Poor water solubility is one of the major challenges to the development of oral dosage forms containing active pharmaceutical ingredients (APIs). Polymorphism in APIs leads to crystals with different surface wettabilities and free energies, which can lead to different dissolution properties. Crystal size and habit further contribute to this variability. An important focus in pharmaceutical research has been on controlling the drug form to improve the solubility and thus bioavailability of APIs. In this regard, heterogeneous crystallization on surfaces and crystallization under confinement have become prominent forms of controlling polymorphism and drug crystal size and habits; however there has not been a thorough review into the emerging field of combining these approaches to control crystallization. This tutorial-style review addresses the major advances that have been made in controlling API forms using combined crystallization methods. By designing templates that not only control the surface functionality but also enable confinement of particles within a porous structure, these combined systems have the potential to provide better control over drug polymorph formation and crystal size and habit. This review further provides a perspective on the future of using a combined crystallization approach and suggests that combining surface templating with confinement provides the advantage of both techniques to rationally design systems for API nucleation.

中文翻译：

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结合表面模板和限制来控制药物结晶


水溶性差是开发含有活性药物成分（API）的口服剂型的主要挑战之一。 API 中的多晶型现象会导致晶体具有不同的表面润湿性和自由能，从而导致不同的溶出特性。晶体尺寸和习性进一步导致了这种变化。药物研究的一个重要焦点是控制药物剂型以提高 API 的溶解度，从而提高生物利用度。在这方面，表面非均相结晶和限域结晶已成为控制多晶型和药物晶体尺寸和习性的突出形式；然而，尚未对结合这些方法来控制结晶的新兴领域进行彻底的审查。这个教程式的评论讨论了使用组合结晶方法控制 API 形式所取得的主要进展。通过设计不仅控制表面功能而且能够将颗粒限制在多孔结构内的模板，这些组合系统有可能更好地控制药物多晶型物的形成以及晶体尺寸和习性。这篇综述进一步提供了对使用组合结晶方法的未来的看法，并建议将表面模板与约束相结合提供了这两种技术的优势，可以合理地设计 API 成核系统。