ABSTRACT
INTRODUCTION Active pharmaceutical ingredients (APIs) are typically orally delivered as solid dosage forms that contain a single crystalline form of the API. This is an artifact of crystalline solids tending to be more stable and reproducible in the context of purifi cation and processing when compared to other types of solid forms such as amorphous solids and solid solutions. Interestingly, the importance of crystal form selection during development of APIs has probably never been higher, and in the past fi ve years pharmaceutical co-crystals have become part of a landscape that was previously occupied only by polymorphs, salts, and solvates/hydrates ( Fig. 1 ) (1-4). Nevertheless, whereas there is a clear need for better understanding and control of crystalline forms in the context of drug development, the concepts of supramolecular synthesis (5-8) and crystal engineering (9-18) remain largely underexploited, and there are many basic questions about pharmaceutical co-crystals that remain unanswered, including their tendency to form polymorphs (19). Furthermore, a number of factors that are critically important in making an API viable as an oral dosage form remain diffi cult to predict or even control:
• Dissolution rate and intrinsic solubility of different crystal forms of an API are variable, and can strongly infl uence bioavailability. This is a particularly salient factor in light of the increasing prevalence of “BCS Class II” drugs (i.e., lowsolubility, high-permeability APIs) (20). • Stability toward temperature and humidity of an API is critically dependent upon crystal packing. • The unpredictability (i.e., lack of obviousness) of crystal structures and physical properties means that there are opportunities and challenges in terms of obtaining and maintaining patent protection for an API.
