Supercritical carbon dioxide solubility measurement and modelling for effective size reduction of nifedipine particles for transdermal application

Overview & Synopsis

Nifedipine (NIF) is a Class II drug of the Biopharmaceutical Classification System (BCS) with low oral bioavailability, low dissolution rate and significant hepatic drug metabolism. The transdermal route using supersaturated systems could be considered. For this purpose, physicochemical properties of NIF such as its dissolution rate, may be a limiting factor and must be improved. Crystallization processes assisted by supercritical carbon dioxide (scCO2) and particularly the Rapid Expansion of Supercritical Solution (RESS) process may improve drug bioavailability by reducing particle size and consequently increasing surface area. This study addresses the reduction of NIF particle size using scCO2-RESS as crystallization process. Experimental solubility studies were performed at different temperature (308 and 318 K) and pressure ranges (9-24 MPa). Solubility data were correlated with two thermodynamic models in order to predict NIF solubility in scCO2. Optimized operating conditions, identified by thermodynamic modelling, allowed the production of thinner NIF particles and a size reduction up to ten fold. Particle size reduction improved NIF dissolution kinetics in aqueous medium: after 90 min, 42 % of raw NIF was released against 80 % for crystallized NIF. The scCO2-RESS process is a solvent free process, that can produce micronized or nanosized crystals able to improve physicochemical properties of poorly water-soluble drugs.