Biopharmaceutical understanding of excipient variability in drug product performance

Student thesis: Doctoral ThesisPhD


Excipients present a challenge for oral drug bioavailability and it is recognized that excipient variability needs to be implemented in Quality by Design (QbD) approaches. The purpose of this thesis was to identify the biopharmaceutical implications of excipient variability on product performance. A systematic literature review identified the critical excipients (lubricants: magnesium stearate (MgSt), binders: hypromellose (HPMC), superdisintegrants: (sodium starch glycolate (SSG), croscarmellose sodium (CCS), crospovidone (CCS)) for oral drug performance and their critical material attributes that were further selected for experimentation. The impact of excipient variability on drug solubility and drug dissolution was examined using model compounds of different physicochemical properties. The effects of the varying composition of the gastrointestinal tract on the impact of excipients on product performance were examined by selecting compendial and biorelevant media and apparatuses of diverse hydrodynamics. Real – time surface dissolution UV imaging was used to characterize excipient behaviour under physiological conditions and to understand the mechanistic role of excipient variability on product performance. Excipient presence and variability affected drug solubility. MgSt and HPMC were considered excipients of high criticality for oral drug performance compared to superdisintegrants. Excipient effects on drug solubility strongly depended on drug physicochemical properties and medium characteristics. Cases where excipient variability may be critical for product performance were demonstrated with the design of roadmaps. Dissolution studies for a highly and a poorly soluble drug from tablets containing variant excipients revealed the criticality of MgSt variability (compared to HPMC and SSG) as faster drug dissolution for a highly soluble compound was observed when decreasing the particle size of MgSt. The influential role of pH, presence of solubilizing components and hydrodynamics on the impact of excipient variability on drug dissolution was revealed. Finally, the visualization of the surface events of superdisintegrant (SSG, CCS) swelling and their impact on drug dissolution revealed that the effects of superdisintegrants on drug dissolution strongly depend on excipient critical material attributes, drug aqueous solubility and pH of the medium. Throughout the studies of this thesis, the use of multivariate data analysis identified the critical biopharmaceutical factors of excipient variability with a potential risk for oral drug absorption.
Date of Award4 Sept 2019
Original languageEnglish
Awarding Institution
  • University of Bath
SupervisorNikoletta Fotaki (Supervisor) & Albert Bolhuis (Supervisor)


  • excipient variability
  • drug product performance
  • solubility
  • dissolution

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