(611a) Role of Solid Solutions in Polymorphic Enantiotropy

No API or chemical entity is completely pure. Impurities are always present in the API crystallization and tend to be entrapped in the isolated solids to varying degrees. A very common impurity entrapment mechanism in crystallization occurs through the formation of solid solutions wherein the impurity molecules substitutionally replace the host molecule in the crystal lattice of the product. The formation of these solid solutions can, and often will, result in significant changes in the thermodynamic properties of the crystalline API, even at low levels. Examples include enhancements in solubility and dissolution rates as well as melting point depressions, parameters which are critical for the controlled release of the drug. At the same time, changes in solubility of the API in the isolation solvents can have a substantial impact on the crystallization itself, especially when several polymorphs are present.

Presented in this talk is an example of this effect, in which the thermodynamic stability of the polymorphic compound anthranilic acid is fundamentally altered through the presence of low levels of the structurally similar compound salicylic acid. Anthranilic acid has three known polymorphs, Form I, II and III, which are all anhydrous. Form I is thermodynamically stable form at low temperatures, and Form III is stable at higher temperatures. As salicylic acid is increasingly entrapped in anthranilic acid, the enantiotropic transition temperature dramatically changes along a two-phase envelope in which both polymorphs exist in equilibrium with each other. The implications for drug development in general and establishing form control during process development are discussed.