mother liquor, the nifedipine in the mother liquor needs to be recycled. However, there are a large number of small polar impurities in the mother liquor, and the impurities are also enriched, which brings difficulties to the recycling of nifedipine. To address this problem, a new method for recovering nifedipine mother liquor to prepare nifedipine has been developed. After crystallization and recrystallization, the operation steps are simple, and the purity of the recovered nifedipine is greater than 99.9%, with a high yield, which improves production efficiency, effectively reduces waste liquid discharge and resource waste, and provides a solution for the reuse of nifedipine in industrial production mother liquor.

[0008] Concept of the present invention: The present invention first performs vacuum distillation-cooling coupled crystallization on the nifedipine mother liquor to obtain a crude product, and then dissolves the sample under heating reflux conditions using an ester solvent (ethyl acetate or isopropyl acetate) to ensure that impurities wrapped inside the crystals can be completely released, and then accurately controls the crystallization process conditions to ensure that impurities can be effectively removed to the greatest extent, so that the purity of the prepared sample is greater than 99.9% without further refining, thereby ensuring that the prepared product is safe, effective and quality-controlled.

[0009] Step 1: Crude Nifedipine The nifedipine mother liquor is first subjected to reduced pressure distillation to recover part of the ethanol, then cooled for crystallization, filtered and dried to obtain a crude nifedipine product.

[0010] The method can first reduce the pressure on a certain amount of nifedipine mother liquor to recover part of the ethanol, and the mass of the recovered ethanol is 70% to 90% of the mass of the mother liquor.

[0011] The cooling and crystallization temperature used in the method is 0°C-20°C, preferably 10°C-15°C, the cooling rate is 10°C / h-20°C / h, and the pulping is kept at this temperature for 1h-3h.

[0012] The drying temperature of this method is 45℃-55℃, and the drying time is 7h-9h.

[0013] Step 2: Nifedipine Boutique Add an appropriate amount of ester solvent to the crude nifedipine, heat under reflux to dissolve, cool until a large amount of solid precipitates, distill under reduced pressure, return to the temperature, cool and crystallize, filter and dry to obtain the refined nifedipine.

[0014] Preferably, the ester solvent used is ethyl acetate or isopropyl acetate.

[0015] Preferably, the mass ratio of nifedipine to the ester solvent is 1:7-1:9.

[0016] Preferably, the temperature at which a large amount of solid is precipitated is 35° C.-45° C., the cooling rate is 5° C. / h-10° C. / h, and the crystallization is carried out at this temperature for 1 h-2 h.

[0017] Preferably, part of the ester solvent is recovered by vacuum distillation, and the mass of the recovered ester solvent is 45%-70% of the mass of the mother liquor.

[0018] Preferably, the temperature during the warming process is 65°C-75°C, and stirring is continued at this temperature for 1h-2h.

[0019] Preferably, the temperature during cooling and crystallization is 0°C-15°C, preferably 5°C-10°C, the cooling rate is 10°C / h-20°C / h, and stirring is continued at this temperature for 2h-3h.

[0020] Preferably, the drying temperature is 45° C.-55° C., and the drying time is 5 h-8 h.

[0021] The technical effect to be achieved by the present invention is as follows: through the technical scheme of the present invention, part of the nifedipine in the nifedipine waste liquid can be recycled and utilized; secondly, the ethanol produced in the recycling process can be used for the production of nifedipine, and the ester solvent produced can be used for the recovery of nifedipine in the next waste liquid, thereby reducing the environmental pollution pressure of waste liquid discharge; meanwhile, the recycling of the solvent recovery process brings huge economic benefits, promotes industrial production, and brings green environmental protection; in addition, the nifedipine product recycled and produced by this method has good purity and high yield, and can meet the drug registration requirements of most countries. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is the HPLC chromatogram of the fine product of nifedipine prepared in Example 1; Figure 2 This is the HPLC chromatogram of the fine product of nifedipine prepared in Example 2; Figure 3 This is the HPLC chromatogram of the fine product of nifedipine prepared in Example 3; Figure 4 This is the HPLC chromatogram of the nifedipine concentrate prepared in Example 4. DETAILED DESCRIPTION

[0023] The detection method for nifedipine-related substances adopts high performance liquid chromatography, and is determined in accordance with the general rules of the fourth part of the 2020 edition of the Chinese Pharmacopoeia 0512. Take about 50 mg of nifedipine, accurately weigh it, put it in a 50 mL volumetric flask, add 15 mL of methanol to dissolve it by ultrasound, dilute it to the scale with the mobile phase, and shake it well.

[0024] Chromatographic conditions: Use octadecylsilane bonded silica gel as filler (Waters SymmetryShield RP184.6×150mm, 3.5μm or chromatographic column with equivalent separation performance); methanol-acetonitrile-water (25:25:50) as mobile phase; detection wavelength is 235nm; column temperature is 30℃; injection volume is 20μL. Example 1

[0025] 3000g of nifedipine mother liquor (content about 2%) was first decompressed to recover 80% of ethanol, then cooled to 5-10℃ at a cooling rate of 20℃ / h, kept at this temperature for crystallization for 3h, filtered, and dried at 45-55℃ for 9h to obtain crude nifedipine yellow crystalline solid powder with a yield of 1.60% and HPLC purity of 96.82%. Add 48g of crude nifedipine to 336g of ethyl acetate, heat under reflux to dissolve, cool to 35-40℃ at a cooling rate of 10℃ / h, keep at this temperature for crystallization for 2h, recover 70% of ethyl acetate by vacuum distillation, then heat back to 70-75℃ and keep for 2h, then cool to 0-5℃ at a cooling rate of 20℃ / h and keep for crystallization for 3h, filter, dry at 45-55℃ for 8h, and obtain 44.41g of nifedipine fine yellow crystalline solid powder with a yield of 92.54% and HPLC purity of 99.91%. Example 2

[0026] 5000g of nifedipine mother liquor (content about 2%) was first concentrated under reduced pressure to recover 70% of ethanol, then cooled to 10-15℃ at a cooling rate of 15℃ / h, kept at this temperature for crystallization for 2h, filtered, and dried at 45-55℃ for 7h to obtain crude nifedipine yellow crystalline solid powder with a yield of 1.48% and HPLC purity of 97.21%. Add 74g of crude nifedipine to 665g of ethyl acetate, heat to reflux to dissolve, cool to 40-45℃ at a cooling rate of 5℃ / h, keep at this temperature for crystallization for 2h, recover 45% of ethyl acetate by vacuum distillation, then heat back to 70-75℃ and keep warm for 2h, then cool to 5-10℃ at a cooling rate of 10℃ / h and keep warm for crystallization for 3h, filter, and dry at 45-55℃ for 5h to obtain 63.83g of nifedipine fine yellow crystalline solid powder with a yield of 86.26% and HPLC purity of 99.97%. Example 3

[0027] 4000g of nifedipine mother liquor (content about 2%) was first concentrated under reduced pressure to recover 90% of ethanol, then cooled to 0℃-5℃ at a cooling rate of 10℃ / h, kept at this temperature for crystallization for 1h, filtered, and dried at 45℃-55℃ for 9h to obtain crude nifedipine yellow crystalline solid powder with a yield of 1.75% and HPLC purity of 96.08%. Add 70g of crude nifedipine to 536g of isopropyl acetate, heat under reflux to dissolve, cool to 40-45℃ at a cooling rate of 5℃ / h and keep warm for crystallization for 1.5h, recover 50% of isopropyl acetate by vacuum distillation, then heat back to 65-70℃ and keep warm for slurrying for 1.5h, then cool to 10-15℃ at a cooling rate of 20℃ / h and keep warm for crystallization for 2h, filter with suction, dry at 45-55℃ for 6h, and obtain 62.28g of nifedipine fine yellow crystalline solid powder with a yield of 88.97% and HPLC purity of 99.93%. Example 4

[0028] 2000g of nifedipine mother liquor (content about 2%) was first concentrated under reduced pressure to recover 85% of ethanol, then cooled to 5-10°C at a cooling rate of 15°C / h, kept warm for 1h for crystallization, filtered, and dried at 45-55°C for 8h to obtain crude nifedipine in the form of yellow crystalline solid powder, with a yield of 1.65% and an HPLC purity of 96.65%. Add 33g of crude nifedipine to 235g of isopropyl acetate, heat to reflux and dissolve, cool to 35-40℃ at a cooling rate of 10℃ / h, keep stirring at this temperature for crystallization for 2h, recover 65% of isopropyl acetate by vacuum distillation, then heat back to 60-65℃, keep stirring for 1h, then cool to 5-10℃ at a cooling rate of 15℃ / h, keep crystallization for 1.5h, filter, dry at 45-55℃ for 7h, and obtain 30.97g of nifedipine fine yellow crystalline solid powder with a yield of 93.86% and HPLC purity of 99.99%.

Claims

1. A method for recovering nifedipine from a nifedipine mother liquor, characterized in that The following steps are involved: Step 1: Preparation of crude nifedipine: First, the nifedipine mother liquor is distilled under reduced pressure to recover part of the ethanol, then cooled for crystallization, filtered, and dried to obtain a crude nifedipine; Step 2: Nifedipine fine product: add ester solvent to the crude nifedipine, heat to reflux to dissolve, cool to a large amount of solid precipitates, distill under reduced pressure, return to the temperature, cool to crystallize, filter and dry to obtain nifedipine fine product.

2. The method according to claim 1, characterized in that Step 1: Recover part of the ethanol by vacuum distillation, wherein the mass of the recovered ethanol is 70% to 90% of the mass of the mother liquor.

3. The method according to any one of claims 1 or 2, characterized in that The cooling and crystallization temperature used in step 1 is 0°C-20°C, the cooling rate is 10°C / h-20°C / h, and stirring is continued at this temperature for 1h-3h. The drying temperature of this method is 45°C-55°C, and the drying time is 7h-9h.

4. The method according to any one of claims 1 or 2, characterized in that The cooling and crystallization temperature used in step 1 is 10°C-15°C.

5. The method according to claim 1, characterized in that The ester solvent used in step 2 is ethyl acetate or isopropyl acetate.

6. The method according to claim 1, characterized in that In step 2, the mass ratio of nifedipine to the ester solvent is 1:7-1:

9.

7. The method according to claim 1, characterized in that Step 2: Cooling to a temperature of 35°C-45°C when a large amount of solid precipitates, with a cooling rate of 5°C / h-10°C / h, and keeping at this temperature for crystallization for 1h-2h.

8. The method according to claim 1, characterized in that Step 2: recover part of the ester solvent by distillation under reduced pressure, wherein the mass of the recovered ester solvent is 45%-70% of the mass of the mother liquor.

9. The method according to claim 1, characterized in that The temperature during the return to temperature in step 2 is 65°C-75°C, and stirring is continued at this temperature for 1h-2h.

10. The method according to claim 1, characterized in that Step 2: The temperature during cooling and crystallization is 0°C-15°C, preferably 5°C-10°C, the cooling rate is 10°C / h-20°C / h, and stirring is continued at this temperature for 2h-3h, the drying temperature is 45°C-55°C, and the drying time is 5h-8h.

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