Contents lists available at ScienceDirect European Journal of Pharmaceutics and Biopharmaceutics journal homepage: www.elsevier.com/locate/ejpb Research paper Molecular-level insight into hot-melt loading and drug release from mesoporous silica carriers D. Lizoňová a,b , J. Mužík a , M. Šoltys a , J. Beránek b , S.G. Kazarian c, ⁎ , F. Štěpánek a, ⁎ a Department of Chemical Engineering, University of Chemistry and Technology Prague, Technicka 3, 166 28 Prague 6, Czech Republic b Zentiva k.s., U Kabelovny 130, Prague 10, Czech Republic c Department of Chemical Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom ABSTRACT Drug amorphisation by loading to inorganic mesoporous carriers represents an emerging area of improving the dissolution rate and bioavailability of poorly water- soluble active pharmaceutical ingredients (APIs). In this work, for the first time, a molecular-level insight into the process of API loading to mesoporous SiO 2 (silica) carriers by the hot-melt impregnation method and its subsequent release during dissolution was obtained using ATR-FTIR spectroscopic imaging. A physical mixture of ibuprofen crystals and mesoporous silica particles was heated and the dynamics of melt loading into the silica pore structure was directly observed in situ by ATR- FTIR spectroscopic imaging. The loss of crystallinity, the redistribution of the API in the silica pore network and the subsequent stabilisation of the amorphous form upon cooling were proven. The API was involved in two different kinds of molecular-level interactions: API dimers in the amorphous bulk, and individual API molecules adsorbed on the silica surface. The melt-loaded silica carriers were comprehensively characterised by DSC, SEM and dissolution tests, which proved dissolution rate enhancement due to amorphisation of the API. Drug release form the hot-melt loaded mesoporous silica carriers was observed in real time and the conditions leading to local re-crystallisation of super-saturated solution of the API were identified. 1. Introduction The bioavailability of Active Pharmaceutical Ingredients (APIs) can generally be limited by their dissolution kinetics or the rate of ab- sorption. The majority of new small-molecule APIs are classified as poorly water soluble [1] and therefore their dissolution rate improve- ment is of high interest in the field of pharmaceutical research. Aqueous solubility and the dissolution rate can be enhanced using various ap- proaches, which include crystal engineering [2–4], nanomilling [5,6], cyclodextrin complexation [7], formation of microemulsions [8] or amorphisation. Formulation of the API in the high-energy amorphous form is a particularly efficient strategy to enhance its solubility, but the metastable amorphous APIs are susceptible to recrystallization [9] and therefore there is a need to stabilise them [10], for example using polymeric carriers. Such formulations are referred to as Amorphous Solid Dispersions (ASD) [10–16] and can be prepared by hot-melt ex- trusion [17] or spray drying [18]. Another emerging amorphisation approach uses inorganic porous carriers with nano-sized capillaries, which allow to keep the API in the amorphous state due to steric inhibition of recrystallization [19,20] (crystallisation is completely suppressed below a certain critical pore diameter thanks to surface energy contribution, which over- compensates the advantageous release of internal energy upon crys- tallisation [21]). The porous carriers can provide higher loading capacities on a mass basis than polymer-stabilised ASDs and faster quantitative release due to the absence of swelling [22]. Among these materials, mesoporous silica particles have been shown to effectively stabilise the amorphous state of APIs [23–25], which leads to fast drug release in the aqueous environment and local supersaturation [26,27]. The high concentration of the drug released from such carriers can enhance the drug absorption and thus improve its bioavailability [28,29]. Silica is an approved pharmaceutical excipient commonly used as a glidant [30] and can be easily surface-modified in order to optimize drug loading and subsequent release in the human body [31]. The drug loading to mesoporous silica can be achieved by solvent immersion, solvent evaporation [32–34] or by hot-melt impregnation methods. The methods employing solvent find use in the case of tem- perature sensitive drugs, but these loading techniques require energy- intensive separation steps (drying/evaporation) [35] and may lead to residual solvent content [36]. The hot-melt loading is fast, does not require any additional purification steps and can even lead to higher loading capacities [37]. However, relatively little is known about the mechanistic details of hot-melt impregnation at the molecular level. Fourier-Transform Infrared (FTIR) spectroscopic imaging is a pow- erful tool which enables spectroscopic and spatial discrimination of individual components within a sample in a short time [38,39]. In pharmaceutical research, FTIR imaging can be utilized in high- throughput screening [40] or to study tablet swelling [41], dissolution https://doi.org/10.1016/j.ejpb.2018.07.013 Received 23 May 2018; Received in revised form 10 July 2018; Accepted 13 July 2018 ⁎ Corresponding authors. E-mail addresses: s.kazarian@imperial.ac.uk (S.G. Kazarian), Frantisek.Stepanek@vscht.cz (F. Štěpánek). European Journal of Pharmaceutics and Biopharmaceutics 130 (2018) 327–335 0939-6411/ © 2018 Elsevier B.V. All rights reserved. T