PHASE-TRANSITION AND HETEROGENEOUS EPITAXIAL NUCLEATION OF HYDRATED AND ANHYDROUS THEOPHYLLINE CRYSTALS

Theophylline crystallizes in the anhydrous or monohydrate form. The solubility of the anhydrous form exceeds the solubility of the monohydrate form below 60-degrees-C. The anhydrous: hydrate phase transition of theophylline in buffered suspensions has been studied by measurement of the supersaturation profile and the crystal size distributions. The role of crystallographic parameters in the nucleation and growth of monohydrate crystals, during dissolution of the anhydrous phase, has been investigated. A solvent-mediated route has been identified and can be described in terms of the dissolution kinetics of the anhydrous phase and the nucleation and growth kinetics of the hydrated phase. The growth rate of the monohydrate crystals depends on the square of the supersaturation and is independent of the stirring rate, which suggests a surface-controlled growth process. The dissolution rate of the anhydrous crystals depends on the 1.5 order of the undersaturation and is inversely proportional to the square root of the crystal size. Anhydrous theophylline crystals act as heterogeneous nucleation substrates for the crystals of the monohydrate phase and these grow epitaxially on the anhydrous crystals. Based on the kinetic equations for dissolution of the anhydrous form and crystallization of the monohydrate form, a computer simulation has been developed that predicts the changes in the concentration of theophylline in solution during the phase transition.