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

The present investigation was aimed at developing a laboratory scale preparation technique for nano-cocrystals comprised 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. 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 Damkohler number which resulted in selection of acetone as a solvent and n-hexane as an anti-solvent. 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 affects the particle size of the nano-cocrystal formulation. Formulation containing 0.3% of 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 selection of solvent, anti-solvent and stabilizers for different nano-cocrystals is also presented which can be applicable for a wide range of drug and coformers with different solubility.

Author(s): Pradip Thakor

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