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

Mallesh Kurakula,¹ AM El-Helw,² Tariq R Sobahi,¹ Magdy Y Abdelaal<sup>1

1</sup>Polymer Research Lab, Department of Chemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia; ²Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia

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

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