Formulation parameters of crystalline nanosuspensions on spray drying processing: A DoE approach

Abstract

Nanocrystalline suspensions offer a promising approach to improve dissolution of BCS class II/IV compounds. Spray drying was utilized as a downstream process to improve the physical and chemical stability of dried nanocrystals. The effect of nanocrystalline suspension formulation variables on spray-drying processing was investigated. Naproxen and indomethacin nanocrystalline formulations were formulated with either Dowfax 2A1 (small molecule) or HPMC E15 (high molecular weight polymer) and spray drying was performed. A DoE approach was utilized to understand the effect of critical formulation variables, i.e. type of stabilizer, type of drug, ratio of drug-to-stabilizer and drug concentration. The powders were analyzed for particle size, moisture content, powder X-ray diffraction and dissolution. A dialysis sac adapter for USP apparatus II was developed which provided good discrimination between aggregated and non-aggregated formulations. Nanocrystal aggregation was dependent on the drug-to-stabilizer ratio. The glass transition temperature and the charge effect played a dominant role on spray-dried powder yield. Those formulations with low drug-to-excipient ratios were less aggregating and showed faster dissolution compared to those formulations with high drug-to-excipient ratios. All stable (less aggregated) formulations were subjected to accelerated storage stability testing. The Flory-Huggins interaction parameter (between drug and excipients) correlated with the spray-dried nanocrystal formulations stability.