Engineered microcrystals for direct surface modification with layer-by-layer technique for optimized dissolution

This investigation relates to a two-step formulation development technique-synthesis of sterically stabilized drug microcrystals followed by direct surface modification by sequential electrostatic adsorption. Stable microcrystals of naproxen were produced by pH-induced reprecipitation in presence of a stabilizer. Sequential layer growth was achieved by the layer-by-layer assembly of biocompatible polyelectrolytes (PEs) and was registered using microelectrophoresis. The coated colloids were characterized using confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). The in vitro controlled release pattern of the drug through the PE diffusion barrier was studied using a diffusion cell assembly at physiological pH of 7.4, both before and after freeze-drying. Thermodynamically stable naproxen microcrystals were obtained by association and had a mean length of 15 mum, and a zeta potential of -37.5 mV and were surface modified efficiently using biocompatible polysaccharide/protein-based PEs. Sufficient charge reversal with each layer was evident indicating layer growth with successive deposition cycles. The coating was complete and homogeneous as visualized under CLSM and SEM. The in vitro release study revealed that the stoichiometry of PEs in the complex coating and its molecular architecture played important roles in forming the diffusion barrier, which offered efficient control of the dissolution rate of drug core (up to 50% lower than bare crystal). The release profile fitted zero order release kinetics. This novel formulation technique enables administration of high concentrations of water insoluble drugs in a stable, tissue compatible form, simultaneously affording sustained release. (C) 2004 Elsevier B.V. All rights reserved.