Cordeiro, TeresaMatos, InêsDanède, FlorenceSotomayor, João C.Fonseca, Isabel M.Corvo, Marta C.Dionísio, MadalenaViciosa, María TeresaAffouard, FrédéricCorreia, Natália T.2023-06-292023-06-292023-04-221999-4923PURE: 64822664PURE UUID: 60ed8a3f-f1aa-45ee-a94b-f46883e2b101Scopus: 85160394158WOS: 000997952200001PubMed: 37242562PubMedCentral: PMC10222570ORCID: /0000-0002-1487-0889/work/151422189http://hdl.handle.net/10362/154626co-financed by the ERDF under the PT2020 Partnership Agreement (POCI-01-0145-FEDER—007265). This research was funded by the Interreg 2 Seas program 2014–2020, and co-funded by the European Regional Development Fund (FEDER) under subsidy contract 2S01-059_IMODE and 2S07-033_ Site Drug. This research was funded by the Program PHC PESSOA 2018 project nbr 4340/40868R. This research was funded by National Funds through FCT—Portuguese Foundation for Science and Technology, reference, LA/P/0056/2020, UIDB/50025/2020-2023, and PTNMR (ROTEIRO/0031/2013), co-financed by ERDF through COMPETE 2020, Portugal, POCI and PORL and FCT through PIDDAC (POCI-01-0145-FEDER-007688). Publisher Copyright: © 2023 by the authors.A rational design of drug delivery systems requires in-depth knowledge not only of the drug itself, in terms of physical state and molecular mobility, but also of how it is distributed among a carrier and its interactions with the host matrix. In this context, this work reports the behavior of simvastatin (SIM) loaded in mesoporous silica MCM-41 matrix (average pore diameter ~3.5 nm) accessed by a set of experimental techniques, evidencing that it exists in an amorphous state (X-ray diffraction, ssNMR, ATR-FTIR, and DSC). The most significant fraction of SIM molecules corresponds to a high thermal resistant population, as shown by thermogravimetry, and which interacts strongly with the MCM silanol groups, as revealed by ATR-FTIR analysis. These findings are supported by Molecular Dynamics (MD) simulations predicting that SIM molecules anchor to the inner pore wall through multiple hydrogen bonds. This anchored molecular fraction lacks a calorimetric and dielectric signature corresponding to a dynamically rigid population. Furthermore, differential scanning calorimetry showed a weak glass transition that is shifted to lower temperatures compared to bulk amorphous SIM. This accelerated molecular population is coherent with an in-pore fraction of molecules distinct from bulklike SIM, as highlighted by MD simulations. MCM-41 loading proved to be a suitable strategy for a long-term stabilization (at least three years) of simvastatin in the amorphous form, whose unanchored population releases at a much higher rate compared to the crystalline drug dissolution. Oppositely, the surface-attached molecules are kept entrapped inside pores even after long-term release assays.287509338engamorphous statedrug delivery developmentdrug releasedrug-carrier multiple interactionsmolecular mobilitysimvastatinPharmaceutical Sciencejournal article10.3390/pharmaceutics15051320https://www.scopus.com/pages/publications/85160394158