{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T23:34:53Z","timestamp":1787614493076,"version":"build-2736575974"},"reference-count":61,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T00:00:00Z","timestamp":1669248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2019s Horizon 2020 research and inno-vation programme under the Marie Sklodowska-Curi","award":["895355"],"award-info":[{"award-number":["895355"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>A key step in the development of a new drug, is the design of drug\u2013excipient complexes that lead to optimal drug release kinetics. Computational chemistry and specifically enhanced sampling molecular dynamics methods can play a key role in this context, by minimizing the need for expensive experiments, and reducing cost and time. Here we show that recent advances in enhanced sampling methodologies can be brought to fruition in this area. We demonstrate the potential of these methodologies by simulating the drug release kinetics of the complex praziquantel\u2013montmorillonite in water. Praziquantel finds promising applications in the treatment of schistosomiasis, but its biopharmaceutical profile needs to be improved, and a cheap material such as the montmorillonite clay would be a very convenient excipient. We simulate the drug release both from surface and interlayer space, and find that the diffusion of the praziquantel inside the interlayer space is the process that limits the rate of drug release.<\/jats:p>","DOI":"10.3390\/pharmaceutics14122586","type":"journal-article","created":{"date-parts":[[2022,11,25]],"date-time":"2022-11-25T02:29:23Z","timestamp":1669343363000},"page":"2586","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Kinetics of Drug Release from Clay Using Enhanced Sampling Methods"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2589-9716","authenticated-orcid":false,"given":"Ana","family":"Borrego-S\u00e1nchez","sequence":"first","affiliation":[{"name":"Center for Human Technologies, Italian Institute of Technology (IIT), Via Enrico Melen 83, 16152 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5051-4120","authenticated-orcid":false,"given":"Jayashrita","family":"Debnath","sequence":"additional","affiliation":[{"name":"Center for Human Technologies, Italian Institute of Technology (IIT), Via Enrico Melen 83, 16152 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Parrinello","sequence":"additional","affiliation":[{"name":"Center for Human Technologies, Italian Institute of Technology (IIT), Via Enrico Melen 83, 16152 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,24]]},"reference":[{"key":"ref_1","unstructured":"(2021, December 10). WHO (World Health Organization), Available online: https:\/\/www.who.int\/health-topics\/schistosomiasis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2253","DOI":"10.1016\/S0140-6736(13)61949-2","article-title":"Human schistosomiasis","volume":"383","author":"Colley","year":"2014","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1016\/S0140-6736(06)69440-3","article-title":"Human schistosomiasis","volume":"368","author":"Gryseels","year":"2006","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/S1473-3099(06)70521-7","article-title":"Schistosomiasis and water resources development: Systematic review, meta-analysis, and estimates of people at risk","volume":"6","author":"Steinmann","year":"2006","journal-title":"Lancet Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/S0001-706X(00)00122-4","article-title":"The global status of schistosomiasis and its control","volume":"77","author":"Chitsulo","year":"2000","journal-title":"Acta Trop."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/0163-7258(85)90020-8","article-title":"Praziquantel: Mechanisms of anti-schistosomal activity","volume":"29","author":"Andrews","year":"1985","journal-title":"Pharmacol. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.ejpb.2004.03.001","article-title":"Classification of orally administered drugs on the World Health Organization model list of essential medicines according to the biopharmaceutics classification system","volume":"58","author":"Lindenberg","year":"2004","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Wen, X., Deng, Z., Xu, Y., Yan, G., Deng, X., Wu, L., Liang, Q., Fang, F., Feng, X., and Yu, M. (2021). Preparation and In Vitro\/In Vivo Evaluation of Orally Disintegrating\/Modified-Release Praziquantel Tablets. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13101567"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Boniatti, J., Januskaite, P., da Fonseca, L.B., Vi\u00e7osa, A.L., Amendoeira, F.C., Tuleu, C., Basit, A.W., Goyanes, A., and R\u00e9, M.-I. (2021). Direct Powder Extrusion 3D Printing of Praziquantel to Overcome Neglected Disease Formulation Challenges in Paediatric Populations. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13081114"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Zanolla, D., Hasa, D., Arhangelskis, M., Schneider-Rauber, G., Chierotti, M.R., Keiser, J., Voinovich, D., Jones, W., and Perissutti, B. (2020). Mechanochemical Formation of Racemic Praziquantel Hemihydrate with Improved Biopharmaceutical Properties. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12030289"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1007\/s00436-002-0751-z","article-title":"Praziquantel","volume":"90","author":"Cioli","year":"2003","journal-title":"Parasitol. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1007\/s00436-012-3151-z","article-title":"Susceptibility or resistance of praziquantel in human schistosomiasis: A review","volume":"111","author":"Wang","year":"2012","journal-title":"Parasitol. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.clay.2006.06.015","article-title":"Use of clays as drug delivery systems: Possibilities and limitations","volume":"36","author":"Aguzzi","year":"2007","journal-title":"Appl. Clay Sci."},{"key":"ref_14","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_15","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/j.colsurfb.2012.10.068","article-title":"The systems containing clays and clay minerals from modified drug release: A review","volume":"103","author":"Figueiras","year":"2013","journal-title":"Colloids Surf. B"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.clay.2016.01.021","article-title":"Drug\u2013clay nanohybrids as sustained delivery systems","volume":"130","author":"Yang","year":"2016","journal-title":"Appl. Clay Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"115","DOI":"10.18433\/J3R617","article-title":"Clay and Polymer-Based Composites Applied to Drug Release: A Scientific and Technological Prospection","volume":"20","author":"Meirelles","year":"2017","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_18","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_19","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_20","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_21","first-page":"255","article-title":"Natural phyllosilicates as excipientes of drugs: Computational approaches","volume":"Volume 3","author":"Fiore","year":"2021","journal-title":"Computational Modeling in Clay Mineralogy"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5076","DOI":"10.1021\/acs.jpclett.0c01125","article-title":"Gaussian Mixture-Based Enhanced Sampling for Statics and Dynamics","volume":"11","author":"Debnath","year":"2020","journal-title":"J. Phys. Chem. Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6500","DOI":"10.1021\/acs.jctc.2c00806","article-title":"Rare Event Kinetics from Adaptive Bias Enhanced Sampling","volume":"18","author":"Ray","year":"2022","journal-title":"J. Chem. Theory Comput."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5438","DOI":"10.1038\/s41467-022-33104-3","article-title":"Water regulates the residence time of Benzamidine in Trypsin","volume":"13","author":"Ansari","year":"2022","journal-title":"Nat. Comm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/0021-9991(77)90121-8","article-title":"Nonphysical sampling distributions in Monte Carlo free-energy estimation: Umbrella sampling","volume":"23","author":"Torrie","year":"1977","journal-title":"J. Comput. Phys."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/0021-9991(87)90054-4","article-title":"Adaptive umbrella sampling: Self-consistent determination of the non-Boltzmann bias","volume":"68","author":"Mezei","year":"1987","journal-title":"J. Comput. Phys."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"14011","DOI":"10.1021\/jp062755j","article-title":"Self-healing umbrella sampling: A non-equilibrium approach for quantitative free energy calculations","volume":"110","author":"Marsili","year":"2006","journal-title":"J. Phys. Chem. B."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"134101","DOI":"10.1063\/1.2844595","article-title":"Adaptively biased molecular dynamics for free energy calculations","volume":"128","author":"Babin","year":"2008","journal-title":"J. Chem. Phys."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"126601","DOI":"10.1088\/0034-4885\/71\/12\/126601","article-title":"Metadynamics: A method to simulate rare events and reconstruct the free energy in biophysics, chemistry and material science","volume":"71","author":"Laio","year":"2008","journal-title":"Rep. Prog. Phys."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4664","DOI":"10.1021\/jp808381s","article-title":"Gaussian-mixture umbrella sampling","volume":"113","author":"Maragakis","year":"2009","journal-title":"J. Phys. Chem. B."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/s11222-015-9613-2","article-title":"Self-healing umbrella sampling: Convergence and efficiency","volume":"27","author":"Fort","year":"2017","journal-title":"Stat. Comput."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s42254-020-0153-0","article-title":"Using metadynamics to explore complex free-energy landscapes","volume":"2","author":"Bussi","year":"2020","journal-title":"Nat. Rev. Phys."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e202100105","DOI":"10.1002\/ijch.202100105","article-title":"Breviarium de Motu Simulato Ad Atomos Pertinenti","volume":"62","author":"Parrinello","year":"2022","journal-title":"Isr. J. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2893","DOI":"10.1103\/PhysRevE.52.2893","article-title":"Predicting slow structural transitions in macromolecular systems: Conformational flooding","volume":"52","year":"1995","journal-title":"Phys. Rev. E"},{"key":"ref_35","first-page":"4665","article-title":"A method for accelerating the molecular dynamics simulation of infrequent events","volume":"106","author":"Voter","year":"1997","journal-title":"Chem. Phys."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"070601","DOI":"10.1103\/PhysRevLett.115.070601","article-title":"Variationally Optimized Free-Energy Flooding for Rate Calculation","volume":"115","author":"McCarty","year":"2015","journal-title":"Phys. Rev. Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1214\/aos\/1176344136","article-title":"Estimating the Dimension of a Model","volume":"6","author":"Schwarz","year":"1978","journal-title":"Ann. Statist."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1006\/jcph.1995.1039","article-title":"Fast Parallel Algorithms for Short-Range Molecular Dynamics","volume":"117","author":"Plimpton","year":"1995","journal-title":"J. Comput. Phys."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1016\/j.cpc.2013.09.018","article-title":"PLUMED 2: New feathers for an old bird","volume":"185","author":"Tribello","year":"2014","journal-title":"Comput. Phys. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"224713","DOI":"10.1063\/1.2202330","article-title":"Interaction energy and surface reconstruction between sheets of layered silicates","volume":"124","author":"Heinz","year":"2006","journal-title":"J. Chem. Phys."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1021\/la3038846","article-title":"Thermodynamically Consistent Force Fields for the Assembly of Inorganic, Organic, and Biological Nanostructures: The INTERFACE Force Field","volume":"29","author":"Heinz","year":"2013","journal-title":"Langmuir"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"18341","DOI":"10.1021\/jp048142t","article-title":"Atomic charges for classical simulations of polar systems","volume":"108","author":"Heinz","year":"2004","journal-title":"J. Phys. Chem. B"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"13538","DOI":"10.1021\/acsomega.8b01026","article-title":"Functional Carboxymethylcellulose\/Zein Bionanocomposite Films Based on Neomycin Supported on Sepiolite or Montmorillonite Clays","volume":"3","author":"Rebitski","year":"2018","journal-title":"ACS Omega"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2905","DOI":"10.1021\/acs.jpcc.6b12467","article-title":"Adsorption of Sulfonamides on Phyllosilicate Surfaces by Molecular Modeling Calculations","volume":"121","year":"2017","journal-title":"J. Phys. Chem. C"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"7182","DOI":"10.1063\/1.328693","article-title":"Polymorphic transitions in single crystals: A new molecular dynamics method","volume":"52","author":"Parrinello","year":"1981","journal-title":"J. Appl. Phys."},{"key":"ref_46","first-page":"250","article-title":"Mass transfer modelling in clay-based material: Estimation of apparent diffusivity of a molecule of interest","volume":"22","author":"Bruneau","year":"2019","journal-title":"C. R. Chim."},{"key":"ref_47","first-page":"20","article-title":"Improvement of the oral praziquantel anthelmintic effect by cyclodextrin complexation","volume":"18","author":"Pinto","year":"2010","journal-title":"J. Drug Target"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4210","DOI":"10.1021\/acs.molpharmaceut.1c00716","article-title":"Investigation of Praziquantel\/Cyclodextrin Inclusion Complexation by NMR and LC-HRMS\/MS: Mechanism, Solubility, Chemical Stability, and Degradation Products","volume":"18","author":"Jug","year":"2021","journal-title":"Mol. Pharm."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"287","DOI":"10.2138\/rmg.2015.80.09","article-title":"Ionic transport in nano-porous clays with consideration of electrostatic effects","volume":"80","author":"Tournassat","year":"2015","journal-title":"Rev. Mineral. Geochem."},{"key":"ref_50","first-page":"3","article-title":"Montmorillonite: An Introduction to Properties and Utilization","volume":"Volume 1","author":"Zoveidavianpoor","year":"2018","journal-title":"Current Topics in the Utilization of Clay in Industrial and Medical Applications"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Krupskaya, V.V., Zakusin, S.V., Tyupina, E.A., Dorzhieva, O.V., Zhukhlistov, A.P., Belousov, P.E., and Timofeeva, M.N. (2017). Experimental Study of Montmorillonite Structure and Transformation of Its Properties under Treatment with Inorganic Acid Solutions. Minerals, 7.","DOI":"10.3390\/min7040049"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/S1572-4352(05)01010-X","article-title":"Chapter 7.3\u2014Clay Mineral Organic Interactions","volume":"Volume 1","author":"Bergaya","year":"2006","journal-title":"Developments in Clay Science, Handbook of Clay Science"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1166\/jnn.2008.18226","article-title":"Polymerically Modified Layered Silicates: An Effective Route to Nanocomposites","volume":"8","author":"Zhang","year":"2008","journal-title":"J. Nanosci. Nanotechnol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.clay.2012.09.028","article-title":"Silylation of clay mineral surfaces","volume":"71","author":"He","year":"2013","journal-title":"Appl. Clay Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.progpolymsci.2013.07.002","article-title":"Intercalation strategies in clay\/polymer hybrids","volume":"39","author":"Chiu","year":"2014","journal-title":"Prog. Polym. Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/S0168-3659(03)00133-0","article-title":"Organosilicate-polymer drug delivery systems: Controlled release and enhanced mechanical properties","volume":"90","author":"Cypes","year":"2003","journal-title":"J. Control. Release"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1098\/rsta.1984.0036","article-title":"Smectite Clay Minerals: Properties and Uses","volume":"311","author":"Odom","year":"1984","journal-title":"Phil. Trans. R. Soc. Lond. A"},{"key":"ref_58","unstructured":"Meyers, R.A. (2003). Microporous materials: Zeolites, clays, and aluminophosphates. Encyclopedia of Physical Science and Technology, Academic Press. [3rd ed.]."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Bleam, W.F. (2012). Chapter 3\u2014Clay mineralogy and Clay Chemistry. Soil and Environmental Chemistry, Academic Press.","DOI":"10.1016\/B978-0-12-415797-2.00003-0"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1080\/17425247.2021.1862792","article-title":"Clay nanoparticles as pharmaceutical carriers in drug delivery systems","volume":"18","author":"Dong","year":"2021","journal-title":"Expert Opinion on Drug Delivery"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2731","DOI":"10.1021\/acs.jpclett.0c00497","article-title":"Rethinking Metadynamics: From Bias Potentials to Probability Distributions","volume":"11","author":"Invernizzi","year":"2020","journal-title":"J. Phys. Chem. Lett."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/12\/2586\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:25:55Z","timestamp":1760145955000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/12\/2586"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,24]]},"references-count":61,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["pharmaceutics14122586"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14122586","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,24]]}}}