Drugs with low water solubility are predisposed to poor and variable oral\nbioavailability and, therefore, to variability in clinical response, that might be overcome\nthrough an appropriate formulation of the drug. Polymorphs (anhydrous and solvate/hydrate\nforms) may resolve these bioavailability problems, but they can be a challenge to ensure\nphysicochemical stability for the entire shelf life of the drug product. Since clinical failures\nof polymorph drugs have not been uncommon, and some of them have been entirely\nunexpected, the Food and Drug Administration (FDA) and the International Conference on\nHarmonization (ICH) has required preliminary and exhaustive screening studies to identify\nand characterize all the polymorph crystal forms for each drug. In the past, the polymorphism\nof many drugs was detected fortuitously or through manual time consuming methods;\ntoday, drug crystal engineering, in particular, combinatorial chemistry and high-throughput\nscreening, makes it possible to easily and exhaustively identify stable polymorphic and/or\nhydrate/dehydrate forms of poorly soluble drugs, in order to overcome bioavailability related\nproblems or clinical failures. This review describes the concepts involved, provides examples\nof drugs characterized by poor solubility for which polymorphism has proven important,\noutlines the state-of-the-art technologies and discusses the pertinent regulations.
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