Abstract
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.
Highlights
Excipient variability and variation can affect final product quality leading to batch failures, altered bioavailability and bioinequivalence within products [1, 2]
Excipients are major components of oral solid dosage forms, and changes in their critical material attributes and/or amount in pharmaceutical formulations may present a challenge for product performance
The current study investigated the impact of magnesium stearate (MgSt) variability on the apparent solubility of drugs with a wide range of physicochemical properties
Summary
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 [3]. Gastrointestinal factors may affect or be affected by excipient performance in pharmaceutical formulations [4]. 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
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