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

Abstract

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.

Keywords:

• atorvastatin
• anti-hyperlipidemia
• chitosan
• cationic charge
• stability
• nanocrystals
• in-vivo efficacy

Acknowledgments

This article is funded by the Deanship of Scientific Research (DSR), King Abdulaziz University, Jeddah. The authors, therefore, acknowledge with thanks DSR for technical and financial support. The authors are also grateful to Mr Hany El-Bassossy, PhD, Department of Pharmacology, Faculty of Pharmacy, King Abdulaziz University for providing invaluable insights in the in-vivo studies.

Disclosure

The authors have no conflicts of interest to disclose.