Chitosan based atorvastatin nanocrystals: effect of cationic charge on particle size, formulation stability, and in-vivo efficacy

Cationic charged chitosan as stabilizer was evaluated in preparation of nanocrystals using probe sonication method. The influence of cationic charge densities of chitosan (low CS(L), medium CS(M), high CS(H) molecular weights) and Labrasol(®) in solubility enhancement and modifying the release was investigated, using atorvastatin (ATR) as poorly soluble model drug. Compared to CS(M) and CS(H); low cationic charge of CS(L) acted as both electrostatic and steric stabilizer by significant size reduction to 394 nm with charge of 21.5 meV. Solubility of ATR-CS(L) increased to 60-fold relative to pure ATR and ATR-L. Nanocrystals were characterized for physiochemical properties. Scanning electron microscopy revealed scaffold-like structures with high surface area. X-ray powder diffractometry and differential scanning calorimetry revealed crystalline to slight amorphous state changes after cationic charge size reduction. Fourier transform-infrared spectra indicated no potent drug-excipient interactions. The enhanced dissolution profile of ATR-CS(L) indicates that sustained release was achieved compared with ATR-L and Lipitor(®). Anti-hyperlipidemic performance was pH dependent where ATR-CS(L) exhibited 2.5-fold higher efficacy at pH 5 compared to pH 6 and Lipitor(®). Stability studies indicated marked changes in size and charge for ATR-L compared to ATR-CS(L) exemplifying importance of the stabilizer. Therefore, nanocrystals developed with CS(L) as a stabilizer is a promising choice to enhance dissolution, stability, and in-vivo efficacy of major Biopharmaceutical Classification System II/IV drugs.