Impact of Monomeric versus Micellar Surfactant and Surfactant-Polymer Interactions on Nucleation-Induction Times of Atazanavir from Supersaturated Solutions

摘要

Supersaturating formulations such as amorphous solid dispersions (ASDs) can lead to solution concentrations much higher than the crystalline solubility achieving enhanced oral bioavailability of poorly aqueous soluble compounds. However, they can potentially crystallize with a loss of their solubility advantage. Various polymers have been extensively used to delay crystallization. Increasingly, surfactants are being incorporated into ASDs to improve processing and dissolution performance. While the effect of polymers has been widely studied, the impact of surfactants on crystallization has not yet been explored to the same extent. In this work, the effect of a commonly used surfactant, sodium dodecyl sulfate (SDS) on the nucleation induction time (NIT) of a model compound, atazanavir (ATZ) was studied. NITs of supersaturated solutions with the same supersaturation ratio (SR) were measured in the presence of various SDS concentrations, ranging from well below the critical micelle concentration (CMC) to well above CMC, in order to evaluate the impacts of monomeric SDS molecules versus SDS micelles. SDS was found to promote crystallization at a certain minimum SDS concentration (critical hemimicelle concentration, CHMC). Further, no additional decrease in NIT was observed once the CMC of SDS was exceeded. To elucidate the mechanism of crystallization induction, fluorescence studies were carried out with crystal slurries. Fluorescence data strongly suggest that SDS hemimicelles present on the nucleus/crystal surface are responsible for the observed shortened induction times in ATZ nucleation. These adsorbed SDS hemimicelles can reduce the crystal-water interfacial energy, promoting nucleation. The combined effect of polymer and surfactant, using concentrations relevant to those produced upon ASD dissolution, was also studied. In the absence of SDS, the polymers inhibited detectable nucleation for >1000 min. In the presence of SDS, cellulosic polymers such as hydroxypropyl methyl cellulose 606 (HPMC-606) and hydroxypropyl methyl cellulose acetate succinate MF (HPMCAS-MF) maintained a similar level of inhibitory effect, whereas polyvinylpyrrolidone/vinyl acetate (PVPVA) lost some of its inhibitory effect.