Pharmaceutical cocrystals: along the path to improved medicines

TLDR

Cocrystals are crystalline solids that can modify drug physicochemical properties without covalent changes, and their diverse compositions—especially ionic cocrystals—make them a key focus in preformulation and drug development. The review aims to update on advances in design, discovery, and development of pharmaceutical cocrystals since 2004. It discusses cocrystal nomenclature, design via hydrogen‑bonded synthons, discovery and synthesis methods, and their development into drug products. Seven recent case studies show that pharmaceutical cocrystals can enhance physicochemical properties and clinical performance, including a newly approved drug product based on an ionic cocrystal.

Abstract

Cocrystals, a long known but understudied class of crystalline solids, have attracted interest from crystal engineers and pharmaceutical scientists in the past decade and are now an integral part of the preformulation stage of drug development. This is largely because cocrystals that contain a drug molecule, pharmaceutical cocrystals, can modify physicochemical properties without the need for covalent modification of the drug molecule. This review presents a brief history of cocrystals before addressing recent advances in design, discovery and development of pharmaceutical cocrystals that have occurred since an earlier review published in 2004. We address four aspects of cocrystals: nomenclature; design using hydrogen-bonded supramolecular synthons; methods of discovery and synthesis; development of pharmaceutical cocrystals as drug products. Cocrystals can be classified into molecular cocrystals (MCCs) that contain only neutral components (coformers) and ionic cocrystals (ICCs), which are comprised of at least one ionic coformer that is a salt. That cocrystals, especially ICCs, offer much greater diversity in terms of composition and properties than single component crystal forms and are amenable to design makes them of continuing interest. Seven recent case studies that illustrate how pharmaceutical cocrystals can improve physicochemical properties and clinical performance of drug substances, including a recently approved drug product based upon an ICC, are presented.