Novel powder property-based indices for predicting segregation risk in multicomponent pharmaceutical blends

Abstract

Powder segregation represents a critical challenge in pharmaceutical manufacturing, potentially compromising product quality through the non-uniform distribution of active ingredients. This study evaluates segregation behavior in pharmaceutical blends containing two model APIs (acetaminophen and ibuprofen sodium) formulated with various excipients (microcrystalline cellulose, lactose, and pregelatinized starch) at different drug loadings (2–10%) and excipient ratios (2 to 4) with mannitol. Near-infrared spectroscopy was employed for content analysis, while a modified Jenike and Johanson tester assessed the segregation propensity. Statistical analysis identified significant interactions between formulation variables, with particle size distribution and flow characteristics emerging as critical factors influencing segregation. A modified segregation index incorporating concentration ratio and drug load demonstrated improved correlation with material properties, with four key parameters identified as significant predictors: D₅₀, D₉₀/D₁₀, and ratio of corresponding flowability and size distribution width between API and the blend. Based on this, two composite parameter indices were finally developed and validated by commercial blends to facilitate rapid assessment of segregation risk during early formulation development, providing a practical approach to developing robust pharmaceutical formulations with reduced segregation risk.