title: A microstructural study of water effects in lipid-based pharmaceutical formulations for liquid filling of capsules.
abstract: Water is known to exhibit pronounced effects on lipid-based formulations (LBFs) and much research has focused on aqueous dispersion and dilution behavior regarding biopharmaceutical performance. From a product quality perspective, it is also critical to study a range of lower water amounts in formulations with respect to capsule filling. The present work addressed the need for a better understanding of LBF microstructure by taking percolation theory into account. The effects of increasing amounts of water on LBFs were analyzed by conductivity, water activity, time-domain nuclear magnetic resonance, and diffusing wave spectroscopy. Results were interpreted using percolation theory and preliminary mechanical tests were conducted on gelatin and hypromellose (HPMC) capsule shells. For both LBF systems, increasing water amounts led to marked changes in the microstructure of the formulations. Percolation laws could be fitted adequately to the data and thresholds were identified for the formation of continuous water channels (ϕwc~0.02-0.06). A new theoretical model was proposed for water activity. The preliminary shell material studies showed that the threshold for generating water channels in the formulation could be correlated to mechanical changes of the capsule shell that were relatively more pronounced in the case of gelatin. This mechanistic study demonstrated the importance of understanding and monitoring of microstructural changes occurring in LBFs with increasing amounts of water, which will help to design quality into the final dosage form.
authors.affiliation: University of Applied Sciences and Arts Northwestern Switzerland, Institute of Pharma Technology, Gründenstrasse 40, CH-4132 Muttenz, Switzerland.
authors.forename: Alexandra H E
authors.initials: AH
authors.lastname: Machado
authors.affiliation: Qualicaps® Co., Ltd., Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Kokubo
authors.affiliation: Qualicaps® Europe, S.A.U., Spain.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Dujovny
authors.affiliation: Qualicaps® Europe, S.A.U., Spain.
authors.forename: Brian
authors.initials: B
authors.lastname: Jones
authors.affiliation: Tillotts Pharma AG, Switzerland.
authors.forename: Claudio
authors.initials: C
authors.lastname: Scialdone
authors.affiliation: Tillotts Pharma AG, Switzerland.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bravo
authors.affiliation: University of Applied Sciences and Arts Northwestern Switzerland, Institute of Pharma Technology, Gründenstrasse 40, CH-4132 Muttenz, Switzerland. Electronic address: martin.kuentz@fhnw.ch.
authors.forename: Martin
authors.initials: M
authors.lastname: Kuentz
mesh_terms: D002214:Capsules / Q000737:chemistry*; D004339:Drug Compounding / Q000379:methods*; D004345:Drug Industry / Q000379:methods; D004553:Electric Conductivity; D008055:Lipids / Q000737:chemistry*; D008956:Models, Chemical; D014867:Water / Q000737:chemistry*
chemical_list: D002214:Capsules; D008055:Lipids; D014867:Water
keywords: Colloids; Continuous water channels; Gelatin; HPMC; Hard-shell capsules; Lipid-based formulations; Percolation theory