Chapter 5. Pharmaceutical Co-crystals—Molecular Design and Process Development

Abstract

Over the past decade, pharmaceutical co-crystals have gained prominent interest in drug development, due to their ability to modify the physicochemical properties of active pharmaceutical ingredients (APIs). Design of co-crystals generally relies on functional groups present on the API and co-former molecules, and hence intermolecular hydrogen bonds (synthons) that are prevalent between these functional groups act as design elements. Molecules that are devoid of potential hydrogen bonding sites have proved to be challenging for co-crystal design. Hence, alternative methods such as a knowledge-based method are useful for such compounds. The method works on a predictive methodology comprising a breadth of knowledge acquired from Cambridge Structural Database, interaction mapping, molecular descriptors, etc. Once a potential co-crystal is selected for further development, it is prerequisite to develop a robust process for preparation of co-crystal in bulk. Solution co-crystallization is a promising method; however, it presents challenges for large scale manufacturing. Hence, understanding ternary phase diagrams and the co-crystallization process is desired. With this background, the current chapter highlights knowledge-based co-crystal design strategies with some representative examples. Process development aspects such as the ternary phase diagram, and the critical parameters that should be considered in process monitoring and control by process analytical technologies will also be highlighted.