title: Microphase separation in solid lipid dosage forms as the cause of drug release instability.
abstract: Although lipid excipients are of increasing interest for development of taste-masked and modified release formulations, the drug release instability and the lack of mechanistic understanding in that regard still prevent their larger-scale application. In this work, we investigated the physical stability of a binary (tripalmitin/polysorbate 65) lipid coating formulation with a known stable polymorphism. The coating composition was characterized using DSC to construct the phase diagram of binary system and polarized light microscopy to display the microstructure organization. The water uptake and the erosion of slabs cast from the coating formulations were investigated post-production and after storage. Subsequently, N-acetylcysteine particles were coated with the selected formulations and the drug release stability was investigated. Additionally, microstructure characterization was performed via SEM and X-ray diffraction. The drug release instability was explained by polysorbate 65 and tripalmitin phase growth during storage, especially at 40°C, suggesting that polysorbate 65 can leak out of tripalmitin spherulitic structures, creating lipophilic and impermeable tripalmitin regions. The growth of polysorbate 65 phase leads to larger hydrophilic channels with reduced tortuosity. This work indicates that for obtaining stable drug release profiles from advanced lipid formulations, microphase separation should be prevented during storage.
authors.affiliation: Research Center Pharmaceutical Engineering GmbH, Graz, Austria; Institute of Pharmaceutical Science, Department of Pharmaceutical Technology, University of Graz, Austria.
authors.forename: Diogo Gomes
authors.initials: DG
authors.lastname: Lopes
authors.affiliation: Research Center Pharmaceutical Engineering GmbH, Graz, Austria; Institute of Pharmaceutical Science, Department of Pharmaceutical Technology, University of Graz, Austria.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Koutsamanis
authors.affiliation: Institute of Pharmaceutical Science, Department of Pharmaceutical Technology, University of Graz, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Becker
authors.affiliation: Research Center Pharmaceutical Engineering GmbH, Graz, Austria.
authors.forename: Otto
authors.initials: O
authors.lastname: Scheibelhofer
authors.affiliation: Research Center Pharmaceutical Engineering GmbH, Graz, Austria; Bruker AXS GmbH, Graz, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Laggner
authors.affiliation: Hermes Arzneimittel GmbH, Großhesselohe, Germany.
authors.forename: Detlev
authors.initials: D
authors.lastname: Haack
authors.affiliation: IOI Oleo GmbH, Witten, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Stehr
authors.affiliation: Institute of Pharmaceutical Science, Department of Pharmaceutical Technology, University of Graz, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.affiliation: Research Center Pharmaceutical Engineering GmbH, Graz, Austria. Electronic address: sharareh.salar-behzadi@rcpe.at.
authors.forename: Sharareh
authors.initials: S
authors.lastname: Salar-Behzadi
mesh_terms: D000111:Acetylcysteine / Q000737:chemistry / Q000493:pharmacokinetics*; D003460:Crystallization; D004339:Drug Compounding; D065546:Drug Liberation; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry; D008055:Lipids / Q000737:chemistry; D010316:Particle Size; D044367:Phase Transition; D011136:Polysorbates / Q000737:chemistry*; D014280:Triglycerides / Q000737:chemistry*
chemical_list: D005079:Excipients; D008055:Lipids; D011136:Polysorbates; D014280:Triglycerides; C005859:tripalmitin; D000111:Acetylcysteine
keywords: Drug release stability; Hot-melt coating; Microphase separation; Polymorphism; Solid lipid excipients