Effect of Binary Additive Combinations on Solution Crystal Growth of the Poorly Water-Soluble Drug, Ritonavir

Combinations of additives (polymers and surfactants) are often used in pharmaceutical products to improve the delivery of poorly water-soluble active pharmaceutical ingredients (API). Additive interactions have not been widely studied and may promote or inhibit crystallization (nucleation and crystal growth) in an unpredictable manner, which in turn has an impact on the extent and duration of supersaturation. In this study, the effect of a series of polymer/polymer and polymer/surfactant combinations on crystal growth inhibition was investigated. Surprisingly, the majority of the polymer/polymer combinations investigated had a synergistic effect on crystal growth inhibition. The effectiveness of the polymer/polymer combinations was ascribed to the formation of interpolymer complexes through hydrophobic interactions that adsorb and interact favorably with the crystallizing solute and/or, interaction of individual polymers at different adsorption sites. The acceleration of crystal growth in the presence of polymer/surfactant combinations was attributed to weakened interactions between the polymer and the surface of the crystallizing solute brought about by the presence of surfactant molecules. Based on these observations, careful evaluation of the impact of combinations of additives on crystallization behavior is recommended in order to optimize the performance of supersaturating dosage forms.