School of Chemistry, University of Hyderabad, Central University P.O., Prof. C. R. Rao Road, Hyderabad 500046, India.
Mol Pharm. 2023 May 1;20(5):2293-2316. doi: 10.1021/acs.molpharmaceut.3c00159. Epub 2023 Mar 28.
Improving the solubility and permeability of drugs via cocrystallization is an important theme in crystal engineering with practical applications for the discovery and development of high bioavailability medicines. The past decade has witnessed a surge of publications on pharmaceutical cocrystals/salts to improve the permeability of Biopharmaceutics Classification System (BCS) class IV drugs. In this review article, the reader is introduced to the fundamentals of drug permeability mechanisms and then examples of pharmaceutical cocrystals and salts designed to enhance drug diffusion and permeability are presented, in order to understand the different structural factors that modulate drug flux and transport across a semipermeable membrane. Broadly, two main phenomena can be summarized from the 50 or so examples: (1) The heterosynthons in hydrogen-bonded drug-coformer aggregates survive long enough in the experimental media such that the drug, which is present in high concentration due to supersaturation, exhibits higher flux across the semipermeable membrane. (2) The coformer or cocrystal is able to reduce the transepithelial electrical resistance (TEER) values of lipid monolayers, which impairs their tight junctions, and facilitates drug passage to improve its diffusion/permeability. The medicinal chemistry literature on high permeability drugs is recapitulated with the idea that these principles may be utilized in the design of high permeability coformers for the synthesis of improved-performance pharmaceutical cocrystals. Enhancing drug solubility and permeability without changing its molecular structure in supramolecular complexes of pharmaceutical cocrystals and salts will address the poor bioavailability challenge for a majority of BCS class II and IV drugs.
通过共晶来提高药物的溶解度和渗透性是晶体工程中的一个重要主题，对于发现和开发高生物利用度的药物具有实际应用价值。过去十年，关于药物共晶/盐以提高生物药剂学分类系统（BCS）IV 类药物渗透性的出版物大量涌现。在这篇综述文章中，读者首先了解药物渗透性机制的基础知识，然后介绍了旨在增强药物扩散和渗透性的药物共晶和盐的设计实例，以了解调节药物通量和跨半透膜运输的不同结构因素。总的来说，可以从大约 50 个实例中总结出两个主要现象：（1）氢键药物共晶形成物聚集体中的异质二聚体在实验介质中存在足够长的时间，使得药物由于过饱和而以高浓度存在，表现出更高的跨半透膜通量。（2）共晶形成物或共晶本身能够降低脂质单层的跨上皮电阻（TEER）值，破坏其紧密连接，促进药物通过以提高其扩散/渗透性。本文还综述了高渗透性药物的药物化学文献，其理念是这些原则可以用于设计高渗透性共晶形成物，以合成具有改善性能的药物共晶。在药物共晶和盐的超分子复合物中不改变药物的分子结构而提高药物的溶解度和渗透性，将解决大多数 BCS II 类和 IV 类药物的生物利用度差的挑战。
