{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T10:50:38Z","timestamp":1777546238140,"version":"3.51.4"},"reference-count":69,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,4,22]],"date-time":"2023-04-22T00:00:00Z","timestamp":1682121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FCT\/MEC","award":["UID\/QUI\/50006\/2019"],"award-info":[{"award-number":["UID\/QUI\/50006\/2019"]}]},{"name":"FCT\/MEC","award":["4340\/40868R"],"award-info":[{"award-number":["4340\/40868R"]}]},{"name":"FCT\/MEC","award":["UIDB\/00100\/2020"],"award-info":[{"award-number":["UIDB\/00100\/2020"]}]},{"name":"FCT\/MEC","award":["UIDP\/00100\/2020"],"award-info":[{"award-number":["UIDP\/00100\/2020"]}]},{"name":"FCT\/MEC","award":["LA\/P\/0056\/2020"],"award-info":[{"award-number":["LA\/P\/0056\/2020"]}]},{"name":"FCT\/MEC","award":["UIDB\/50025\/2020-2023"],"award-info":[{"award-number":["UIDB\/50025\/2020-2023"]}]},{"name":"FCT\/MEC","award":["ROTEIRO\/0031\/2013"],"award-info":[{"award-number":["ROTEIRO\/0031\/2013"]}]},{"name":"FCT\/MEC","award":["PINFRA\/22161\/2016"],"award-info":[{"award-number":["PINFRA\/22161\/2016"]}]},{"name":"FCT\/MEC","award":["POCI-01-0145-FEDER-007688"],"award-info":[{"award-number":["POCI-01-0145-FEDER-007688"]}]},{"name":"FCT\/MEC","award":["SFRH\/BD\/114653\/2016"],"award-info":[{"award-number":["SFRH\/BD\/114653\/2016"]}]},{"name":"FCT\/MEC","award":["IF\/01242\/2014\/CP1224\/CT0008"],"award-info":[{"award-number":["IF\/01242\/2014\/CP1224\/CT0008"]}]},{"name":"ERDF","award":["UID\/QUI\/50006\/2019"],"award-info":[{"award-number":["UID\/QUI\/50006\/2019"]}]},{"name":"ERDF","award":["4340\/40868R"],"award-info":[{"award-number":["4340\/40868R"]}]},{"name":"ERDF","award":["UIDB\/00100\/2020"],"award-info":[{"award-number":["UIDB\/00100\/2020"]}]},{"name":"ERDF","award":["UIDP\/00100\/2020"],"award-info":[{"award-number":["UIDP\/00100\/2020"]}]},{"name":"ERDF","award":["LA\/P\/0056\/2020"],"award-info":[{"award-number":["LA\/P\/0056\/2020"]}]},{"name":"ERDF","award":["UIDB\/50025\/2020-2023"],"award-info":[{"award-number":["UIDB\/50025\/2020-2023"]}]},{"name":"ERDF","award":["ROTEIRO\/0031\/2013"],"award-info":[{"award-number":["ROTEIRO\/0031\/2013"]}]},{"name":"ERDF","award":["PINFRA\/22161\/2016"],"award-info":[{"award-number":["PINFRA\/22161\/2016"]}]},{"name":"ERDF","award":["POCI-01-0145-FEDER-007688"],"award-info":[{"award-number":["POCI-01-0145-FEDER-007688"]}]},{"name":"ERDF","award":["SFRH\/BD\/114653\/2016"],"award-info":[{"award-number":["SFRH\/BD\/114653\/2016"]}]},{"name":"ERDF","award":["IF\/01242\/2014\/CP1224\/CT0008"],"award-info":[{"award-number":["IF\/01242\/2014\/CP1224\/CT0008"]}]},{"name":"Interreg 2 Seas program 2014\u20132020","award":["UID\/QUI\/50006\/2019"],"award-info":[{"award-number":["UID\/QUI\/50006\/2019"]}]},{"name":"Interreg 2 Seas program 2014\u20132020","award":["4340\/40868R"],"award-info":[{"award-number":["4340\/40868R"]}]},{"name":"Interreg 2 Seas program 2014\u20132020","award":["UIDB\/00100\/2020"],"award-info":[{"award-number":["UIDB\/00100\/2020"]}]},{"name":"Interreg 2 Seas program 2014\u20132020","award":["UIDP\/00100\/2020"],"award-info":[{"award-number":["UIDP\/00100\/2020"]}]},{"name":"Interreg 2 Seas program 2014\u20132020","award":["LA\/P\/0056\/2020"],"award-info":[{"award-number":["LA\/P\/0056\/2020"]}]},{"name":"Interreg 2 Seas program 2014\u20132020","award":["UIDB\/50025\/2020-2023"],"award-info":[{"award-number":["UIDB\/50025\/2020-2023"]}]},{"name":"Interreg 2 Seas program 2014\u20132020","award":["ROTEIRO\/0031\/2013"],"award-info":[{"award-number":["ROTEIRO\/0031\/2013"]}]},{"name":"Interreg 2 Seas program 2014\u20132020","award":["PINFRA\/22161\/2016"],"award-info":[{"award-number":["PINFRA\/22161\/2016"]}]},{"name":"Interreg 2 Seas program 2014\u20132020","award":["POCI-01-0145-FEDER-007688"],"award-info":[{"award-number":["POCI-01-0145-FEDER-007688"]}]},{"name":"Interreg 2 Seas program 2014\u20132020","award":["SFRH\/BD\/114653\/2016"],"award-info":[{"award-number":["SFRH\/BD\/114653\/2016"]}]},{"name":"Interreg 2 Seas program 2014\u20132020","award":["IF\/01242\/2014\/CP1224\/CT0008"],"award-info":[{"award-number":["IF\/01242\/2014\/CP1224\/CT0008"]}]},{"name":"European Regional Development Fund (FEDER)","award":["UID\/QUI\/50006\/2019"],"award-info":[{"award-number":["UID\/QUI\/50006\/2019"]}]},{"name":"European Regional Development Fund (FEDER)","award":["4340\/40868R"],"award-info":[{"award-number":["4340\/40868R"]}]},{"name":"European Regional Development Fund (FEDER)","award":["UIDB\/00100\/2020"],"award-info":[{"award-number":["UIDB\/00100\/2020"]}]},{"name":"European Regional Development Fund (FEDER)","award":["UIDP\/00100\/2020"],"award-info":[{"award-number":["UIDP\/00100\/2020"]}]},{"name":"European Regional Development Fund (FEDER)","award":["LA\/P\/0056\/2020"],"award-info":[{"award-number":["LA\/P\/0056\/2020"]}]},{"name":"European Regional Development Fund (FEDER)","award":["UIDB\/50025\/2020-2023"],"award-info":[{"award-number":["UIDB\/50025\/2020-2023"]}]},{"name":"European Regional Development Fund (FEDER)","award":["ROTEIRO\/0031\/2013"],"award-info":[{"award-number":["ROTEIRO\/0031\/2013"]}]},{"name":"European Regional Development Fund (FEDER)","award":["PINFRA\/22161\/2016"],"award-info":[{"award-number":["PINFRA\/22161\/2016"]}]},{"name":"European Regional Development Fund (FEDER)","award":["POCI-01-0145-FEDER-007688"],"award-info":[{"award-number":["POCI-01-0145-FEDER-007688"]}]},{"name":"European Regional Development Fund (FEDER)","award":["SFRH\/BD\/114653\/2016"],"award-info":[{"award-number":["SFRH\/BD\/114653\/2016"]}]},{"name":"European Regional Development Fund (FEDER)","award":["IF\/01242\/2014\/CP1224\/CT0008"],"award-info":[{"award-number":["IF\/01242\/2014\/CP1224\/CT0008"]}]},{"name":"PHC PESSOA 2018 project","award":["UID\/QUI\/50006\/2019"],"award-info":[{"award-number":["UID\/QUI\/50006\/2019"]}]},{"name":"PHC PESSOA 2018 project","award":["4340\/40868R"],"award-info":[{"award-number":["4340\/40868R"]}]},{"name":"PHC PESSOA 2018 project","award":["UIDB\/00100\/2020"],"award-info":[{"award-number":["UIDB\/00100\/2020"]}]},{"name":"PHC PESSOA 2018 project","award":["UIDP\/00100\/2020"],"award-info":[{"award-number":["UIDP\/00100\/2020"]}]},{"name":"PHC PESSOA 2018 project","award":["LA\/P\/0056\/2020"],"award-info":[{"award-number":["LA\/P\/0056\/2020"]}]},{"name":"PHC PESSOA 2018 project","award":["UIDB\/50025\/2020-2023"],"award-info":[{"award-number":["UIDB\/50025\/2020-2023"]}]},{"name":"PHC PESSOA 2018 project","award":["ROTEIRO\/0031\/2013"],"award-info":[{"award-number":["ROTEIRO\/0031\/2013"]}]},{"name":"PHC PESSOA 2018 project","award":["PINFRA\/22161\/2016"],"award-info":[{"award-number":["PINFRA\/22161\/2016"]}]},{"name":"PHC PESSOA 2018 project","award":["POCI-01-0145-FEDER-007688"],"award-info":[{"award-number":["POCI-01-0145-FEDER-007688"]}]},{"name":"PHC PESSOA 2018 project","award":["SFRH\/BD\/114653\/2016"],"award-info":[{"award-number":["SFRH\/BD\/114653\/2016"]}]},{"name":"PHC PESSOA 2018 project","award":["IF\/01242\/2014\/CP1224\/CT0008"],"award-info":[{"award-number":["IF\/01242\/2014\/CP1224\/CT0008"]}]},{"name":"National Funds through FCT\u2014Portuguese Foundation for Science and Technology","award":["UID\/QUI\/50006\/2019"],"award-info":[{"award-number":["UID\/QUI\/50006\/2019"]}]},{"name":"National Funds through FCT\u2014Portuguese Foundation for Science and Technology","award":["4340\/40868R"],"award-info":[{"award-number":["4340\/40868R"]}]},{"name":"National Funds through FCT\u2014Portuguese Foundation for Science and Technology","award":["UIDB\/00100\/2020"],"award-info":[{"award-number":["UIDB\/00100\/2020"]}]},{"name":"National Funds through FCT\u2014Portuguese Foundation for Science and Technology","award":["UIDP\/00100\/2020"],"award-info":[{"award-number":["UIDP\/00100\/2020"]}]},{"name":"National Funds through FCT\u2014Portuguese Foundation for Science and Technology","award":["LA\/P\/0056\/2020"],"award-info":[{"award-number":["LA\/P\/0056\/2020"]}]},{"name":"National Funds through FCT\u2014Portuguese Foundation for Science and Technology","award":["UIDB\/50025\/2020-2023"],"award-info":[{"award-number":["UIDB\/50025\/2020-2023"]}]},{"name":"National Funds through FCT\u2014Portuguese Foundation for Science and Technology","award":["ROTEIRO\/0031\/2013"],"award-info":[{"award-number":["ROTEIRO\/0031\/2013"]}]},{"name":"National Funds through FCT\u2014Portuguese Foundation for Science and Technology","award":["PINFRA\/22161\/2016"],"award-info":[{"award-number":["PINFRA\/22161\/2016"]}]},{"name":"National Funds through FCT\u2014Portuguese Foundation for Science and Technology","award":["POCI-01-0145-FEDER-007688"],"award-info":[{"award-number":["POCI-01-0145-FEDER-007688"]}]},{"name":"National Funds through FCT\u2014Portuguese Foundation for Science and Technology","award":["SFRH\/BD\/114653\/2016"],"award-info":[{"award-number":["SFRH\/BD\/114653\/2016"]}]},{"name":"National Funds through FCT\u2014Portuguese Foundation for Science and Technology","award":["IF\/01242\/2014\/CP1224\/CT0008"],"award-info":[{"award-number":["IF\/01242\/2014\/CP1224\/CT0008"]}]},{"name":"PTNMR","award":["UID\/QUI\/50006\/2019"],"award-info":[{"award-number":["UID\/QUI\/50006\/2019"]}]},{"name":"PTNMR","award":["4340\/40868R"],"award-info":[{"award-number":["4340\/40868R"]}]},{"name":"PTNMR","award":["UIDB\/00100\/2020"],"award-info":[{"award-number":["UIDB\/00100\/2020"]}]},{"name":"PTNMR","award":["UIDP\/00100\/2020"],"award-info":[{"award-number":["UIDP\/00100\/2020"]}]},{"name":"PTNMR","award":["LA\/P\/0056\/2020"],"award-info":[{"award-number":["LA\/P\/0056\/2020"]}]},{"name":"PTNMR","award":["UIDB\/50025\/2020-2023"],"award-info":[{"award-number":["UIDB\/50025\/2020-2023"]}]},{"name":"PTNMR","award":["ROTEIRO\/0031\/2013"],"award-info":[{"award-number":["ROTEIRO\/0031\/2013"]}]},{"name":"PTNMR","award":["PINFRA\/22161\/2016"],"award-info":[{"award-number":["PINFRA\/22161\/2016"]}]},{"name":"PTNMR","award":["POCI-01-0145-FEDER-007688"],"award-info":[{"award-number":["POCI-01-0145-FEDER-007688"]}]},{"name":"PTNMR","award":["SFRH\/BD\/114653\/2016"],"award-info":[{"award-number":["SFRH\/BD\/114653\/2016"]}]},{"name":"PTNMR","award":["IF\/01242\/2014\/CP1224\/CT0008"],"award-info":[{"award-number":["IF\/01242\/2014\/CP1224\/CT0008"]}]},{"name":"FCT through PIDDAC","award":["UID\/QUI\/50006\/2019"],"award-info":[{"award-number":["UID\/QUI\/50006\/2019"]}]},{"name":"FCT through PIDDAC","award":["4340\/40868R"],"award-info":[{"award-number":["4340\/40868R"]}]},{"name":"FCT through PIDDAC","award":["UIDB\/00100\/2020"],"award-info":[{"award-number":["UIDB\/00100\/2020"]}]},{"name":"FCT through PIDDAC","award":["UIDP\/00100\/2020"],"award-info":[{"award-number":["UIDP\/00100\/2020"]}]},{"name":"FCT through PIDDAC","award":["LA\/P\/0056\/2020"],"award-info":[{"award-number":["LA\/P\/0056\/2020"]}]},{"name":"FCT through PIDDAC","award":["UIDB\/50025\/2020-2023"],"award-info":[{"award-number":["UIDB\/50025\/2020-2023"]}]},{"name":"FCT through PIDDAC","award":["ROTEIRO\/0031\/2013"],"award-info":[{"award-number":["ROTEIRO\/0031\/2013"]}]},{"name":"FCT through PIDDAC","award":["PINFRA\/22161\/2016"],"award-info":[{"award-number":["PINFRA\/22161\/2016"]}]},{"name":"FCT through PIDDAC","award":["POCI-01-0145-FEDER-007688"],"award-info":[{"award-number":["POCI-01-0145-FEDER-007688"]}]},{"name":"FCT through PIDDAC","award":["SFRH\/BD\/114653\/2016"],"award-info":[{"award-number":["SFRH\/BD\/114653\/2016"]}]},{"name":"FCT through PIDDAC","award":["IF\/01242\/2014\/CP1224\/CT0008"],"award-info":[{"award-number":["IF\/01242\/2014\/CP1224\/CT0008"]}]},{"name":"FCT","award":["UID\/QUI\/50006\/2019"],"award-info":[{"award-number":["UID\/QUI\/50006\/2019"]}]},{"name":"FCT","award":["4340\/40868R"],"award-info":[{"award-number":["4340\/40868R"]}]},{"name":"FCT","award":["UIDB\/00100\/2020"],"award-info":[{"award-number":["UIDB\/00100\/2020"]}]},{"name":"FCT","award":["UIDP\/00100\/2020"],"award-info":[{"award-number":["UIDP\/00100\/2020"]}]},{"name":"FCT","award":["LA\/P\/0056\/2020"],"award-info":[{"award-number":["LA\/P\/0056\/2020"]}]},{"name":"FCT","award":["UIDB\/50025\/2020-2023"],"award-info":[{"award-number":["UIDB\/50025\/2020-2023"]}]},{"name":"FCT","award":["ROTEIRO\/0031\/2013"],"award-info":[{"award-number":["ROTEIRO\/0031\/2013"]}]},{"name":"FCT","award":["PINFRA\/22161\/2016"],"award-info":[{"award-number":["PINFRA\/22161\/2016"]}]},{"name":"FCT","award":["POCI-01-0145-FEDER-007688"],"award-info":[{"award-number":["POCI-01-0145-FEDER-007688"]}]},{"name":"FCT","award":["SFRH\/BD\/114653\/2016"],"award-info":[{"award-number":["SFRH\/BD\/114653\/2016"]}]},{"name":"FCT","award":["IF\/01242\/2014\/CP1224\/CT0008"],"award-info":[{"award-number":["IF\/01242\/2014\/CP1224\/CT0008"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/pharmaceutics15051320","type":"journal-article","created":{"date-parts":[[2023,4,24]],"date-time":"2023-04-24T01:35:44Z","timestamp":1682300144000},"page":"1320","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Evidence of Strong Guest\u2013Host Interactions in Simvastatin Loaded in Mesoporous Silica MCM-41"],"prefix":"10.3390","volume":"15","author":[{"given":"Teresa","family":"Cordeiro","sequence":"first","affiliation":[{"name":"LAQV-REQUIMTE, Department of Chemistry, NOVA School of Science and Technology, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal"}]},{"given":"In\u00eas","family":"Matos","sequence":"additional","affiliation":[{"name":"LAQV-REQUIMTE, Department of Chemistry, NOVA School of Science and Technology, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal"}]},{"given":"Florence","family":"Dan\u00e8de","sequence":"additional","affiliation":[{"name":"Univ. Lille, CNRS, INRAE, Centrale Lille, UMR 8207 - UMET - Unit\u00e9 Mat\u00e9riaux et Transformations, F-59000 Lille, France"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4589-0591","authenticated-orcid":false,"given":"Jo\u00e3o C.","family":"Sotomayor","sequence":"additional","affiliation":[{"name":"LAQV-REQUIMTE, Department of Chemistry, NOVA School of Science and Technology, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal"}]},{"given":"Isabel M.","family":"Fonseca","sequence":"additional","affiliation":[{"name":"LAQV-REQUIMTE, Department of Chemistry, NOVA School of Science and Technology, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0890-6133","authenticated-orcid":false,"given":"Marta C.","family":"Corvo","sequence":"additional","affiliation":[{"name":"i3N|Cenimat, Materials Science Department, NOVA School of Science and Technology, NOVA University, 2829-516 Caparica, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1487-0889","authenticated-orcid":false,"given":"Madalena","family":"Dion\u00edsio","sequence":"additional","affiliation":[{"name":"LAQV-REQUIMTE, Department of Chemistry, NOVA School of Science and Technology, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal"}]},{"given":"Mar\u00eda Teresa","family":"Viciosa","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences, Department of Chemical Engineering, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Affouard","sequence":"additional","affiliation":[{"name":"Univ. Lille, CNRS, INRAE, Centrale Lille, UMR 8207 - UMET - Unit\u00e9 Mat\u00e9riaux et Transformations, F-59000 Lille, France"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3714-3190","authenticated-orcid":false,"given":"Nat\u00e1lia T.","family":"Correia","sequence":"additional","affiliation":[{"name":"Univ. Lille, CNRS, INRAE, Centrale Lille, UMR 8207 - UMET - Unit\u00e9 Mat\u00e9riaux et Transformations, F-59000 Lille, France"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1021\/mp034006h","article-title":"Molecular Properties of WHO Essential Drugs and Provisional Biopharmaceutical Classification","volume":"1","author":"Kasim","year":"2004","journal-title":"Mol. Pharm."},{"key":"ref_2","unstructured":"(2023, March 26). DrugStats Database ClinCalc DrugStats Database. Available online: https:\/\/clincalc.com\/DrugStats\/."},{"key":"ref_3","unstructured":"Brittain, H.G. (1993). Analytical Profiles of Drug Substances and Excipients, Elsevier."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.pharmthera.2006.03.003","article-title":"Pharmacokinetic and Pharmacodynamic Alterations of 3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG-CoA) Reductase Inhibitors: Drug\u2013Drug Interactions and Interindividual Differences in Transporter and Metabolic Enzyme Functions","volume":"112","author":"Shitara","year":"2006","journal-title":"Pharmacol. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.3109\/03639045.2011.645830","article-title":"Enhanced Dissolution Rate and Oral Bioavailability of Simvastatin Nanocrystal Prepared by Sonoprecipitation","volume":"38","author":"Jiang","year":"2012","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1002\/jps.2600800905","article-title":"Relative Lipophilicities, Solubilities, and Structure\u2013Pharmacological Considerations of 3-Hydroxy-3-Methylglutaryl-Coenzyme A (HMG-CoA) Reductase Inhibitors Pravastatin, Lovastatin, Mevastatin, and Simvastatin","volume":"80","author":"Serajuddin","year":"1991","journal-title":"J. Pharm. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1248\/bpb.25.346","article-title":"Evaluation of Myopathy Risk for HMG-CoA Reductase Inhibitors by Urethane Infusion Method","volume":"25","author":"Matsuyama","year":"2002","journal-title":"Biol. Pharm. Bull."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.ejpb.2006.11.013","article-title":"Preparation and Characterization of Simvastatin\/Hydroxypropyl-\u03b2-Cyclodextrin Inclusion Complex Using Supercritical Antisolvent (SAS) Process","volume":"66","author":"Jun","year":"2007","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1023\/A:1016212804288","article-title":"A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and in Vivo Bioavailability","volume":"12","author":"Amidon","year":"1995","journal-title":"Pharm. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.ajps.2014.05.005","article-title":"Pharmaceutical Particle Technologies: An Approach to Improve Drug Solubility, Dissolution and Bioavailability","volume":"9","author":"Khadka","year":"2014","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/j.ddstr.2004.11.020","article-title":"Formulation Design: New Drugs from Old","volume":"1","author":"Crowley","year":"2004","journal-title":"Drug Discov. Today Ther. Strateg."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1186\/s12944-019-1139-8","article-title":"Parenteral Systems for Statin Delivery: A Review","volume":"18","author":"Korani","year":"2019","journal-title":"Lipids Health Dis."},{"key":"ref_13","first-page":"1536","article-title":"Assessment of Simvastatin Niosomes for Pediatric Transdermal Drug Delivery","volume":"23","author":"Zidan","year":"2016","journal-title":"Drug Deliv."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Salem, H.F., Kharshoum, R.M., Abou-Taleb, H.A., Farouk, H.O., and Zaki, R.M. (2021). Fabrication and Appraisal of Simvastatin via Tailored Niosomal Nanovesicles for Transdermal Delivery Enhancement: In Vitro and In Vivo Assessment. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13020138"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.bej.2013.08.007","article-title":"Enhanced Bioavailability and Hypolipidemic Activity of Simvastatin Formulations by Particle Size Engineering: Physicochemical Aspects and in Vivo Investigations","volume":"79","author":"Chavhan","year":"2013","journal-title":"Biochem. Eng. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"193","DOI":"10.3109\/02652048.2014.995726","article-title":"Micronisation of Simvastatin by the Supercritical Antisolvent Technique: In Vitro\u2013in Vivo Evaluation","volume":"32","author":"Patel","year":"2015","journal-title":"J. Microencapsul."},{"key":"ref_17","first-page":"591","article-title":"Simvastatin Solid Lipid Nanoparticles for Oral Delivery: Formulation Development and In Vivo Evaluation","volume":"75","author":"Padhye","year":"2013","journal-title":"Indian J. Pharm. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"27","DOI":"10.14227\/DT170210P27","article-title":"Dissolution Improvement of Simvastatin by Surface Solid Dispersion Technology","volume":"17","author":"Rao","year":"2010","journal-title":"Dissolution Technol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1208\/s12249-008-9176-z","article-title":"Co-Solvent Evaporation Method for Enhancement of Solubility and Dissolution Rate of Poorly Aqueous Soluble Drug Simvastatin: In Vitro\u2013In Vivo Evaluation","volume":"9","author":"Pandya","year":"2008","journal-title":"AAPS PharmSciTech"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.ijpharm.2003.12.028","article-title":"Development of Self-Microemulsifying Drug Delivery Systems (SMEDDS) for Oral Bioavailability Enhancement of Simvastatin in Beagle Dogs","volume":"274","author":"Kang","year":"2004","journal-title":"Int. J. Pharm."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"118960","DOI":"10.1016\/j.ijpharm.2019.118960","article-title":"Improving the Drug Load and in Vitro Performance of Supersaturated Self-Nanoemulsifying Drug Delivery Systems (Super-SNEDDS) Using Polymeric Precipitation Inhibitors","volume":"575","author":"Bannow","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"21532","DOI":"10.3390\/molecules201219784","article-title":"Characterization of Amorphous and Co-Amorphous Simvastatin Formulations Prepared by Spray Drying","volume":"20","author":"Craye","year":"2015","journal-title":"Molecules"},{"key":"ref_23","first-page":"77","article-title":"Arginine Complexes with Simvastatin: Apparent Solubility, In Vitro Dissolution and Solid State Characterization","volume":"15","author":"Tripathy","year":"2018","journal-title":"Curr. Drug Deliv."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1007\/s11095-005-4594-z","article-title":"Spray-Dried Amorphous Solid Dispersions of Simvastatin, a Low Tg Drug: In Vitro and in Vivo Evaluations","volume":"22","author":"Ambike","year":"2005","journal-title":"Pharm. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1080\/03639040500272025","article-title":"Physico-Chemical Characterization and Stability Study of Glassy Simvastatin","volume":"31","author":"Ambike","year":"2005","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1021\/mp400455r","article-title":"A Stable Amorphous Statin: Solid-State NMR and Dielectric Studies on Dynamic Heterogeneity of Simvastatin","volume":"11","author":"Nunes","year":"2014","journal-title":"Mol. Pharm."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1021\/cg700913m","article-title":"Physicochemical Properties and Stability of Two Differently Prepared Amorphous Forms of Simvastatin","volume":"8","author":"Graeser","year":"2008","journal-title":"Cryst. Growth Des."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.ejpb.2008.07.010","article-title":"Influence of Particle Size and Preparation Methods on the Physical and Chemical Stability of Amorphous Simvastatin","volume":"71","author":"Zhang","year":"2009","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1208\/s12249-020-01687-z","article-title":"Understanding Concomitant Physical and Chemical Transformations of Simvastatin During Dry Ball Milling","volume":"21","author":"Modhave","year":"2020","journal-title":"AAPS PharmSciTech"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.ejpb.2012.02.004","article-title":"Co-Amorphous Simvastatin and Glipizide Combinations Show Improved Physical Stability without Evidence of Intermolecular Interactions","volume":"81","author":"Strachan","year":"2012","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Nandi, U., Ajiboye, A.L., Patel, P., Douroumis, D., and Trivedi, V. (2021). Preparation of Solid Dispersions of Simvastatin and Soluplus Using a Single-Step Organic Solvent-Free Supercritical Fluid Process for the Drug Solubility and Dissolution Rate Enhancement. Pharmaceuticals, 14.","DOI":"10.3390\/ph14090846"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1016\/j.jmst.2019.04.027","article-title":"Bioactive Glass Nanotube Scaffold with Well-Ordered Mesoporous Structure for Improved Bioactivity and Controlled Drug Delivery","volume":"35","author":"Xiao","year":"2019","journal-title":"J. Mater. Sci. Technol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Song, K., Tang, Z., Song, Z., Meng, S., Yang, X., Guo, H., Zhu, Y., and Wang, X. (2022). Hyaluronic Acid-Functionalized Mesoporous Silica Nanoparticles Loading Simvastatin for Targeted Therapy of Atherosclerosis. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14061265"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Knapik-Kowalczuk, J., Kramarczyk, D., Chmiel, K., Romanova, J., Kawakami, K., and Paluch, M. (2020). Importance of Mesoporous Silica Particle Size in the Stabilization of Amorphous Pharmaceuticals\u2014The Case of Simvastatin. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12040384"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"110541","DOI":"10.1016\/j.micromeso.2020.110541","article-title":"Ibuprofen Incorporated into Unmodified and Modified Mesoporous Silica: From Matrix Synthesis to Drug Release","volume":"310","author":"Cordeiro","year":"2021","journal-title":"Microporous Mesoporous Mater."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.jnoncrysol.2014.10.020","article-title":"Optimization of MCM-41 Type Silica Nanoparticles for Biological Applications: Control of Size and Absence of Aggregation and Cell Cytotoxicity","volume":"408","author":"Varache","year":"2015","journal-title":"J. Non. Cryst. Solids"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"29247","DOI":"10.1038\/srep29247","article-title":"Zero-Valent Fe Confined Mesoporous Silica Nanocarriers (Fe(0) @ MCM-41) for Targeting Experimental Orthotopic Glioma in Rats","volume":"6","author":"Shevtsov","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Skwira, A., Szewczyk, A., Konopacka, A., G\u00f3rska, M., Majda, D., S\u0105dej, R., and Prokopowicz, M. (2019). Silica-Polymer Composites as the Novel Antibiotic Delivery Systems for Bone Tissue Infection. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12010028"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Alharthi, S., Ziora, Z.M., Janjua, T., Popat, A., and Moyle, P.M. (2022). Formulation and Biological Evaluation of Mesoporous Silica Nanoparticles Loaded with Combinations of Sortase A Inhibitors and Antimicrobial Peptides. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14050986"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1021\/acs.molpharmaceut.0c00908","article-title":"How Molecular Mobility, Physical State, and Drug Distribution Influence the Naproxen Release Profile from Different Mesoporous Silica Matrices","volume":"18","author":"Cordeiro","year":"2021","journal-title":"Mol. Pharm."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Kremer, F., and Sch\u00f6nhals, A. (2003). Broadband Dielectric Spectroscopy, Springer Berlin Heidelberg.","DOI":"10.1007\/978-3-642-56120-7"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s11244-011-9631-z","article-title":"Improvement in the Pore Size Distribution for Ordered Mesoporous Materials with Cylindrical and Spherical Pores Using the Kelvin Equation","volume":"54","author":"Barrera","year":"2011","journal-title":"Top. Catal."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1021\/ja01145a126","article-title":"The Determination of Pore Volume and Area Distributions in Porous Substances. I. Computations from Nitrogen Isotherms","volume":"73","author":"Barrett","year":"1951","journal-title":"J. Am. Chem. Soc."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5349","DOI":"10.1021\/acs.molpharmaceut.8b00818","article-title":"Polymorphism in Simvastatin: Twinning, Disorder, and Enantiotropic Phase Transitions","volume":"15","author":"Bernardes","year":"2018","journal-title":"Mol. Pharm."},{"key":"ref_45","unstructured":"McCrum, N., Williams, B., and Read, G. (1967). Anelastic and Dielectric Effects in Polymeric Solids, Wiley."},{"key":"ref_46","unstructured":"Smith, W., Forester, T.R., and Todorov, I.T. (2012). The DL POLY Classic User Manual, Daresbury Laboratory. 1.9."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"245201","DOI":"10.1103\/PhysRevB.67.245201","article-title":"Large Well-Relaxed Models of Vitreous Silica, Coordination Numbers, and Entropy","volume":"67","author":"Vink","year":"2003","journal-title":"Phys. Rev. B"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"6319","DOI":"10.1063\/1.471292","article-title":"Properties of Liquid Acetone in Silica Pores: Molecular Dynamics Simulation","volume":"104","author":"Zerda","year":"1996","journal-title":"J. Chem. Phys."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"9226","DOI":"10.1063\/1.1614206","article-title":"Grand Canonical Monte Carlo Simulation Study of Water Structure on Hydrophilic Mesoporous and Plane Silica Substrates","volume":"119","author":"Puibasset","year":"2003","journal-title":"J. Chem. Phys."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"11127","DOI":"10.1039\/b911859d","article-title":"Molecular Dynamics Simulation of Nanoconfined Glycerol","volume":"11","author":"Busselez","year":"2009","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"11225","DOI":"10.1021\/ja9621760","article-title":"Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids","volume":"118","author":"Jorgensen","year":"1996","journal-title":"J. Am. Chem. Soc."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.powtec.2016.12.035","article-title":"Efficient Adsorption of a Mixture of Polycyclic Aromatic Hydrocarbons (PAHs) by Si\u2013MCM\u201341 Mesoporous Molecular Sieve","volume":"308","author":"Costa","year":"2017","journal-title":"Powder Technol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"6382","DOI":"10.1021\/cm061551c","article-title":"Solid-State NMR Study of Ibuprofen Confined in MCM-41 Material","volume":"18","author":"Aussenac","year":"2006","journal-title":"Chem. Mater."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1021\/acsami.6b12647","article-title":"Multifunctional Peptide-Amphiphile End-Capped Mesoporous Silica Nanoparticles for Tumor Targeting Drug Delivery","volume":"9","author":"Cheng","year":"2017","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.colsurfb.2018.07.015","article-title":"Gold Modified Polydopamine Coated Mesoporous Silica Nano-Structures for Synergetic Chemo-Photothermal Effect","volume":"171","author":"Rahoui","year":"2018","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1039\/C6SM01879C","article-title":"Clogging of Microfluidic Systems","volume":"13","author":"Dressaire","year":"2017","journal-title":"Soft Matter"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Bouhid de Aguiar, I., and Schro\u00ebn, K. (2020). Microfluidics Used as a Tool to Understand and Optimize Membrane Filtration Processes. Membranes, 10.","DOI":"10.3390\/membranes10110316"},{"key":"ref_58","first-page":"o428","article-title":"Simvastatin","volume":"C59","author":"Jegorov","year":"2003","journal-title":"Acta Crystallogr. Sect. C Cryst. Struct. Commun."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1007\/s11224-009-9579-9","article-title":"Simvastatin: Structure Solution of Two New Low-Temperature Phases from Synchrotron Powder Diffraction and ss-NMR","volume":"21","author":"Jegorov","year":"2010","journal-title":"Struct. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3955","DOI":"10.1021\/jp0498163","article-title":"Through-Bonds and Through-Space Solid-State NMR Correlations at Natural Isotopic Abundance: Signal Assignment and Structural Study of Simvastatin","volume":"108","author":"Brus","year":"2004","journal-title":"J. Phys. Chem. A"},{"key":"ref_61","unstructured":"Silverstein, R.M., Bassler, G.C., and Morril, T.C. (1991). Spectrometric Identification of Organic Compounds, John Wiley & Sons."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2713","DOI":"10.1021\/mp400132r","article-title":"Energetics and Structure of Simvastatin","volume":"10","author":"Bernardes","year":"2013","journal-title":"Mol. Pharm."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Kremer, F., and Sch\u00f6nhals, A. (2003). Broadband Dielectric Spectroscopy, Springer Berlin Heidelberg.","DOI":"10.1007\/978-3-642-56120-7"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Kremer, F. (2014). Dynamics in geometrical confinement, Springer.","DOI":"10.1007\/978-3-319-06100-9"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1146\/annurev-physchem-032210-103343","article-title":"Dynamics of Nanoconfined Supercooled Liquids","volume":"62","author":"Richert","year":"2011","journal-title":"Annu. Rev. Phys. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Kremer, F. (2014). Dynamics in Geometrical Confinement, Springer.","DOI":"10.1007\/978-3-319-06100-9"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Kremer, F., and Sch\u00f6nhals, A. (2003). Broadband Dielectric Spectroscopy, Springer Berlin Heidelberg.","DOI":"10.1007\/978-3-642-56120-7"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"6506","DOI":"10.1021\/acs.langmuir.2c00521","article-title":"Structural and Dynamical Properties of Liquids in Confinements: A Review of Molecular Dynamics Simulation Studies","volume":"38","author":"Horstmann","year":"2022","journal-title":"Langmuir"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"044704","DOI":"10.1063\/1.4862648","article-title":"Water Confinement in Nanoporous Silica Materials","volume":"140","author":"Renou","year":"2014","journal-title":"J. Chem. Phys."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/5\/1320\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:21:23Z","timestamp":1760124083000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/5\/1320"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,22]]},"references-count":69,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["pharmaceutics15051320"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics15051320","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,22]]}}}