Preparation and optimization of nano-sized cocrystals using a quality by design approach

Abstract

The present investigation was aimed at developing a laboratory-scale preparation technique for nano-cocrystals composed of a water-insoluble drug and a water-soluble coformer. The challenge was to prepare a nano-sized system while maintaining the integrity of the cocrystals. Carbamazepine–nicotinamide was selected as a model cocrystal for this study. An anti-solvent precipitation technique was investigated utilizing various solvents (ethanol, ethyl acetate, and acetone), anti-solvents (water, n-hexane) and stabilizers (Span 80, PVPVA-64, poloxamer-407) for producing nano-cocrystals. Preliminary screening was performed based on solubility and the Damkohler number which resulted in the selection of acetone as a solvent and n-hexane as an anti-solvent. The L-18 Hunter design was applied for studying the effect of five independent variables (type of stabilizer, concentration of stabilizer, sonication time, temperature and stirring speed) on the particle size (response variable). The experimental outcome indicated that the type of stabilizer and its concentration significantly affect the particle size of the nano-cocrystal formulation. The formulation containing 0.3% PVPVA-64 was found to be stable with the lowest particle size, i.e. D10 = 68.9 ± 9.5 nm, D50 = 138.2 ± 16.6 nm, and D90 = 260.3 ± 17.96 nm. Further, the optimized formulation was characterized by differential scanning calorimetry, powder X-ray diffraction, and ATR-FTIR spectroscopy. A decision tree to aid in the selection of solvent, anti-solvent and stabilizer for different nano-cocrystals is also presented which can be applicable for a wide range of drugs and coformers with different solubility.