Date Published: May 21, 2020
Publisher: Springer International Publishing
Author(s): P. Zarmpi, T. Flanagan, E. Meehan, J. Mann, Nikoletta Fotaki.
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.
Excipient variability (changes in material properties) and variation (changes in amount) can affect final product quality leading to batch failures, altered bioavailability and bioinequivalence within products [1, 2]. The need for successful implementation of excipient variability in Quality by Design (QbD) approaches is widely recognized. Excipients may present challenges in a biopharmaceutical perspective as their presence may impact drug stability, solubility, permeability and overall product performance . Gastrointestinal factors may affect or be affected by excipient performance in pharmaceutical formulations . Varying the critical material attributes of certain excipients may be problematic for oral drug absorption. Understanding the biopharmaceutical risks of excipient variability would be beneficial towards the development of robust oral solid dosage forms.
The presence of certain critical excipients and changes in their critical material attributes in oral dosage forms can affect product performance. MgSt is a commonly used lubricant in immediate-release formulations but it can compromise drug dissolution. The current study focused on identifying the biopharmaceutical implications of MgSt presence and variability on drug apparent solubility. Solubility studies showed that for the majority of cases, the presence of MgSt significantly decreased drug apparent solubility due to its hydrophobic nature. The extent of the changes in drug apparent solubility depended on the material attributes of the studied MgSt brands, with excipient CRS and PSD being the most influential. The complex nature of excipient variability was revealed as the effects of excipient properties on drug apparent solubility strongly related to drug physicochemical properties (drug ionization, drug lipophilicity, drug aqueous solubility) and medium characteristics (pH/presence of bile salts). Cases where lower magnesium stearate levels may affect drug solubility will be considered for future work.