Impact of Process Parameters on Particle Size Involved in Media Milling Technique Used for Preparing Clotrimazole Nanocrystals for the Management of Cutaneous Candidiasis.

Clotrimazole is widely used for the management of cutaneous candidiasis infection. The low solubility of clotrimazole and excipient-related topical side effects (of currently available marketed products) cause the compromised efficacy of the therapy with poor patient compliance. In the present investigation, a clotrimazole nanocrystal-based nanogel was developed. Clotrimazole nanocrystals were optimized with studying the impact of individual process parameters of the media milling technique. The optimum level of individual process parameters was considered in the development of optimized batches. A promising result was obtained with a non-ionic stabilizer, polysorbate 80, at a concentration of 1.5%w/v, showing a distinct reduction in the particle size from above 31 µm to 264 nm and a polydispersity index of 0.211 with media milling at 1500 rpm for 6 h. This result was found to be in concordance with the TEM images, revealing a sharp diminution in particle morphology. Powder X-ray diffraction and differential scanning calorimetry results revealed crystallinity of clotrimazole (CTZ) in nanocrystal form. The optimized nanocrystal suspension was formulated into nanogel with carbopol 934, having a viscosity of 86.43 ± 2.06 Pa s at 25°C, which enhanced the ease of application of CTZ nanocrystals topically. A diffusion study showed around 82% of CTZ is transported across the membrane with the flux of 110.07 µg cm-2 h-1. In vivo results of the nanogel revealed improvement in CTZ release with 52% CTZ retention in different strata of the skin. The developed nanogel showed a significant improvement in the eradication of fungal infection within 10 days of application over Candida albicans-induced Wistar rat model. In a nutshell, the CTZ nanocrystal-loaded nanogel could achieve the goal of retaining CTZ in skin layers providing a prolonged effect and was able to treat cutaneous candidiasis in a short span with improved compliance for the candidiasis patients.