Risk Assessment of Factors Affecting Physical and Chemical Stability of Solid Dispersions of Poorly-Soluble Drugs

Solid dispersions are one of the most promising strategies to overcome the poor aqueous solubility of some drug substances. However, the physical and chemical instability of solid dispersions has limited their use. The purpose of this study was to assess the risk of factors affecting the dissolution and chemical stability of solid dispersion products of poorly-water-soluble drugs. Five poorly-water-soluble drug substances were subjected to forced degradation studies, pH-dependent stability testing and excipient-drug substance compatibility testing and testing for effect of manufacturing parameters then the experimental data were analysed. FT-IR results and compatibility studies showed that carrier type variability and drug-to-carrier ratio could critically affect the chemical stability of the solid dispersions. Anova results showed that mixing time, evaporation temperature and milling size were the statistically-significant manufacturing parameters affecting the dissolution stability and/or degradation percentage of poorly-soluble drugs. Results of photostability studies showed that light had high risk to the chemical stability of poorly-soluble drugs. By applying Quality by Design (QbD) principles it was concluded that besides polymorphism, zeta potential, dose–to-solubility ratio and water content, carrier type, drug-to-carrier ratio, mixing time, evaporation temperature, milling size and light were determined as the critical factors affecting the dissolution stability and chemical degradation of poorly-soluble drugs. This conclusion will be the basis for subsequent design of acceptable robust specifications and successful stability protocols allowing to obtain a physically and chemically-stable solid drug product.