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CN104059086B - 一种阿莫西林晶体及其制备方法 - Google Patents

一种阿莫西林晶体及其制备方法 Download PDF

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CN104059086B
CN104059086B CN201410274773.9A CN201410274773A CN104059086B CN 104059086 B CN104059086 B CN 104059086B CN 201410274773 A CN201410274773 A CN 201410274773A CN 104059086 B CN104059086 B CN 104059086B
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amoxicillin
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amoxycilline trihydrate
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CN104059086A (zh
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胡帅
李凌峰
管倩
李坤鹏
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Henan Muxiang Biotechnology Co ltd
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Henan Soar Veterinary Pharmaceutical Co Ltd
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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
    • 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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Abstract

本发明属于兽药技术领域，具体公开了一种阿莫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11.20±0.2、12.30±0.2、16.84±0.2、17.08±0.2、18.80±0.2、22.58±0.2、23.14±0.2和26.85±0.2处存在特征峰。将阿莫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20-50℃，以120-280rppm速率重新搅拌析晶，过滤，滤饼用2-4℃的前述有机溶剂洗涤，35-60℃真空干燥至恒重，即得目标阿莫西林晶体；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

一种阿莫西林晶体及其制备方法
技术领域
本发明属于兽药技术领域，具体涉及一种阿莫西林晶体及其制备方法。
背景技术
阿莫西林是广谱青霉素类抗生素，于1972年由BEECHAM首次推向市场。1981年，BEECHAM又推出了其与克拉维酸钾的复方制剂，可以作用于产β-内酰胺酶的微生物，更加延伸了其抗菌谱。阿莫西林已被列入联合国卫生组织的基本药物清单。阿莫西林又名羟氨苄青霉素，化学名:(2S,5R,6R)-3,3-二甲基-6-[(R)-(-)-2-氨基-2-(4-羟基苯基)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：C16H19N3O5S·3H2O，结构式：
本品为白色或类白色结晶性粉末，味微苦，微溶于水，不溶于乙醇。阿莫西林能抑制细菌外层细胞壁的合成，对革兰氏阳性和阴性菌有较强的杀菌作用。对革兰氏阳性菌的抗菌作用与Penicillin相同或较低，对革兰氏阴性菌如淋球菌、流感杆菌、百日咳杆菌、大肠杆菌、布氏杆菌等的作用较强，临床上主要用于泌尿系统、呼吸系统、胆道等的感染。1987年该药首次进入世界销售额领先的前50种畅销药行列，位居第31位，销售额为2.75亿美元，1996年位居第15位，销售额高达13.84亿美元。到目前为止，已连续十多年保持世界畅销药的地位，居世界抗感染药的首位。
药物的晶型直接关系着其溶解性、溶解度、稳定性、溶出性和生物利用度等性质，因此药物的多晶型研究是药品生产质量控制和药物研究过程中不可缺少的重要组成部分。
发明内容
本发明的目的在于提供一种阿莫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：
一种阿莫西林晶体：使用Cu-Kα射线、以2θ角度表示的X-射线粉末衍射在11.20±0.2、12.30±0.2、16.84±0.2、17.08±0.2、18.80±0.2、22.58±0.2、23.14±0.2和26.85±0.2处存在特征峰。
所述阿莫西林晶体的制备方法：将阿莫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20-50℃，以120-280rppm速率重新搅拌析晶，过滤，滤饼用2-4℃的前述有机溶剂洗涤，35-60℃真空干燥至恒重，即得目标阿莫西林晶体；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。
将阿莫西林投入到有机溶剂中时，以ml/g计，有机溶剂的使用量为阿莫西林的30倍以上，最佳为60-90倍。
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。
阿莫西林作为已知化合物，本发明阿莫西林晶体与现有阿莫西林的化学组成相同，具有与现有阿莫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、胆道等的感染。
本发明的优点：本发明阿莫西林晶体水中溶解性好，提高了阿莫西林的溶解度，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，其中原料药阿莫西林参考文献（郑玉林.阿莫西林合成工艺改进.《中国抗生素杂志》2010年04期）制备获得。
实施例1：
将阿莫西林投入到80倍（以ml/g计）的二氯甲烷中，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5.1，停止搅拌，将滤液冷却至40℃，并以180rppm的速率重新搅拌析晶3小时，过滤，用4℃的二氯甲烷洗涤固体，35℃真空干燥至恒重，即得稳定的阿莫西林晶体，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：11.20、12.30、16.84、17.08、18.80、22.58、23.14、26.85。
实施例2：
将阿莫西林投入到90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20℃，并以150rppm的速率重新搅拌析晶3小时，过滤，用2℃的MIBK洗涤固体，55℃真空干燥至恒重，即得稳定的阿莫西林晶体，其X-射线粉末衍射特征峰数据与实施例1一致。
实施例3：
将阿莫西林投入60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；将滤液冷却至50℃，停止搅拌，加入氨水调节溶液pH值至为5.0，并以230rppm的速率重新搅拌析晶3小时，过滤，用3℃的二氯甲烷-乙酸乙酯混合溶剂（体积比1：1）洗涤固体，40℃真空干燥至恒重，即得稳定的阿莫西林晶体，其X-射线粉末衍射特征峰数据与实施例1一致。
实施例4：
将阿莫西林投入60倍（以ml/g计）的异丙醇-丙酮混合溶剂（体积比1：2）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；将滤液冷却至50℃，停止搅拌，加入氨水调节溶液pH值至为5.0，并以210rppm的速率重新搅拌析晶3小时，过滤，用3℃的异丙醇-丙酮混合溶剂（体积比1：2）洗涤固体，60℃真空干燥至恒重，即得稳定的阿莫西林晶体，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
取未处理过的阿莫西林{按郑玉林.阿莫西林合成工艺改进.《中国抗生素杂志》2010年04期制备}和实施例1-4制备的阿莫西林晶体各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版中国药典第二部阿莫西林）测定滤液中阿莫西林的含量，结果见下表，可知：本发明阿莫西林晶体水中溶解性好，提高了阿莫西林的溶解度，因而其溶出度和生物利用度高、药物活性增强。

Claims (3)

1.一种阿莫西林晶体的制备方法，该阿莫西林晶体使用Cu-Kα射线、以2θ角度表示的X-射线粉末衍射在11.20±0.2、12.30±0.2、16.84±0.2、17.08±0.2、18.80±0.2、22.58±0.2、23.14±0.2和26.85±0.2处存在特征峰，其特征在于：将阿莫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20-50℃，以120-280rppm速率重新搅拌析晶，过滤，滤饼用2-4℃的前述有机溶剂洗涤，35-60℃真空干燥至恒重，即得目标阿莫西林晶体；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：将阿莫西林投入到有机溶剂中时，以ml/g计，有机溶剂的使用量为阿莫西林的30倍以上。
3.如权利要求1所述的制备方法，其特征在于：以ml/g计，有机溶剂的使用量为阿莫西林的60-90倍。
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GB678508A (en) * 1948-01-02 1952-09-03 Merck & Co Inc Preparation of crystalline benzylpenicillinic acid-diisopropyl etherate
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CN101845053B (zh) * 2010-03-09 2012-07-25 河北科技大学 一种分离提纯阿莫西林三水化合物的方法
CN102660621B (zh) * 2012-05-04 2014-10-22 联邦制药(内蒙古)有限公司 一种改进的酶法制备阿莫西林的方法
CN102718778A (zh) * 2012-07-02 2012-10-10 天津市嘉凡生物科技有限公司 阿莫西林a晶型
CN102731528A (zh) * 2012-07-02 2012-10-17 天津市嘉凡生物科技有限公司 阿莫西林c晶型
CN103012430B (zh) * 2013-01-16 2014-08-06 湖北济生医药有限公司 美洛西林钠化合物及其药物组合物
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CN103833774A (zh) * 2014-03-21 2014-06-04 山东新时代药业有限公司 一种从克拉维酸钾混粉中回收有效成分的方法

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Registration number: Y2021980016170

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Denomination of invention: A type of amoxicillin crystal and its preparation method

Granted publication date: 20160413

Pledgee: China Construction Bank Corporation Zhengzhou Railway Sub Branch

Pledgor: HENAN SOAR VETERINARY PHARMACEUTICAL Co.,Ltd.|HENAN MUXIANG BIOTECHNOLOGY Co.,Ltd.

Registration number: Y2024980004821

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Address after: No. 9, Yugang Road, Airport Economic Comprehensive Experimental Zone, Zhengzhou City, Henan Province, 451162

Patentee after: Henan Muxiang Biotechnology Co.,Ltd.

Country or region after: China

Address before: 451162 airport road five, Zhengzhou, Henan

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Change date: 20250821

Registration number: Y2024980004821

Pledgor after: Henan Muxiang Biotechnology Co.,Ltd.

Pledgor before: HENAN SOAR VETERINARY PHARMACEUTICAL Co.,Ltd.

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Granted publication date: 20160413

Pledgee: China Construction Bank Corporation Zhengzhou Railway Sub Branch

Pledgor: Henan Muxiang Biotechnology Co.,Ltd.|HENAN MUXIANG BIOTECHNOLOGY Co.,Ltd.

Registration number: Y2024980004821

PE01 Entry into force of the registration of the contract for pledge of patent right
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Denomination of invention: Amoxicillin crystal and preparation method thereof

Granted publication date: 20160413

Pledgee: China Construction Bank Corporation Zhengzhou Railway Sub Branch

Pledgor: Henan Muxiang Biotechnology Co.,Ltd.

Registration number: Y2025980058732