Theory and Thermodynamics of Polymorphism

摘要

Many drugs exhibit polymorphism, which is commonly defined as the ability of arnsubstance to exist in two or more crystalline phases that have different arrangementsrnand/or conformations of the molecules in the crystal lattice. Polymorphs may bernenantiotropes, each of which has its own range of stability, or monotropes, one of whichrnis unstable at all temperatures under normal (atmospheric) pressures. Burger, Ramburgerrnand others have developed thermodynamic rules to determine whether polymorphs arernenantiotropes or monotropes. In solid pharmaceutical formulations, the polymorph withrnthe lowest thermodynamic activity, if bioavailable, is usually preferred because of itsrngreater stability. The ability of a particular polymorph to crystallize is usually determinedrnby both kinetic and thermodynamic factors, which are discussed. Ostwald's rule of stagesrnrecognizes the common dominance of kinetic factors that often yield a metastablernpolymorph. Etter and coworkers have suggested that a supersaturated solution contains arnvariety of molecular aggregates, each of which is an embryo for a particular polymorphrnand competes for solute molecules. The nature of these aggregates is an emergingrnresearch area. The relative tendencies of the competing aggregates to grow to the size of arncritical nucleus and subsequently to form a crystal are determined by competingrnthermodynamic and kinetic factors. The appearance of new polymorphs and the apparentrndisappearance of existing polymorphs are discussed in terms of these competing factors.