1、聚合物异相成核对药物晶型的选择杨柳，茹敏良，郎美东*上海，华东理工大学，材料科学与工程学院，200237同一药物的不同晶型在溶解度、溶出速率、熔点、密度、生物相容性和稳定性等方面都可能有显著的差异，从而不同程度地影响药物的生物利用度、疗效、稳定性及安全性 1 。晶体多晶型的发现和选择，是固体化学中一个突出的问题。但是没有可行的方法来生产出一个给定化合物的所有稳定晶型。本文采用的方法，是通过不同的聚合物包括商业可生产的聚合物和合成的交联聚合物异相成核来控制晶体多晶型现象 2。这种新方法的优点是可以发现多种晶型，并且可以在同一溶剂和温度的条件下只简单的变化聚合物基层的性质就可以选择性的生产出一个给
2、定的晶型 3。奥美拉唑（omeprazole ） 。已知晶型有 3 种，都是通过重结晶法获得的，但是奥美拉唑对温度升高非常敏感，易产生分解产物与溶剂一起混入结晶中，造成结晶的不纯和不稳定 4。通过本方法在常温下即可得到其所有晶型，且不同聚合物对晶型的选择性不同。实验方法：本实验采用 100 种不同聚合物。配制奥美拉唑的甲醇溶液，浓度为Figure 1 chemical structure of omeprazoleFigure 2.X-ray powder diffractogram of omeprazole form AFigure 3.X-ray powder diffractogram
3、 of omeprazole form BNH3COSCH2ONCH33O3c=1.0g/100ml，将溶液加入已经放入聚合物的 96 孔板中，待溶剂慢慢挥发后，晶体即析出。表 1 聚合物与奥美拉唑 3 种晶型的对应关系Form A Form B Form C1，2-聚丁二烯聚（1-丁烯）聚乙烯，氯化/氯磺酸化聚（p-亚苯基砜醚）丙烯腈/丁二烯/苯乙烯树脂乙烯/醋酸乙烯酯共聚物尼龙 6/9，尼龙 6/12，尼龙 11聚对苯二酸乙烯酯苯乙烯/丙烯腈共聚物乙烯/丙烯酸共聚物甲基乙烯醚/马来酸共聚物聚丙烯酸参考文献:1居文政，陶开春，胡津丽。药物多晶型与临床疗效.中国药师， 2000,3(6):36
4、92Meidong Lang, Adam L., Grzesiak and Adam J. Matzger. The use of polymer heteronuclei for crystalline polymorph selection.J.AM.CHEM.SOC.,2002,124(50):148353Christopher P. Price , Adam L., Grzesiak and Adam J. Matzger. Crystalline polymorph selection and discovery with polymer heteronuclei. J.AM.CHE
5、M.SOC.,2005,127(15):55124Karin, David. New crystalline form of omeprazole. WO99/08500,1999The use of polymer heteronuclei for crystalline polymorph selectionYang liu，Ru minliang，Lang meidong*Institute of Biomaterials, School of Materials Science and Engineering, East China University of Science and
6、Technology, Shanghai 200237, ChinaAbstract: We report methodology to control the phenomenon of crystal polymorphism through the use of diverse libraries of polymer heteronuclei including both commercially available polymers and combinatorially synthesized cross-linked polymers. This new approach for
7、 exploring polymorph space offers the advantage of high throughput crystallization to discover multiple polymorphs combined with the ability to selectively produce a given form from a single solvent and temperature condition by simply varying the nature of polymer substrate. This technique is succes
8、sfully demonstrated on the pharmaceutical omeprazole. High throughput screening, accomplished by optical microscopy and X-ray powder diffraction, identified the selective production of the three polymorphs of omeprazole. The effect of monomer functionality on the selective polymorph production of omeprazole was also discussed.Key words: polymer-heteronuclei polymorph omeprazole X-ray diffraction
