Journal of Drug Delivery Science and Technology 60 (2020) 102019 Available online 20 August 2020 1773-2247/© 2020 Elsevier B.V. All rights reserved. Research paper Polyglycerol esters of fatty acids as safe and stable matrix forming tableting excipients: A structure-function analysis Sharareh Salar-Behzadi a, b, * , Julia Karrer a , Valon Demiri a , Brenda Barrios a , Carolina Corzo a, b , Claudia Meindl c , Dirk Lochmann d , Sebastian Reyer d a Research Center Pharmaceutical Engineering GmbH, Graz, Austria b Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology, University of Graz, Graz, Austria c Center for Medical Research, Medical University of Graz, Graz, Austria d IOI OLEO GmbH, Witten, Germany A R T I C L E INFO Keywords: Polyglycerol esters of fatty acids Direct compression Matrix tablets Lipid-based excipient Solid-state Stability ABSTRACT This work describes a novel approach for the development of extended release matrix tablets with stable per- formance via direct compaction. Selected molecules belong to polyglycerol esters of fatty acids (PGFAs) - a group of lipid-based excipients (LBE) with advanced solid-state stability - were used for developing extended release tablets. Metformin HCl as a freely water soluble API was used as model substance. Three PGFA compounds with a HLB range of 1.8–4.5 were selected as matrix forming agents. The deformation behavior of tableting blends with and without PGFAs and their fow properties studied. Blends composing PGFAs showed reduced yield pressure and decreased internal friction between particles, suggesting the tendency to plastic behavior of PGFAs and improved fow properties of their blends, respectively. The blends of selected lipids with API and fller were directly processable via direct compression without any pretreatment such as granulation. The resulted tablets showed desired tensile strength and friability. Application of PGFAs with different HLB allowed the tailoring of API release profle for different time periods with the same concentration of lipid in the tablet. The stable release profle was related to the stable solid state of lipids as matrix agent. No in vitro cytotoxic effect was observed by assessing the dehydrogenase activity. 1. Introduction Being one of the oldest dosage forms, tablets are still the most worldwide accepted form with the advantage of large scale production at low cost. Direct compression (DC) is the most straightforward and simplest method to produce tablets [1]. DC has the advantage of being cost effective with inherent continuous nature, which fts to the concept of continuous manufacturing with the aim of providing higher yields with reduced amount of out-of-specifcation (OOS) products combined with shorter processing time and lower costs [2–4]. DC is desired for the manufacturing of extended release tablets in the most simple and cost effective way of blending the API with fller, lubricant and matrix forming agent followed by DC to provide matrix tablets [1]. In this re- gard, there is also a growing interest for using lipid-based excipients (LBE) as matrix forming agents, because of the natural lipophilicity of these materials, which makes them promising agents for the develop- ment of extended release formulations [4]. Moreover, they are mostly naturally occurring materials that are predominantly digestible with “Generally Recognized as Safe” (GRAS) status [4]. However, application of DC for lipid-based matrix formulations is challenging, due to the suboptimal tableting properties of blends, for instance insuffcient fowability or compressability, and the insuffcient tensile strength or improper release behavior of compressed matrix tablets [4]. The ob- tained granules are afterwards processed into tablets as fnal form or as intermediate product with modifed release properties [4–7]. The extended release can be fnalized by a flm coating step with polymeric excipients. Polymeric excipients have been also used as binder to improve the granulation of lipid-based formulations or to improve their compressability [4–8]. Although this kind of formulation development results in matrix tablets with appropriate tablet properties and desired release profle, it is far away from being cost effective and simple. This is due to the need of co-processing of excipients in order to provide desire compression properties or the need of a chain of manufacturing pro- cesses e.g. granulation, followed by tableting and coating to provide the desired fnal product [4–9]. Moreover, the processes such as melt * Corresponding author. Research Center for Pharmaceutical Engineering GmbH, Inffeldgasse 13, 8010, Graz, Austria. E-mail address: sharareh.salar@rcpe.at (S. Salar-Behzadi). Contents lists available at ScienceDirect Journal of Drug Delivery Science and Technology journal homepage: www.elsevier.com/locate/jddst https://doi.org/10.1016/j.jddst.2020.102019 Received 12 June 2020; Received in revised form 1 August 2020; Accepted 14 August 2020