{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T13:21:04Z","timestamp":1787923264969,"version":"build-2784847793"},"reference-count":46,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Bumetanide is an efficient diuretic drug with poor water solubility and dissolution rate. In this study, bumetanide\/synthetic saponite systems with enhanced solubility and dissolution rate are developed. Different synthetic strategies (hydrothermal and sol\u2013gel) and aluminum contents are explored to prepare saponites with adjustable stacking. Bumetanide loading is achieved by a solution method. The synthetic route is feasible and scalable. Crystalline and non-crystalline bumetanide co-exist in the hybrids, and the non-crystalline fraction prevails in stacked saponite-based composites. Electrostatic interaction occurs between the negatively charged smectite layers and the protonated anilinic group, and the molecules accommodate within the interlayer spacing of stacked saponites. Compared with bumetanide, all the composites improve water solubility, wettability, and dissolution rate in simulated gastric conditions (pH 1.2 and 4.5) and deionized water. The samples with drug intercalation and a reduced fraction of crystalline bumetanide are the best-performing. The drug release is favoured at pH \u2265 4.5, as electrostatic repulsion occurs between the saponite layers and the carboxylate group of bumetanide. The complete release of the bumetanide dose, not achieved in sufficiently short times for all the fluids considered, is reached in the formulation with appropriate excipients. Bumetanide\/saponite composites revealed performant and tuneable systems for bumetanide solubility and dissolution rate enhancement.<\/jats:p>","DOI":"10.3390\/molecules31173015","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T12:27:46Z","timestamp":1787920066000},"page":"3015","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Bumetanide\/Synthetic Saponite Composites: Performant Systems for Enhanced Drug Dissolution Rate"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2975-4362","authenticated-orcid":false,"given":"Valeria","family":"Friuli","sequence":"first","affiliation":[{"name":"Department of Drug Sciences, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1064-7196","authenticated-orcid":false,"given":"Doretta","family":"Capsoni","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Physical Chemistry Section & C.S.G.I. (Consorzio Interuniversitario per lo Sviluppo dei Sistemi a Grande Interfase), University of Pavia, Via Taramelli 12, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1408-8846","authenticated-orcid":false,"given":"Lauretta","family":"Maggi","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1958-2998","authenticated-orcid":false,"given":"Giovanna","family":"Bruni","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Physical Chemistry Section & C.S.G.I. (Consorzio Interuniversitario per lo Sviluppo dei Sistemi a Grande Interfase), University of Pavia, Via Taramelli 12, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1967-4811","authenticated-orcid":false,"given":"Elena","family":"Cassera","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9900-6203","authenticated-orcid":false,"given":"Claudia","family":"Urru","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Physical Chemistry Section & C.S.G.I. (Consorzio Interuniversitario per lo Sviluppo dei Sistemi a Grande Interfase), University of Pavia, Via Taramelli 12, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1124\/pr.112.005660","article-title":"Strategies to Address Low Drug Solubility in Discovery and Development","volume":"65","author":"Williams","year":"2013","journal-title":"Pharmacol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"11514","DOI":"10.1021\/acs.chemrev.1c00987","article-title":"Crystal Engineering of Pharmaceutical Cocrystals in the Discovery and Development of Improved Drugs","volume":"122","author":"Bolla","year":"2022","journal-title":"Chem. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6035","DOI":"10.1039\/c2ce25846c","article-title":"Perphenazine \u2013Fumaric Acid Salts with Improved Solubility: Preparation, Physico-Chemical Characterization and in Vitro Dissolution","volume":"14","author":"Bruni","year":"2012","journal-title":"CrystEngComm"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1007\/s10973-019-09197-2","article-title":"Probenecid and Benzamide: Cocrystal Prepared by a Green Method and Its Physico-Chemical and Pharmaceutical Characterization","volume":"140","author":"Bruni","year":"2020","journal-title":"J. Therm. Anal. Calorim."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6703","DOI":"10.1021\/acs.cgd.2c00883","article-title":"Cocrystal and Coamorphous Solid Forms of Enzalutamide with Saccharin: Structural Characterization and Dissolution Studies","volume":"22","author":"Prashanth","year":"2022","journal-title":"Cryst. Growth Des."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Massaro, M., Colletti, C.G., Lazzara, G., and Riela, S. (2018). The Use of Some Clay Minerals as Natural Resources for Drug Carrier Applications. J. Funct. Biomater., 9.","DOI":"10.3390\/jfb9040058"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.clay.2017.12.024","article-title":"Biopharmaceutical Improvement of Praziquantel by Interaction with Montmorillonite and Sepiolite","volume":"160","author":"Carazo","year":"2018","journal-title":"Appl. Clay Sci."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Borrego-S\u00e1nchez, A., S\u00e1nchez-Espejo, R., Garc\u00eda-Vill\u00e9n, F., Viseras, C., and Sainz-D\u00edaz, C.I. (2020). Praziquantel\u2013Clays as Accelerated Release Systems to Enhance the Low Solubility of the Drug. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12100914"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1007\/s10973-016-5719-9","article-title":"Use of Phyllosilicate Clay Mineral to Increase Solubility Olanzapine","volume":"127","author":"Lyra","year":"2017","journal-title":"J. Therm. Anal. Calorim."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Maggi, L., Urru, C., Friuli, V., Ferrara, C., Conti, D.M., Bruni, G., and Capsoni, D. (2023). Synthesis and Characterization of Carvedilol-Etched Halloysite Nanotubes Composites with Enhanced Drug Solubility and Dissolution Rate. Molecules, 28.","DOI":"10.3390\/molecules28083405"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Gomes, D.M., Meirelles, L.M.A., Araujo, P.M., de Sousa, R.W.R., Ferreira, P.M.P., Gutierrez, S.J.C., de Medeiros, M.d.G.F., and Raffin, F.N. (2023). Improving Riparin-A Dissolution through a Laponite Based Nanohybrid. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15082136"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Friuli, V., Urru, C., Ferrara, C., Conti, D.M., Bruni, G., Maggi, L., and Capsoni, D. (2024). Design of Etched- and Functionalized-Halloysite\/Meloxicam Hybrids: A Tool for Enhancing Drug Solubility and Dissolution Rate. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16030338"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"109152","DOI":"10.1016\/j.surfin.2026.109152","article-title":"Preparation of Perphenazine\/Clay Minerals Nanocomposites for Enhanced Dissolution Rate in Aqueous Solutions","volume":"89","author":"Urru","year":"2026","journal-title":"Surf. Interfaces"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Kumaresan, S., Pawar, R.R., Kevadiya, B.D., and Bajaj, H.C. (2019). Synthesis of Saponite Based Nanocomposites to Improve the Controlled Oral Drug Release of Model Drug Quinine Hydrochloride Dihydrate. Pharmaceuticals, 12.","DOI":"10.3390\/ph12030105"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.clay.2009.03.004","article-title":"Physicochemical Characterizations and Release Studies of Nicotine\u2013Magnesium Aluminum Silicate Complexes","volume":"44","author":"Pongjanyakul","year":"2009","journal-title":"Appl. Clay Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.ijpharm.2008.04.012","article-title":"Controlled Release of Donepezil Intercalated in Smectite Clays","volume":"359","author":"Park","year":"2008","journal-title":"Int. J. Pharm."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9969","DOI":"10.1039\/D0NJ00253D","article-title":"An Overview of the Recent Synthesis and Functionalization Methods of Saponite Clay","volume":"44","author":"Carniato","year":"2020","journal-title":"New J. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.clay.2010.06.019","article-title":"Synthesis of Clay Minerals","volume":"50","author":"Zhang","year":"2010","journal-title":"Appl. Clay Sci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Ponce, C.P., and Kloprogge, J.T. (2020). Urea-Assisted Synthesis and Characterization of Saponite with Different Octahedral (Mg, Zn, Ni, Co) and Tetrahedral Metals (Al, Ga, B), a Review. Life, 10.","DOI":"10.20944\/preprints202008.0240.v1"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.clay.2018.11.002","article-title":"Modification, Hybridization and Applications of Saponite: An Overview","volume":"168","author":"Zhou","year":"2019","journal-title":"Appl. Clay Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.clay.2010.01.007","article-title":"Current Challenges in Clay Minerals for Drug Delivery","volume":"48","author":"Viseras","year":"2010","journal-title":"Appl. Clay Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1136\/bmj.1.5794.211","article-title":"Bumetanide: Potent New \u201cLoop\u201d Diuretic","volume":"1","author":"Asbury","year":"1972","journal-title":"Br. Med. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1038\/clpt.1986.112","article-title":"Kinetics, Dynamics, and Bioavailability of Bumetanide in Healthy Subjects and Patients with Chronic Renal Failure","volume":"39","author":"Lau","year":"1986","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1007\/s004670050514","article-title":"The Clinical Pharmacology of Loop Diuretics in the Pediatric Patient","volume":"12","author":"Eades","year":"1998","journal-title":"Pediatr. Nephrol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1111\/j.1365-2125.1977.tb00664.x","article-title":"Fate of [14C]-Bumetanide in Man","volume":"4","author":"Pentikainen","year":"1977","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1002\/ddr.20443","article-title":"Evaluation of the pKa Values and Ionization Sequence of Bumetanide Using 1H and 13C NMR and UV Spectroscopy","volume":"72","author":"Song","year":"2011","journal-title":"Drug Dev. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2428","DOI":"10.1039\/c2ce06631a","article-title":"Sodium and Potassium Salts of Bumetanide Trihydrate: Impact of Counterion on Structure, Aqueous Solubility and Dehydration Kinetics","volume":"14","author":"Ong","year":"2012","journal-title":"CrystEngComm"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"9180","DOI":"10.1021\/jp503256k","article-title":"Mechanochemical Synthesis of Bumetanide\u20134-Aminobenzoic Acid Molecular Cocrystals: A Facile and Green Approach to Drug Optimization","volume":"118","author":"Bruni","year":"2014","journal-title":"J. Phys. Chem. B"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1021\/acs.cgd.9b01195","article-title":"Novel Pharmaceutical Cocrystals and Salts of Bumetanide","volume":"20","author":"Allu","year":"2020","journal-title":"Cryst. Growth Des."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Friuli, V., Maggi, L., Bruni, G., Caso, F., and Bini, M. (2024). Hydroxyapatite Nanorods Based Drug Delivery Systems for Bumetanide and Meloxicam, Poorly Water Soluble Active Principles. Nanomaterials, 14.","DOI":"10.3390\/nano14010113"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1107\/S1600576719014092","article-title":"Mercury 4.0: From Visualization to Analysis, Design and Prediction","volume":"53","author":"Macrae","year":"2020","journal-title":"J. Appl. Cryst."},{"key":"ref_32","unstructured":"(Chemsketch, 2025). Chemsketch, version 2.2."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1016\/j.pnsc.2023.12.007","article-title":"Control the Growth of Fe3O4 on the Surface of Saponite and Its Redox Effect on Cr (VI)","volume":"33","author":"Huang","year":"2023","journal-title":"Progress. Nat. Sci. Mater. Int."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.micromeso.2007.05.038","article-title":"Understanding Physico\u2013Chemical Properties of Saponite Synthetic Clays","volume":"107","author":"Bisio","year":"2008","journal-title":"Microporous Mesoporous Mater."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"931","DOI":"10.2138\/am.2005.1616","article-title":"Synthesis and Characterization of Saponite Clays","volume":"90","author":"Vogels","year":"2005","journal-title":"Am. Mineral."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4225","DOI":"10.1021\/acs.cgd.7b00531","article-title":"Supramolecular Synthons in Bumetanide Cocrystals and Ternary Products","volume":"17","author":"Allu","year":"2017","journal-title":"Cryst. Growth Des."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1017\/S0885715619000125","article-title":"Crystal Structure of Bumetanide, C17H20N2O5S","volume":"34","author":"Diulus","year":"2019","journal-title":"Powder Diffr."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"120232","DOI":"10.1016\/j.ces.2024.120232","article-title":"Salt Hydrates as a Source to Form Co-Amorphous Systems When Prepared in the Absence of Water: Hydrogen Bond Analysis","volume":"296","author":"Deng","year":"2024","journal-title":"Chem. Eng. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1590\/S0104-66322011000100011","article-title":"Precipitation of Amorphous SiO2 Particles and Their Properties","volume":"28","year":"2011","journal-title":"Braz. J. Chem. Eng."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/S0924-2031(00)00056-4","article-title":"The Effect of Synthesis Temperature on the FT-Raman and FT-IR Spectra of Saponites","volume":"23","author":"Kloprogge","year":"2000","journal-title":"Vib. Spectrosc."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Kloprogge, J.T., and Ponce, C.P. (2021). Spectroscopic Studies of Synthetic and Natural Saponites: A Review. Minerals, 11.","DOI":"10.3390\/min11020112"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/j.saa.2014.06.113","article-title":"Comparing Vibrational Spectra of Free Bumetanide and Its Solutions","volume":"134","author":"Bolukbasi","year":"2015","journal-title":"Spectrochim. Acta Part A Mol. Biomol. Spectrosc."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.clay.2015.05.004","article-title":"Microwave Synthesis of Delaminated Acid Saponites Using Quaternary Ammonium Salt or Polymer as Template. Study pH Influence","volume":"114","author":"Gebretsadik","year":"2015","journal-title":"Appl. Clay Sci."},{"key":"ref_44","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Petersson, G.A., and Nakatsuji, H. (Gaussian 16, 2016). Gaussian 16, revision C.01."},{"key":"ref_45","unstructured":"(2018). Bumetanide Tablets, Official Monograph, 2018. United States Pharmacopeia (USP42-NF37), United States Pharmacopeia Convention, Inc."},{"key":"ref_46","unstructured":"Reagents (2023). Solution\/Buffer Solutions. United States Pharmacopeia (USP43-NF38), United States Pharmacopeial Convention, Inc."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/17\/3015\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T12:28:40Z","timestamp":1787920120000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/17\/3015"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,28]]},"references-count":46,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["molecules31173015"],"URL":"https:\/\/doi.org\/10.3390\/molecules31173015","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,28]]}}}