CN104059085B - 一种氨苄西林晶体及其制备方法 - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
- C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
- C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
- C07D499/64—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms
- C07D499/68—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms with aromatic rings as additional substituents on the carbon chain
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/18—Separation; Purification
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明属于兽药技术领域，具体公开了一种氨苄西林晶体及其制备方法。使用Cu-Kα射线、以2θ角度表示的X-射线粉末衍射在11.30±0.2、12.20±0.2、14.08±0.2、15.82±0.2、18.70±0.2、20.18±0.2、22.13±0.2和23.82±0.2处存在特征峰。将氨苄西林投入到有机溶剂中，在氮气保护下边搅拌边加热回流溶解，溶解澄清后趁热滤去不溶物，加入氨水调节溶液pH值至4.9-5.1，停止搅拌，将滤液冷却至0-5℃，以100-130rppm速率重新搅拌析晶，析晶后的溶液，加入稳定剂，搅拌分散均匀后，经均质制成200~500纳米混悬液，混悬液经流化干燥后即得目标氨苄西林晶体；所述有机溶剂为乙酸乙酯、丙酮、异丙醇、MIBK、二氯甲烷中的一种或两种以上的组合。
Description
技术领域
本发明属于兽药技术领域，具体涉及一种氨苄西林晶体及其制备方法。
背景技术
氨苄西林是第一个半合成的广谱的青霉素，是将青霉素G苄基上的氢以游离氨基取代，因其有吸电子的氨基而能够耐酸。但口服吸收的效果差，不能够耐酶为它的缺点。氨苄西林为一种半合成青霉素，耐酸，且血清蛋白的结合率低，尿浓度较高，并能渗入到痰液达到杀菌的作用。它具有天然青霉素的抗菌谱性，主要用在治疗呼吸道、泌尿道及软组织方面的感染，尤其对于肺炎特别好的疗效。对于化脓性链球菌、流感嗜血杆菌、肺炎球菌、肺炎杆菌及大肠埃希菌等茧兰阳性及阴性菌有比较好的效果。氨苄西林又名氨苄青霉素，化学名：(2S,5R,6R)-3,3-二甲基-6-[(R)-(-)-2-氨基-2-苯基乙酰氨基]-7-氧代-4-硫杂-1-氮杂双环[3.2.0]庚烷-2-甲酸三水合物，分子式：C16H19N3O4S·3H2O，结构式：
本品为为两性化合物，游离酸为白色结晶性粉末(含3分子结晶水)，味微苦，在水中微溶，在乙醇、氯仿、乙醚或不挥发性油中不溶；在稀碱或稀酸溶液中溶解。氨节西林最终大部分都是以制剂的形势供给医疗的应用，氨节西林的晶型与疗效关系密切，对氨节西林的理化性质、生物的利用度、相关制剂的质量等一些方面都有比较大的影响。
发明内容
本发明的目的在于提供一种氨苄西林晶体及其制备方法。
为实现上述目的，本发明采取的技术方案如下：
一种氨苄西林晶体：使用Cu-Kα射线、以2θ角度表示的X-射线粉末衍射在11.30±0.2、12.20±0.2、14.08±0.2、15.82±0.2、18.70±0.2、20.18±0.2、22.13±0.2和23.82±0.2处存在特征峰，粒径在200~500纳米之间。
所述氨苄西林晶体的制备方法：将氨苄西林投入到有机溶剂中，在氮气保护下边搅拌边加热回流溶解，溶解澄清后趁热滤去不溶物，加入氨水调节溶液pH值至4.9-5.1，停止搅拌，将滤液冷却至0-5℃，以100-130rppm速率重新搅拌析晶，析晶后的溶液，加入稳定剂，搅拌分散均匀后，经均质制成200~500纳米混悬液，混悬液经流化干燥后即得目标氨苄西林晶体；所述有机溶剂为乙酸乙酯、丙酮、异丙醇、MIBK(甲基异丁酮)、二氯甲烷中的一种或两种以上的组合。
将氨苄西林投入到有机溶剂中时，以ml/g计，有机溶剂的使用量为氨苄西林的20倍以上，最佳为30-50倍。
所述稳定剂为泊洛沙姆、十二烷基硫酸钠钠、聚乙烯醇中的一种或两种以上的混合物，稳定剂在析晶后的溶液中的质量百分含量为5-20%。
所述均质的条件为：均质压力500~1000bar、循环3~12次。
本发明过程中，曾多次尝试有利于晶型稳定的有机溶剂，意外地发现，当用足倍量的特殊溶剂、恒定速率的搅拌析晶操作，是获得目标产物的关键。
氨苄西林作为已知化合物，本发明氨苄西林晶体与现有氨苄西林的化学组成相同，具有与现有氨苄西林本身相同的用途，比如临床上主要用于泌尿系统、呼吸系统及软组织方面的感染。
本发明的优点：本发明氨苄西林晶体水中溶解性好，提高了氨苄西林的溶解度，溶出度和生物利用度高，药物活性增强。
具体实施方式
以下实施例主要是用于进一步说明本发明，而不是限制本发明的范围；其中，原料药氨苄西林参考文献（王金良.氨苄西林结晶工艺研究.《河北科技大学》2011年，确定的工艺条件：氨水浓度15%，氨水滴加速度2ml/min，结晶温度5℃，搅拌速度100r/min，养晶时间2h）制备获得。
实施例1：
将氨苄西林投入到40倍（以ml/g计）的异丙醇中，在氮气保护下边搅拌边加热回流约20分钟，溶解澄清，趁热滤去不溶物；加入氨水调节溶液pH值至为5.1，停止搅拌，将滤液冷却至5℃，并以100rppm的速率重新搅拌析晶12小时，析晶后的溶液，加入泊洛沙姆188至其在溶液中的质量百分含量为10wt%，搅拌分散均匀后，经高压均质机的高压泵吸入泵体，在800bar的均质压力下，循环10次，制成300纳米的混悬液，混悬液经流化床干燥后即得纳米级氨苄西林晶体，使用Cu-Kα射线、以2θ角度表示的X-射线粉末衍射特征峰数据为：11.30、12.20、14.08、15.82、18.70、20.18、22.13、23.82。
实施例2：
将氨苄西林投入到30倍（以ml/g计）的MIBK中，在氮气保护下边搅拌边加热回流约20分钟，溶解澄清后趁热滤去不溶物；加入氨水调节溶液pH值至4.9，停止搅拌，将滤液冷却至0℃，并以110rppm的速率重新搅拌析晶18小时，析晶后的溶液，加入十二烷基硫酸钠至其在溶液中的质量百分含量为5wt%，搅拌分散均匀后，经高压均质机的高压泵吸入泵体，在1000bar的均质压力下，循环4次，制成200纳米的混悬液，混悬液经流化床干燥后即得纳米级氨苄西林晶体，其X-射线粉末衍射特征峰数据与实施例1一致。
实施例3：
将氨苄西林投入到30倍（以ml/g计）的二氯甲烷-乙酸乙酯混合溶剂（体积比1：1）中，在氮气保护下边搅拌边加热回流约15分钟，溶解澄清，趁热滤去不溶物；加入氨水调节溶液pH值至5.0，停止搅拌，将滤液冷却至2℃，并以130rppm的速率重新搅拌析晶20小时，过滤，析晶后的溶液，加入聚乙烯醇至其在溶液中的质量百分含量为20wt%，搅拌分散均匀后，经高压均质机的高压泵吸入泵体，在500bar的均质压力下，循环12次，制成400纳米的混悬液，混悬液经流化床干燥后即得纳米级氨苄西林晶体，其X-射线粉末衍射特征峰数据与实施例1一致。
实施例4：
将氨苄西林投入到30倍（以ml/g计）的异丙醇-丙酮混合溶剂（体积比1：1）中，在氮气保护下边搅拌边加热回流约15分钟，溶解澄清，趁热滤去不溶物；加入氨水调节溶液pH值至5.0，停止搅拌，将滤液冷却至5℃，并以120rppm的速率重新搅拌析晶20小时，过滤，析晶后的溶液，加入聚乙烯醇至其在溶液中的质量百分含量为20wt%，搅拌分散均匀后，经高压均质机的高压泵吸入泵体，在500bar的均质压力下，循环12次，制成400纳米的混悬液，混悬液经流化床干燥后即得纳米级氨苄西林晶体，其X-射线粉末衍射特征峰数据与实施例1一致。
溶解性试验
取未处理过的氨苄西林（按王金良.氨苄西林结晶工艺研究.《河北科技大学》2011年，确定的工艺条件制备）和实施例1-4制备的氨苄西林纳米晶体各1g，加水50ml，25℃下振摇10次，观察药物在水中的分散性。静置6h后取饱和溶液，过滤，采用高效液相色谱法（2010版中国药典第二部氨苄西林）测定滤液中氨苄西林的含量，结果见下表，可知：本发明氨苄西林晶体水中溶解性好，提高了氨苄西林的溶解度，因而其溶出度和生物利用度高、药物活性增强。
Claims (5)
1.一种氨苄西林晶体的制备方法，该氨苄西林晶体使用Cu-Kα射线、以2θ角度表示的X-射线粉末衍射在11.30±0.2、12.20±0.2、14.08±0.2、15.82±0.2、18.70±0.2、20.18±0.2、22.13±0.2和23.82±0.2处存在特征峰，粒径在200~500纳米之间，其特征在于：将氨苄西林投入到有机溶剂中，在氮气保护下边搅拌边加热回流溶解，溶解澄清后趁热滤去不溶物，加入氨水调节溶液pH值至4.9-5.1，停止搅拌，将滤液冷却至0-5℃，以100-130rppm速率重新搅拌析晶，析晶后的溶液，加入稳定剂，搅拌分散均匀后，经均质制成200~500纳米混悬液，混悬液经流化干燥后即得目标氨苄西林晶体；所述有机溶剂为乙酸乙酯、丙酮、异丙醇、MIBK、二氯甲烷中的一种或两种以上的组合。
2.如权利要求1所述的制备方法，其特征在于：将氨苄西林投入到有机溶剂中时，以ml/g计，有机溶剂的使用量为氨苄西林的20倍以上。
3.如权利要求2所述的制备方法，其特征在于：有机溶剂的使用量为氨苄西林的30-50倍。
4.如权利要求1所述的制备方法，其特征在于：所述稳定剂为泊洛沙姆、十二烷基硫酸钠钠、聚乙烯醇中的一种或两种以上的混合物，稳定剂在析晶后的溶液中的质量百分含量为5-20%。
5.如权利要求1所述的制备方法，其特征在于：所述均质的条件为：均质压力500~1000bar、循环3~12次。
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