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Excipients are major components of oral solid dosage forms, and changes in their critical material attributes (excipient variability) and/or amount (excipient variation) in pharmaceutical formulations may present a challenge for product performance. Understanding the biopharmaceutical factors affecting excipient performance is recommended for the successful implementation of excipient variability on Quality by Design (QbD) approaches. The current study investigated the impact of magnesium stearate (MgSt) variability on the apparent solubility of drugs with a wide range of physicochemical properties (drug ionization, drug lipophilicity, drug aqueous solubility). Compendial and biorelevant media were used to assess the role of gastrointestinal (GI) conditions on the excipient effects on drug apparent solubility. The lipophilic nature of MgSt decreased the apparent solubility of most compounds. The reduction in drug apparent solubility was more pronounced for highly soluble and/or highly ionized drugs and in presence of more highly crystalline or smaller particle size MgSt. The use of multivariate data analysis revealed the critical physicochemical and biopharmaceutical factors and the complex nature of excipient variability on the reduction in drug apparent solubility. The construction of a roadmap combining drug, excipient and medium characteristics allowed the identification of the cases where the presence of excipient or excipient variability may present risks for oral drug performance.   Electronic supplementary material  The online version of this article (10.1208/s12248-020-00449-w) contains supplementary material, which is available to authorized users.

Impact of Magnesium Stearate Presence and Variability on Drug Apparent Solubility Based on Drug Physicochemical Properties