Selective growth of a stable drug polymorph by suppressing the nucleation of corresponding metastable polymorphs
Selective growth of a stable drug polymorph by suppressing the nucleation of corresponding metastable polymorphs
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DOI：
10.1002/anie.200605257
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Thalladi, Venkat R.
中科院分区：
文献类型：
--
作者：
Cox, Jason R.;Ferris, Lori A.;Thalladi, Venkat R.
早期发现药物稳定的药物多晶型物在药物开发中至关重要，以避免配方问题和拯救生命的药物从市场上撤出的可能性。[1]消失的多晶型物的故事在化学文献中是众所周知的;[2]这些故事中的大多数都是由于后期出现的化学稳定的多晶型物取代了先前存在的亚稳态形式。[3]利托那韦是一种蛋白酶抑制剂药物，在上市两年后不得不被召回，这就说明了这个问题。[1]在这项研究中，我们报告了全氟烷基封端的硅烷单层[4]在促进吲哚美辛（一种非甾体抗炎药）的稳定多晶型（g型）的排他性生长方面的独特能力。[5]这种选择性生长不是由g型的增强成核促进的，而是由亚稳多晶型物（a型）的抑制成核促进的。我们还表明，硅烷单分子膜上制作的玻璃瓶表面，（与在载玻片上制造的单层相反）使多晶型物的伴随结晶最小化。（硫醇自组装单层，[6]朗缪尔单层，[7]和单晶面[8]）和非结构化（硅烷单层[9]和聚合物颗粒[10]）表面来研究有机和无机化合物的晶体生长。[11]在结构化和非结构化表面上观察到多晶型选择性;在生长界面处由一定水平的几何互补性辅助的化学互补性被认为是负责所观察到的选择性。[12]吲哚美辛具有几种官能团（羧基、叔酰胺基、甲氧基、氯;图1a），我们探索了带有不同官能团的硅烷单层（3-9，图2）对其晶体生长的影响。在所有的实验中，我们使用裸玻璃（1）和等离子体氧化玻璃（2）作为对照。吲哚美辛从乙醇中同时结晶为a和g多晶型物。[13]这两种多晶型物具有不同的晶体结构（a：P21，Z '= 3，g：P1，Z'= 1），[14]熔融
Early discovery of thermodynamically stable drug polymorphs is critical in pharmaceutical development to avoid formulation problems and potential withdrawal of the lifesaving drugs from the market.[1] Tales of disappearing polymorphs are well known in chemical literature;[2] most of these tales are attributable to the late-stage appearance of a thermodynamically stable polymorph that replaced the previously existing metastable form.[3] Ritonavir, a proteaseinhibitor drug that had to be recalled after being on the market for two years, exemplifies this problem.[1] In this study, we report the unique ability of perfluoroalkyl-terminated silane monolayers [4] in promoting the exclusive growth of the stable polymorph (g form) of indomethacin, a nonsteroidal anti-inflammatory drug.[5] This selective growth is promoted not by the enhanced nucleation of the g form, but by the suppressed nucleation of the metastable polymorph (a form). We also show that silane monolayers fabricated on the surfaces of glass vials (as opposed to monolayers fabricated on glass slides) minimize concomitant crystallization of polymorphs.Several researchers have used structured (thiol selfassembled monolayers,[6] Langmuir monolayers,[7] and single-crystal faces [8]) and nonstructured (silane monolayers [9] and polymer particles [10]) surfaces to study the crystal growth of organic and inorganic compounds.[11] Polymorph selectivity is observed on structured and nonstructured surfaces; chemical complementarity assisted by some level of geometric complementarity at the growth interface is assumed to be responsible for the observed selectivity.[12] Indomethacin possesses several functionalities (carboxy, tertiary amido, methoxy, chloro; Figure1a) and we have explored the influence of silane monolayers bearing different functional groups (3–9, Figure2) on its crystal growth. In all the experiments, we used bare-glass (1) and plasma-oxidizedglass (2) substrates as controls. Indomethacin crystallizes concomitantly as a and g polymorphs from ethanol.[13] These two polymorphs have distinct crystal structures (a: P21, Z’= 3, g: P1, Z’= 1),[14] melting