{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T01:22:22Z","timestamp":1791422542273,"version":"4.3.3"},"reference-count":46,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,8,15]],"date-time":"2024-08-15T00:00:00Z","timestamp":1723680000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2019s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie","award":["847568"],"award-info":[{"award-number":["847568"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>This research work dives into the complexity of hot-melt extrusion (HME) and its influence on drug stability, focusing on solid dispersions containing 30% of glibenclamide and three 50:50 polymer blends. The polymers used in the study are Ethocel Standard 10 Premium, Kollidon SR and Affinisol HPMC HME 4M. Glibenclamide solid dispersions are characterized using thermal analyses (thermogravimetric analysis (TGA) and differential scanning calorimetry), X-ray diffraction and scanning electron microscopy. This study reveals the transformation of glibenclamide into impurity A during the HME process using mass spectrometry and TGA. Thus, it enables the quantification of the extent of degradation. Furthermore, this work shows how polymer\u2013polymer blend matrices exert an impact on process parameters, the active pharmaceutical ingredient\u2019s physical state, and drug release behavior. In vitro dissolution studies show that the polymeric matrices investigated provide extended drug release (over 24 h), mainly dictated by the polymer\u2019s chemical nature. This paper highlights how glibenclamide is degraded during HME and how polymer selection crucially affects the sustained release dynamics.<\/jats:p>","DOI":"10.3390\/pharmaceutics16081071","type":"journal-article","created":{"date-parts":[[2024,8,16]],"date-time":"2024-08-16T04:29:57Z","timestamp":1723782597000},"page":"1071","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Impact of Hot-Melt Extrusion on Glibenclamide\u2019s Physical and Chemical States and Dissolution Behavior: Case Studies with Three Polymer Blend Matrices"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2443-5003","authenticated-orcid":false,"given":"Nina","family":"Zupan","sequence":"first","affiliation":[{"name":"Univ. Lille, Inserm, CHU Lille, U1008, F-59000 Lille, France"},{"name":"Univ. Lille, CNRS, INRAE, Centrale Lille, UMR 8207-UMET, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ines","family":"Yous","sequence":"additional","affiliation":[{"name":"Univ. Lille, Inserm, CHU Lille, U1008, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Danede","sequence":"additional","affiliation":[{"name":"Univ. Lille, CNRS, INRAE, Centrale Lille, UMR 8207-UMET, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Verin","sequence":"additional","affiliation":[{"name":"Univ. Lille, Inserm, CHU Lille, U1008, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mostafa","family":"Kouach","sequence":"additional","affiliation":[{"name":"Univ. Lille, CHU Lille, ULR 7365-GRITA, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Foulon","sequence":"additional","affiliation":[{"name":"Univ. Lille, CHU Lille, ULR 7365-GRITA, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4176-1925","authenticated-orcid":false,"given":"Emeline","family":"Dudognon","sequence":"additional","affiliation":[{"name":"Univ. Lille, CNRS, INRAE, Centrale Lille, UMR 8207-UMET, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7111-6105","authenticated-orcid":false,"given":"Susanne","family":"Florin Muschert","sequence":"additional","affiliation":[{"name":"Univ. Lille, Inserm, CHU Lille, U1008, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"58","DOI":"10.7324\/JAPS.2019.90708","article-title":"Characterization of Eudragit types and Kollidon SR inter-polymer complexes and their effects on the drug release","volume":"9","author":"Choiri","year":"2019","journal-title":"J. Appl. Pharm. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1080\/03639045.2021.1908342","article-title":"Ternary solid dispersions: Classification and formulation considerations","volume":"47","author":"Borde","year":"2021","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1080\/03639040701498759","article-title":"Pharmaceutical Applications of Hot-Melt Extrusion: Part I","volume":"33","author":"Crowley","year":"2007","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"118989","DOI":"10.1016\/j.ijpharm.2019.118989","article-title":"Systematic screening of pharmaceutical polymers for hot melt extrusion processing: A comprehensive review","volume":"576","author":"Thakkar","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Censi, R., Gigliobianco, M., Casadidio, C., and Di Martino, P. (2018). Hot Melt Extrusion: Highlighting Physicochemical Factors to Be Investigated While Designing and Optimizing a Hot Melt Extrusion Process. Pharmaceutics, 10.","DOI":"10.3390\/pharmaceutics10030089"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1016\/j.drudis.2015.01.012","article-title":"Polymeric formulations for drug release prepared by hot melt extrusion: Application and characterization","volume":"20","author":"Frijlink","year":"2015","journal-title":"Drug Discov. Today"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.ddtec.2011.10.002","article-title":"The use of amorphous solid dispersions: A formulation strategy to overcome poor solubility and dissolution rate","volume":"9","year":"2012","journal-title":"Drug Discov. Today Technol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3237","DOI":"10.1002\/jps.24541","article-title":"Amorphous Solid Dispersions: Utilization and Challenges in Drug Discovery and Development","volume":"104","author":"He","year":"2015","journal-title":"J. Pharm. Sci."},{"key":"ref_9","unstructured":"Kolter, K., Karl, M., and Gryczke, A. (2012). Hot-Melt Extrusion with BASF Pharma Polymers, BASF SE. [2nd ed.]."},{"key":"ref_10","first-page":"100062","article-title":"Towards predicting the product quality in hot-melt extrusion: Small scale extrusion","volume":"2","author":"Alva","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref_11","first-page":"100776","article-title":"Development of a hot-melt extrusion (HME) process to produce drug loaded AffinisolTM 15LV filaments for fused filament fabrication (FFF) 3D printing","volume":"29","author":"Prasad","year":"2019","journal-title":"Addit. Manuf."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"103843","DOI":"10.1016\/j.jddst.2022.103843","article-title":"Production and characterization of glibenclamide incorporated PLA filaments for 3D printing by fused deposition modeling","volume":"77","author":"Kukkonen","year":"2022","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.ijpharm.2019.01.038","article-title":"Hot-melt extrusion process impact on polymer choice of glyburide solid dispersions: The effect of wettability and dissolution","volume":"559","author":"Alshafiee","year":"2019","journal-title":"Int. J. Pharm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.apsb.2013.06.007","article-title":"Use of polymer combinations in the preparation of solid dispersions of a thermally unstable drug by hot-melt extrusion","volume":"3","author":"Liu","year":"2013","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.ejpb.2017.05.014","article-title":"Processing thermally labile drugs by hot-melt extrusion: The lesson with gliclazide","volume":"119","author":"Huang","year":"2017","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.ejps.2015.09.010","article-title":"Process design and control of a twin screw hot melt extrusion for continuous pharmaceutical tamper-resistant tablet production","volume":"87","author":"Kessler","year":"2016","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1093\/jaoac\/91.4.709","article-title":"Ultraviolet-Photodiode Array and High-Performance Liquid Chromatographic\/Mass Spectrometric Studies on Forced Degradation Behavior of Glibenclamide and Development of a Validated Stability-Indicating Method","volume":"91","author":"Bansal","year":"2008","journal-title":"J. AOAC Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1016\/j.xphs.2023.02.019","article-title":"Role of Crystal Disorder and Mechanoactivation in Solid-State Stability of Pharmaceuticals","volume":"112","author":"Iyer","year":"2023","journal-title":"J. Pharm. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.ejpb.2009.09.007","article-title":"Fusion production of solid dispersions containing a heat-sensitive active ingredient by hot melt extrusion and Kinetisol\u00ae dispersing","volume":"74","author":"DiNunzio","year":"2010","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1208\/s12249-010-9431-y","article-title":"Dissolution Enhancement of a Drug Exhibiting Thermal and Acidic Decomposition Characteristics by Fusion Processing: A Comparative Study of Hot Melt Extrusion and KinetiSol\u00ae Dispersing","volume":"11","author":"Hughey","year":"2010","journal-title":"AAPS PharmSciTech"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1021\/mp4004145","article-title":"Unravelling the Relationship between Degree of Disorder and the Dissolution Behavior of Milled Glibenclamide","volume":"11","author":"Mah","year":"2014","journal-title":"Mol. Pharm."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1692","DOI":"10.1021\/mp100077c","article-title":"Study of the Amorphous Glibenclamide Drug: Analysis of the Molecular Dynamics of Quenched and Cryomilled Material","volume":"7","author":"Wojnarowska","year":"2010","journal-title":"Mol. Pharm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2381","DOI":"10.1021\/mp500107s","article-title":"Amino Acids as Co-amorphous Excipients for Simvastatin and Glibenclamide: Physical Properties and Stability","volume":"11","author":"Laitinen","year":"2014","journal-title":"Mol. Pharm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/0378-5173(91)90425-N","article-title":"Characterization of glibenclamide glassy state","volume":"67","author":"Hassan","year":"1991","journal-title":"Int. J. Pharm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1998","DOI":"10.1002\/jps.20424","article-title":"The Influence of Thermal and Mechanical Preparative Techniques on the Amorphous State of Four Poorly Soluble Compounds","volume":"94","author":"Patterson","year":"2005","journal-title":"J. Pharm. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.ejpb.2011.07.009","article-title":"Thermal degradation of amorphous glibenclamide","volume":"80","author":"Rehder","year":"2012","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_27","unstructured":"Yuce, C. (2024, January 11). Twin-Screw Extrusion Applications in the Pharmaceutical Industry. Proceedings of the Master 2 Pharmacie Gal\u00e9nique Industrielle Program Formation, Lille, France."},{"key":"ref_28","first-page":"100131","article-title":"How bulk fluid renewal can affect in vitro drug release from PLGA implants: Importance of the experimental set-up","volume":"4","author":"Bassand","year":"2022","journal-title":"Int. J. Pharm. X"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1208\/s12249-015-0426-6","article-title":"Investigation of Thermal and Viscoelastic Properties of Polymers Relevant to Hot Melt Extrusion, IV: AffinisolTM HPMC HME Polymers","volume":"17","author":"Gupta","year":"2016","journal-title":"AAPS PharmSciTech"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1208\/s12249-015-0395-9","article-title":"A New Extrudable Form of Hypromellose: AFFINISOLTM HPMC HME","volume":"17","author":"Huang","year":"2016","journal-title":"AAPS PharmSciTech"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1208\/pt0802050","article-title":"Stabilization of hot-melt extrusion formulations containing solid solutions using polymer blends","volume":"8","author":"Prodduturi","year":"2007","journal-title":"AAPS PharmSciTech"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/978-1-4614-8432-5_2","article-title":"Twin Screw Extrusion for Pharmaceutical Processes","volume":"Volume 9","author":"Repka","year":"2013","journal-title":"Melt Extrusion"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1021\/acs.molpharmaceut.0c00811","article-title":"Ternary Amorphous Solid Dispersions Containing a High-Viscosity Polymer and Mesoporous Silica Enhance Dissolution Performance","volume":"18","author":"Hanada","year":"2021","journal-title":"Mol. Pharm."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.addr.2021.03.006","article-title":"Specific mechanical energy\u2014An essential parameter in the processing of amorphous solid dispersions","volume":"173","author":"Thompson","year":"2021","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.chroma.2008.09.060","article-title":"Identification and structural characterization of biodegradation products of atenolol and glibenclamide by liquid chromatography coupled to hybrid quadrupole time-of-flight and quadrupole ion trap mass spectrometry","volume":"1210","year":"2008","journal-title":"J. Chromatogr. A"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Haynes, W.M. (2016). CRC Handbook of Chemistry and Physics, CRC Press. [97th ed.].","DOI":"10.1201\/9781315380476"},{"key":"ref_37","unstructured":"Budavari, S., O\u2019Neil, M.J., Smith, A., Heckelman, P.E., Obenchain, J.R., Gallipeau, J.A.R., and D\u2019Arecea, M.A. (1996). The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, Merck & Co. Inc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1039\/C6CE02295B","article-title":"Polymorphism, isostructurality and physicochemical properties of glibenclamide salts","volume":"19","author":"Suresh","year":"2017","journal-title":"CrystEngComm"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"105380","DOI":"10.1016\/j.ejps.2020.105380","article-title":"Physiologically based pharmacokinetic model outputs depend on dissolution data and their input: Case examples glibenclamide and dipyridamole","volume":"151","author":"Klumpp","year":"2020","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4192","DOI":"10.1021\/acs.molpharmaceut.7b00198","article-title":"Validation of Dissolution Testing with Biorelevant Media: An OrBiTo Study","volume":"14","author":"Mann","year":"2017","journal-title":"Mol. Pharm."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1007\/s11095-009-0021-1","article-title":"Understanding the Behavior of Amorphous Pharmaceutical Systems during Dissolution","volume":"27","author":"Alonzo","year":"2010","journal-title":"Pharm. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1080\/07366578308079439","article-title":"Chemical and Physical Structure of Polymers as Carriers for Controlled Release of Bioactive Agents: A Review","volume":"23 Pt C","author":"Langer","year":"1983","journal-title":"J. Macromol. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.jconrel.2009.08.027","article-title":"Modeling drug release from PVAc\/PVP matrix tablets","volume":"141","author":"Siepmann","year":"2010","journal-title":"J. Control. Release"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"105266","DOI":"10.1016\/j.ejps.2020.105266","article-title":"Investigation of semi-solid formulations for 3D printing of drugs after prolonged storage to mimic real-life applications","volume":"146","author":"Aita","year":"2020","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/S0168-3659(03)00075-0","article-title":"Development and evaluation of sustained release mini-matrices prepared via hot melt extrusion","volume":"89","author":"Vervaet","year":"2003","journal-title":"J. Control. Release"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/j.ijpharm.2003.09.037","article-title":"Physicochemical properties and mechanism of drug release from ethyl cellulose matrix tablets prepared by direct compression and hot-melt extrusion","volume":"269","author":"Crowley","year":"2004","journal-title":"Int. J. Pharm."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/8\/1071\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:37:18Z","timestamp":1760110638000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/8\/1071"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,15]]},"references-count":46,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["pharmaceutics16081071"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics16081071","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,15]]}}}