Submicron crystals have the potential to enhance dissolution rates and absorption efficiency of active ingredients with low aqueous solubility used in pharmaceutical formulations and in a wide range of specialty chemicals. Precipitation from solution offers a direct and cost effective method to produce micron-sized and submicron particles. However, a precise knowledge of the particle formation mechanisms, involving the primary process of nucleation and crystal growth, is essential to control crystallization in this size range. Producing submicron crystals of organic compounds by antisolvent or reactive precipitation methods, as compared to inorganic crystals (ionic salts and metal oxides), is even more challenging due to their relatively slow nucleation rates at moderate supersaturation levels. Further, the presence of directional H-bonding in molecular crystals can lead to faster growth along certain facets resulting in crystals with higher aspect ratios.
In this research work, nucleation and growth phenomena of organic crystals from solution were investigated experimentally, with the aim of understanding the effects of solution conditions and process variables on submicron crystallization process. Initially, nucleation kinetics of the model compound, naproxen (a poorly water-soluble drug), was determined at various solute concentrations and in the presence of polymeric additives that are typically used to stabilize colloidal crystal dispersions. Nucleation rates were calculated from multiple induction time measurements at a constant supersaturation using a statistical approach. The results showed a reasonably good agreement between experimentally determined nucleation rates and that predicted using classical nucleation theory relationship. While the polymeric additive polyvinylpyrolidone (PVP) significantly promoted the nucleation kinetics in the entire range of supersaturation studied, the effect of hydroxypropyl methyl cellulose (HPMC) on the nucleation kinetics was supersaturation dependent. Thermodynamic and kinetic parameters for nucleation of naproxen crystals were derived from the experimental data and, in turn, linked to the mechanisms underpinning the effects of polymeric additives in producing submicron crystal dispersions.