Drug polymorphism and dosage form design: a practical perspective.

Abstract

Formulators are charged with the responsibility to formulate a product which is physically and chemically stable, manufacturable, and bioavailable. Most drugs exhibit structural polymorphism, and it is preferable to develop the most thermodynamically stable polymorph of the drug to assure reproducible bioavailability of the product over its shelf life under a variety of real-world storage conditions. There are occasional situations in which the development of a metastable crystalline or amorphous form is justified because a medical benefit is achieved. Such situations include those in which a faster dissolution rate or higher concentration are desired, in order to achieve rapid absorption and efficacy, or to achieve acceptable systemic exposure for a low-solubility drug. Another such situation is one in which the drug remains amorphous despite extensive efforts to crystallize it. If there is no particular medical benefit, there is less justification for accepting the risks of intentional development of a metastable crystalline or amorphous form. Whether or not there is medical benefit, the risks associated with development of a metastable form must be mitigated by laboratory work which provides assurance that (a) the largest possible form change will have no substantive effect on product quality or bioavailability, and/or (b) a change will not occur under all reasonable real-world storage conditions, and/or (c) analytical methodology and sampling procedures are in place which assure that a problem will be detected before dosage forms which have compromised quality or bioavailability can reach patients.