Crystallizing Micronized Particles of a Poorly Water-Soluble Active Pharmaceutical Ingredient: Nucleation Enhancement by Polymeric Additives

摘要

Antisolvent precipitation aided by polymeric additives has increasingly been explored as a method to produce micron-sized/submicron particles of active pharmaceutical ingredients with low aqueous solubility so as to enhance their dissolution rate and absorption efficiency. This work is aimed toward understanding the role of these additives in mediating crystal nucleation and the growth process. Nucleation kinetics of naproxen, a poorly water-soluble drug, from an ethanol-water solvent mixture at various solute concentrations and in the presence of additives such as polyvinylpyrolidone (PVP) and hydroxypropyl methyl cellulose (HPMC) was investigated. At a given supersaturation, the crystal nucleation rate was calculated from probability distribution of the induction times measured' in stirred, small-volume batch solutions. The analysis revealed that PVP additive significantly promotes the nucleation kinetics in the entire range of supersaturation examined, whereas the effect of HPMC on the nucleation kinetics is supersaturation-dependent. Furthermore, the nucleation rates determined as a function of supersaturation followed the trend predicted using the classical nucleation theory (CNT) and indicated the occurrence of heterogeneous nucleation. Thermodynamic and kinetic parameters derived from the CNT equation; together with the crystal habit and size data, 'were used to elucidate the mechanisms underpinning the effect of polymeric additives on nucleation kinetics.