CN115093340B - 一种溴芬酸钠倍半水合物的制备方法 - Google Patents
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- HZFGMQJYAFHESD-UHFFFAOYSA-M bromfenac sodium Chemical compound [Na+].NC1=C(CC([O-])=O)C=CC=C1C(=O)C1=CC=C(Br)C=C1 HZFGMQJYAFHESD-UHFFFAOYSA-M 0.000 title claims abstract description 10
- 229950011307 bromfenac sodium sesquihydrate Drugs 0.000 title abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 36
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims abstract description 26
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims abstract description 19
- 229960003655 bromfenac Drugs 0.000 claims abstract description 19
- ZBPLOVFIXSTCRZ-UHFFFAOYSA-N bromfenac Chemical compound NC1=C(CC(O)=O)C=CC=C1C(=O)C1=CC=C(Br)C=C1 ZBPLOVFIXSTCRZ-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 19
- 239000011734 sodium Substances 0.000 claims abstract description 19
- 238000001035 drying Methods 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 239000012046 mixed solvent Substances 0.000 claims description 11
- 230000001105 regulatory effect Effects 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- 229960002716 bromfenac sodium Drugs 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000012265 solid product Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 2
- 238000004537 pulping Methods 0.000 claims description 2
- 238000000967 suction filtration Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 3
- 239000012043 crude product Substances 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract description 6
- 239000002904 solvent Substances 0.000 abstract description 6
- 239000012535 impurity Substances 0.000 abstract description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 abstract description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 4
- 150000003839 salts Chemical class 0.000 abstract description 4
- 239000003963 antioxidant agent Substances 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 238000002425 crystallisation Methods 0.000 abstract description 2
- 230000008025 crystallization Effects 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 229910017053 inorganic salt Inorganic materials 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 4
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- CASOXAYOCHCWQU-UHFFFAOYSA-N butan-2-one;ethanol Chemical compound CCO.CCC(C)=O CASOXAYOCHCWQU-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000001760 anti-analgesic effect Effects 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 229940122204 Cyclooxygenase inhibitor Drugs 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010039705 Scleritis Diseases 0.000 description 1
- SOYCMDCMZDHQFP-UHFFFAOYSA-N amfenac Chemical class NC1=C(CC(O)=O)C=CC=C1C(=O)C1=CC=CC=C1 SOYCMDCMZDHQFP-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
- C07C227/42—Crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
本发明公开了一种溴芬酸钠倍半水合物的制备方法。本发明通过对溴芬酸钠析晶溶剂、干燥温度等制备条件的优化,仅使用环保溶剂水、乙醇、丁酮就实现了纯度大于99.5%,单个杂质小于0.1%的溴芬酸钠倍半水合物的制备。本发明避免了醚类试剂的使用,环境效益好;避免了丙酮的使用,减少苯类溶剂的引入;避免抗氧化剂的使用,减少了无机盐的引入。本发明解决了目前制备溴芬酸钠倍半水合物的工艺纯度低、单杂高、收率低、无机盐残留高等技术问题。
Description
技术领域
本发明属于医药技术领域,具体涉及一种溴芬酸钠倍半水合物的制备方法。
背景技术
溴芬酸钠是2-氨基-3-苯甲酰基苯乙酸类衍生物,由日本Senju公司开发,具有强力消炎、镇痛作用,适用于外眼部及前眼部的炎症性疾病的对症治疗(结膜炎、巩膜炎、术后炎症)。与同类药物相比,其消炎镇痛作用是其他同类消炎药的10倍,是最有效的环氧合酶抑制剂。临床研究表明,溴芬酸钠滴眼液具有良好的耐受性,对眼内压无影响,能够有效降低眼部副作用的发生几率,给药方式简便,患者接受度高,具有广阔的市场前景。
溴芬酸钠有三种主要晶型:无水物、一水化合物和倍半水合物。
研究表明,溴芬酸钠无水物、一水化合物具有引湿性,稳定性较差,溴芬酸钠倍半水合物无引湿性,稳定性好,制剂选用的为溴芬酸钠倍半水合物。能够合成出具有优良性能的溴芬酸钠倍半水合物原料药,满足临床治疗外眼部及前眼部的炎症性疾病的需要具有重大意义。
溴芬酸钠倍半水合物具有如下结构:
发明内容
本发明的目的是提供一种溴芬酸钠倍半水合物的制备方法,解决目前制备溴芬酸钠倍半水合物的工艺纯度低、单杂高、收率低、无机盐残留高等技术问题。
所述的溴芬酸钠倍半水合物的制备方法为:
1)将溴芬酸钠粗品用乙醇常温打浆,抽滤,滤饼干燥;
2)将水、乙醇、丁酮混合溶剂加热到30-40℃,然后加入步骤1)干燥后的固体产物,搅拌溶解;使用乙酸调节pH至8.0-10.0,在30-40℃下滴加5倍体积的乙醇、丁酮混合溶剂;降温至15-25℃,调节转速至10-40rpm,搅拌10h;
3)最后抽滤,20-50℃干燥,得到溴芬酸钠倍半水合物。
步骤1)所用的乙醇含水量不超过10%。
步骤1)所述的干燥温度为40-50℃。
所述步骤2)的水、乙醇、丁酮混合溶剂中水、乙醇与丁酮的体积比为1-3:3:3。
所述步骤2)中步骤1)干燥后的固体产物加入水、乙醇、丁酮混合溶剂的投加量为0.1-0.5g/mL,优选0.2g/mL。
所述步骤2)的乙醇、丁酮混合溶剂中乙醇与丁酮的体积比为1:1。
所述步骤2)乙酸调节pH至9.0-9.5。
所述步骤2)降温后,调节转速至10-15rpm。
所述步骤3)的干燥温度为40-45℃。
与现有技术相比,本发明具有以下有益效果:通过对溴芬酸钠析晶溶剂、干燥温度等制备条件的优化,仅使用环保溶剂水、乙醇、丁酮就实现了纯度大于99.5%,单个杂质小于0.1%的溴芬酸钠倍半水合物的制备。本发明避免了醚类试剂的使用,环境效益好;避免了丙酮的使用,减少苯类溶剂的引入;避免抗氧化剂的使用,减少了无机盐的引入。
具体实施方式
下面结合具体实施方式对本发明进行进一步的详细描述,给出的实施例仅为了阐述本发明,而不是为了限制本发明的范围。
实施例1
(1)称量10.0g溴芬酸钠粗品,加入到100ml 95%乙醇中,常温打浆2h,使用砂芯漏斗抽滤,得滤饼于50℃干燥10h,得溴芬酸钠9.5g。
(2)配制体积比为1:1的乙醇丁酮混合溶剂。
(3)量取乙醇丁酮混合溶剂40ml,加入10ml纯化水,搅拌混合均匀;加入步骤(1)得到的溴芬酸钠9.5g,加热到40℃,搅拌溶解;使用乙酸调节pH至9.5,保温40℃,再滴加5倍体积的乙醇丁酮混合溶剂;降温至20℃,调节转速至15rpm,搅拌10h。
(4)最后抽滤,45℃干燥,得到溴芬酸钠倍半水合物8.75g,质量收率为87.5%,纯度为99.72%,单个最大杂质的含量为0.041%,水分含量为7.53%。
以上的仅是本发明的优选实施方式,应当指出,对于本领域的研究人员来说,在不脱离本发明创造构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。
Claims (4)
1.一种溴芬酸钠倍半水合物的制备方法,其特征在于,所述的制备方法的具体步骤为:
1)将溴芬酸钠粗品用乙醇常温打浆,抽滤,滤饼40-50℃干燥;
2)将体积比为1-3:3: 3的水、乙醇、丁酮混合溶剂加热到30-40℃,然后按0.1-0.5g/mL加入步骤1)干燥后的固体产物,搅拌溶解;使用乙酸调节pH至8.0-10.0,在30-40℃下滴加5倍体积的乙醇、丁酮混合溶剂;降温至15-25℃,调节转速至10-40rpm,搅拌10h;
3)最后抽滤,20-50℃干燥,得到溴芬酸钠倍半水合物;
步骤1)所用的乙醇含水量不超过10%;
所述步骤2) 的乙醇、丁酮混合溶剂中乙醇与丁酮的体积比为1:1。
2.根据权利要求1所述的制备方法,其特征在于,所述步骤2)乙酸调节pH至9.0-9.5。
3.根据权利要求1所述的制备方法,其特征在于,所述步骤2)降温后,调节转速至10-15rpm。
4.根据权利要求1所述的制备方法,其特征在于,所述步骤3)的干燥温度为40-45℃。
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EP0221753A2 (en) * | 1985-10-28 | 1987-05-13 | A.H. ROBINS COMPANY, INCORPORATED (a Delaware corporation) | Transdermal treatment for pain and inflammation with 2-amino-3-aroylbenzeneacetic acids, salts and esters |
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