Media milling and design of experiment: Process optimization using DoE for wet media milling of retinoic acid

Abstract

Isotretinoin (13-cis-retinoinc acid) is a BCS Class II drug with poor water solubility. It is known to be one of the most useful vitamin A derivatives which affects all the major factors involved in the pathogenesis of acne. This thesis was to explore the application of wet media milling technique for the preparation of nanosized isotretinoin in order to improve its oral bioavailability. Preliminary trials were performed to study the practicability of media milling and process setting. Selected parameters and stabilizing effect of lecithin were assessed. A systematic optimization of selected parameters, bead volume and agitator speed, of wet media milling process was conducted with the aid of a 2 factor 2 level experimental design. Particle size D (3,2) was taken as response and as the criteria for validation. The effect and significance of parameters, bead load and agitator speed, were analysed with polynomial equation and suggested the bead load was known to have the most significant impact on the milling. Validation of this designed model has shown good agreement between the predicted and actual response. The effect of tween 80 and lecithin stabilizers were further studied with this optimized operation parameters showed that lecithin was more effective for particle stabilization than tween 80. Lecithin stabilized isotretinoin nanoparticles have shown minimal particle size growth as compared to the batch prepared without stabilization through a 3 month stability study. In vitro drug dissolution study of the prepared isotretinoin nanoparticles by media milling showed faster drug release when compared with unmilled isotretinoin and marked product at various dissolution conditions. Optimized formulation was also characterized using SEM, XPRD and FTIR. The rheology study of the milled isotretinoin suggests that the milled isotretinoin blend possessed Non-Newtonian pseudoplastic properties. By taking isotretinoin as an example, this study has supported that nanoparticle formulation produced by media milling with stabilized particles seems to be very effective and robust, dealing with undesired situations associate with solubility by improving its dissolution rate. Utilizing of factorial designing tool such as Design of Experiments (DoE) has proven to be a convenient and efficient approach to accelerate the development time significantly while maintaining the quality, safety and efficacy of therapeutic product.