Colloids and Surfaces B: Biointerfaces 166 (2018) 24–28 Contents lists available at ScienceDirect Colloids and Surfaces B: Biointerfaces journal homepage: www.elsevier.com/locate/colsurfb Release kinetics and cell viability of ibuprofen nanocrystals produced by melt-emulsification A.R. Fernandes a,b , J. Dias-Ferreira a , C. Cabral a,c , M.L. Garcia d,e , E.B. Souto a,b,∗ a Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal b REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal c Center for Neuroscience and Cell Biology & Institute for Biomedical Imaging and Life Sciences (CNC-IBILI), University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal d Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy, University of Barcelona, 08028, Barcelona, Spain e Institute of Nanoscience and nanotechnology (IN2UB). Faculty of Pharmacy, University of Barcelona, 08028, Barcelona, Spain a r t i c l e i n f o Article history: Received 25 July 2017 Received in revised form 27 February 2018 Accepted 2 March 2018 Available online 5 March 2018 Chemical compound studied in this article: Ibuprofen (PubChem CID: 3672) Keywords: Nanocrystals Poorly water soluble drugs Release kinetics Caco-2 cells AlamarBlue ® Cell viability a b s t r a c t The clinical use of poorly water-soluble drugs has become a big challenge in pharmaceutical development due to the compromised bioavailability of the drugs in vivo. Nanocrystals have been proposed as a formu- lation strategy to improve the dissolution properties of these drugs. The benefits of using nanocrystals in drug delivery, when compared to other nanoparticles, are related to their production facilities, simple structure, and suitability for a variety of administration routes. High pressure homogenization (HPH) is the most promising production process, which can be employed at low or high temperatures. Ibuprofen nanocrystals with a mean size below 175 nm, and polydispersity below 0.18, have been produced by melt- emulsification, followed by HPH. Two nanocrystal formulations, differing on the surfactant composition, have been produced, their in vitro ibuprofen release tested in Franz diffusion cells and adjusted to several kinetic models (zero order, first order, Higuchi, Hixson-Crowell, Korsmeyer-Peppas, Baker-Lonsdale and Weibull model). Cell viability was assessed at 3, 6 and 24 h of incubation on human epithelial colorec- tal cells (Caco-2) by AlamarBlue ® colorimetric assay. For both formulations, Caco-2 cells viability was dependent on the drug concentration and time of exposure. © 2018 Published by Elsevier B.V. 1. Introduction Pharmaceutical nanocrystals are innovative drug carriers, produced by down-sizing technology from the microscale to nanoscale, aiming to dramatically change the physicochemical properties of compounds. Nanocrystals are drug nanosuspensions of solid particles, surface-stabilized with a surfactant layer, featur- ing a size in the nanometer range (i.e. mean diameter below 1 m) [1]. In the beginning of the 90s, Elan Nanosystems (San Francisco, CA, USA) preferentially encouraged the use of nanocrystals for oral bioavailability enhancement instead of the use of microcrystals, which were suspended in water [2]. Nanosuspensions consist of the dispersion of drug nanocrystals in liquid media [3]. The dispersed solid particles are usually stabilized by surfactants or polymeric sta- ∗ Corresponding author at: Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), Pólo das Ciências da Saúde, Azinhaga de Santa Comba, Coimbra, 3000-548, Portugal. E-mail addresses: ebsouto@ff.uc.pt, ebsouto@ebsouto.pt (E.B. Souto). bilizers [4]. Water, aqueous or non-aqueous solutions can be used as dispersion media [5]. Comparing to conventional dosage forms, the bioavailability of drug nanocrystals increases significantly, both by the increased surface area and by the fact that particles are made of 100% of drug [6]. This property contributes for the achievement of a high therapeutic concentration at the site of action, thus exhibiting an improved pharmacological effect [7]. In addition, due to their high loading capacity, nanocrystals are very effective in transport- ing drugs [5]. Nanocrystals are usually stabilized by electrostatic and/or steric stabilization by surfactants such as lecithin, alone or in combination with sodium cholate or non-ionic surfactants, e.g. Tween 80, poloxamer 188 and polyvinylpyrrolidone. These surfac- tants are accepted for intravenous injection, while using binary or ternary mixtures of electrostatic and steric surfactants was found to be effective for long-term stability [8,9]. For other administra- tion routes, e.g. oral administration, several other surfactants can be also used [10]. Several methods have been described to solubilize poorly water soluble drugs, however the selection depends on the chemical https://doi.org/10.1016/j.colsurfb.2018.03.005 0927-7765/© 2018 Published by Elsevier B.V.