Crystalline polymorph selection and discovery with polymer heteronuclei
Crystalline polymorph selection and discovery with polymer heteronuclei
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DOI：
10.1021/ja042561m
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发表时间：
2005-04-20
影响因子：
15
通讯作者：
Matzger, AJ
中科院分区：
文献类型：
--
作者：
Price, CP;Grzesiak, AL;Matzger, AJ
结晶多晶型物的发现和选择性生产是固态化学中的一个突出问题，在工业上例如在药物和颜料的制造中具有重要意义。尽管做出了相当大的努力，但不存在可靠的方法来生产给定化合物的所有稳定的多晶型物。在这里，我们报告的方法来控制晶体多态性的现象，通过使用不同的图书馆的聚合物异核，包括市售的聚合物和组合合成的交联聚合物。这种探索多晶型空间的新方法提供了高通量结晶的优点，以发现多种多晶型物，并具有通过简单地改变聚合物基质的性质从单一溶剂和温度条件选择性地产生给定形式的能力。该技术已在药物对乙酰氨基酚、磺胺甲恶唑和卡马西平以及药物中间体5-甲基-2-[（2-硝基苯基）氨基]-3-噻吩甲腈（ROY）上成功证明。通过光学显微镜和拉曼光谱完成的高通量筛选鉴定了对乙酰氨基酚的两种稳定多晶型物和所有六种稳定形式的ROY的选择性生产。此外，发现了一种新形式的卡马西平和两种新形式的磺胺甲恶唑;在这些情况下，获得单晶，使两种新的四晶型系统的结构表征。
The discovery and selective production of crystalline polymorphs, an outstanding problem in solid-state chemistry, is of great importance industrially in, for example, the manufacture of pharmaceuticals and pigments. Despite considerable efforts, no reliable method exists to produce all of the stable polymorphs of a given compound. Herein, 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 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 the polymer substrate. This technique is successfully demonstrated on the pharmaceuticals acetaminophen, sulfamethoxazole, and carbamazepine and on the pharmaceutical intermediate 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY). High throughput screening, accomplished by optical microscopy and Raman spectroscopy, identified the selective production of the two stable polymorphs of acetaminophen and all six stable forms of ROY. Furthermore, one new form of carbamazepine and two new forms of sulfamethoxazole were discovered; in these cases, single crystals were obtained enabling the structural characterization of two new tetramorphic systems.