Excipients are major components of oral solid dosage forms, and variations in their critical material properties (excipient variability) and/or amounts (excipient variability) in pharmaceutical formulations can present challenges to product performance. An understanding of biopharmaceutical factors that affect excipient performance is recommended to successfully implement a Quality by Design (QbD) approach to excipient variability. The current study investigated the effect of magnesium stearate (MgSt) variability on the apparent solubility of drugs with a wide range of physicochemical properties (drug ionization, drug lipophilicity, drug water solubility). Pharmacopoeial and biorelevant media are used to assess the effect of gastrointestinal (GI) conditions on the effect of excipients on the apparent solubility of a drug. The lipophilicity of MgSt reduces the apparent solubility of most compounds. The decrease in apparent drug solubility was more pronounced for highly soluble and/or highly ionized drugs, and in the presence of higher crystallinity or smaller particle sizes of MgSt. The use of multivariate data analysis revealed the complexity of key physicochemical and biopharmaceutical factors and excipient variability on the reduction of apparent drug solubility. Building a roadmap that combines drug, excipient, and vehicle properties can identify situations where the presence of excipients or excipient variability may pose a risk to oral drug performance.
Excipient variability (variation in material properties) and variation (variation in quantity) can affect final product quality, leading to batch failure, altered bioavailability, and intra-product bioinequivalence [1, 2]. The need to successfully implement excipient variability in a Quality by Design (QbD) approach is widely recognized. Excipients can pose challenges from a biopharmaceutical perspective, as their presence may affect drug stability, solubility, permeability, and overall product performance . Gastrointestinal factors may affect or be influenced by the performance of excipients in pharmaceutical formulations . Altering key material properties of certain excipients may affect the absorption of orally administered drugs. Understanding the biopharmaceutical risks of excipient variability will facilitate the development of robust oral solid dosage forms.
Due to its excellent properties, magnesium stearate (MgSt) is a commonly used lubricant in tablet manufacturing stearate. Typical excipient levels used in immediate release formulations are between 0.25–5% w/w . MgSt affects drug release because it acts as a water repellant by forming a hydrophobic film around drug particles [7, 8] [9, 10]. MgSt may adhere to the metal or powder/particle surface through its polar Mg2+ [5, 11], while non-polar fatty acids stay away from the coating surface and negatively affect product performance  (Fig. 1a). Polar heads forming mono- or multi-particulate layers around particles [12, 13] have also been suggested as a coating method for solid dosage forms.