Comprehensive quality by design approach for stable nanocrystalline drug products

Abstract The novelty of the present research is application of a comprehensive quality by design (QbD) approach to minimize errors in product optimization and validation for the development of a stable nanocrystalline zileuton (BCS class II drug) formulation. A QbD approach was used to identify, optimize and validate the critical processes parameters (wet media milling and spray drying) and critical formulation parameters (drug and excipient concentrations). The milling time, milling speed, inlet temperature, aspirator rate, feed flow rate and drug concentration had a significant influence on the particle size and total product yield of the nanocrystalline zileuton. Trehalose compared to mannitol was determined to be a better stabilizer during spray drying processing. Stability studies revealed the following trend after 12 months: 4 °C (most stable) >25 °C/60% RH > 40 °C/75% RH (least stable) for the optimized spray-dried nanocrystalline zileuton in terms of physicochemical attributes, crystallinity and in vitro dissolution testing. Based on the comprehensive QbD approach, stable spray-dried nanocrystalline zileuton was obtained with exceptionally high total product yield (∼80% w/w) and small particle size (276.4 ± 27.54 nm) with low PDI (0.109 ± 0.056 units). Drug release from the formulations followed a particle size dependent dissolution trend. Additionally, pH switch dissolution testing indicated that complete drug release from the nanoformulations was observed at intestinal pH (pH 6.8) within 1–2 h of the shift from the stomach pH (pH 1.2).