Quality by design approach to understand the process of nanosuspension preparation.

摘要

Quality by design (QbD) principles were explored to maximize the understanding of the unit operation of microfluidization, for the preparation of nanosuspensions using indomethacin as a model drug. The effects of key formulation and process variables (drug concentration, stabilizer type, stabilizer concentration, temperature, milling time and microfluidization pressure) were investigated by executing a 2(5-1) factorial design. Particle size, zeta potential and the physical form of the drug constituted the critical quality attributes (CQAs). Multiple linear regression analysis and ANOVA were employed to identify and estimate the effect of important parameters, establish their relationship with CQAs, create design space and model the process of microfluidization for predictive purposes. In order of importance, milling time, microfluidization pressure, stabilizer type, temperature and stabilizer concentration were identified as critical parameters affecting the formation and stability of nanosuspensions. Interaction between homogenization pressure, temperature and milling time also significantly affected the nanosuspension particle size. No correlation was found between the zeta potential and the storage stability. No change in the physical form of indomethacin was observed on storage for 28 days at 4 degrees C and 25 degrees C. This research highlights the level of understanding that can be accomplished through a well designed study based on the philosophy of QbD.