{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T02:00:57Z","timestamp":1780538457341,"version":"3.54.1"},"reference-count":38,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T00:00:00Z","timestamp":1758499200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"INVITE GmbH"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: The principal function of pharmaceutical blister packaging is to provide protection for the drug product. Moisture is regarded as a critical factor in the physical and chemical aging of drug products. The present work proposes a modeling framework to predict the performance of tablet blister materials based on the moisture uptake profile of the drug product as well as degradation characteristics of the drug substance, while the consumption of water due to degradation is included. Methods: The model incorporates three kinetic superimposed processes that define moisture uptake and drug stability. The processes of permeation, sorption and degradation are each described with a rate constant. Based on a mass balance, these rate processes are interconnected and the relative humidity in the blister cavity is predicted. Results: In a case study, the model was applied to demonstrate the feasibility of predicting the stability of blistered tablets. By establishing a correlation between the moisture uptake of the tablet and the drug stability demonstrated in the model, it was feasible to predict the drug content over shelf life. Conclusions: Modeling of the drug stability of blister-packed products enables a rational packaging which offers novel possibilities for reducing material in order to avoid overpackaging of pharmaceutical products. As some of the commonly used barrier materials are considered to not be sustainable, this model can be used to consider a rationally justified reduction or even abandonment of the barrier materials.<\/jats:p>","DOI":"10.3390\/pharmaceutics17091233","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T12:08:03Z","timestamp":1758542883000},"page":"1233","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Predictive Modeling of Drug Product Stability in Pharmaceutical Blister Packs"],"prefix":"10.3390","volume":"17","author":[{"given":"Jan","family":"Pech","sequence":"first","affiliation":[{"name":"Laboratory of Solids Process Engineering, Department of Biochemical and Chemical Engineering, Technical University Dortmund, Emil-Figge-Str. 68, 44227 Dortmund, Germany"},{"name":"INVITE GmbH, Otto-Bayer-Str. 32, 51061 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Kaminski","sequence":"additional","affiliation":[{"name":"Bayer Consumer Care AG, Peter Merian-Str. 84, 4052 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Markus","sequence":"additional","affiliation":[{"name":"Bayer AG, Kaiser-Wilhelm-Allee 1, 51373 Leverkusen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1583-7156","authenticated-orcid":false,"given":"Werner","family":"Hoheisel","sequence":"additional","affiliation":[{"name":"Bayer AG, Kaiser-Wilhelm-Allee 1, 51373 Leverkusen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Heumann","sequence":"additional","affiliation":[{"name":"INVITE GmbH, Otto-Bayer-Str. 32, 51061 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8364-7958","authenticated-orcid":false,"given":"Judith","family":"Winck","sequence":"additional","affiliation":[{"name":"Laboratory of Solids Process Engineering, Department of Biochemical and Chemical Engineering, Technical University Dortmund, Emil-Figge-Str. 68, 44227 Dortmund, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6217-9902","authenticated-orcid":false,"given":"Markus","family":"Thommes","sequence":"additional","affiliation":[{"name":"Laboratory of Solids Process Engineering, Department of Biochemical and Chemical Engineering, Technical University Dortmund, Emil-Figge-Str. 68, 44227 Dortmund, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,22]]},"reference":[{"key":"ref_1","unstructured":"European Commission (2019). The European Green Deal, European Commission."},{"key":"ref_2","unstructured":"European Parliament and Council of the European Union (2025). Regulation (EU) 2025\/40 of the European Parliament and of the Council of 19 December 2024 on Packaging and Packaging Waste, Amending Regulation (EU) 2019\/1020 and Directive (EU) 2019\/904, and repealing Directive 94\/62\/EC, European Union."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.1016\/j.xphs.2022.05.001","article-title":"Ensuring Product Stability\u2014Choosing the Right Excipients","volume":"111","author":"Veronica","year":"2022","journal-title":"J. Pharm. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/0378-5173(90)90221-O","article-title":"The molecular basis of moisture effects on the physical and chemical stability of drug in the solid state","volume":"62","author":"Ahlneck","year":"1990","journal-title":"Int. J. Pharm."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Gonz\u00e1lez-Gonz\u00e1lez, O., Ramirez, I.O., Ramirez, B.I., O\u2019Connell, P., Ballesteros, M.P., Torrado, J.J., and Serrano, D.R. (2022). Drug Stability: ICH versus Accelerated Predictive Stability Studies. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14112324"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0378-5173(01)00670-6","article-title":"The effects of packaging on the stability of a moisture sensitive compound","volume":"221","author":"Allinson","year":"2001","journal-title":"Int. J. Pharm."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Salmenper\u00e4, H., Kauppi, S., Dahlbo, H., and Fj\u00e4der, P. (2022). Increasing the Circularity of Packaging along Pharmaceuticals Value Chain. Sustainability, 14.","DOI":"10.3390\/su14084715"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Ding, Q., and Zhu, H. (2023). The Key to Solving Plastic Packaging Wastes: Design for Recycling and Recycling Technology. Polymers, 15.","DOI":"10.3390\/polym15061485"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"100423","DOI":"10.1016\/j.scp.2021.100423","article-title":"Sustainability of blisters for medicines in tablet form","volume":"21","year":"2021","journal-title":"Sustain. Chem. Pharm."},{"key":"ref_10","first-page":"91","article-title":"Pharmaceutical Blister: Influence of Color and Types of Films in Drug Packaging","volume":"17","author":"Pereira","year":"2016","journal-title":"Vis\u00e3o Acad\u00eamica"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1248\/cpb.28.1099","article-title":"Stability of Packaged Solid Dosage Forms. II. Shelf-life Prediction for Packaged Sugar-coated Tablets Liable to Moisture and Heat Damage","volume":"28","author":"Nakabayashi","year":"1980","journal-title":"Chem. Pharm. Bull."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/0378-5173(92)90164-W","article-title":"Use of the sorption-desorption moisture transfer model to assess the utility of a desiccant in a solid product","volume":"84","author":"Kontny","year":"1992","journal-title":"Int. J. Pharm."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0378-5173(01)00693-7","article-title":"Application of sorption\u2013desorption moisture transfer modeling to the study of chemical stability of a moisture sensitive drug product in different packaging configurations","volume":"223","author":"Gawronski","year":"2001","journal-title":"Int. J. Pharm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1177\/875608799801400206","article-title":"Modeling the Moisture Content of a Pharmaceutical Tablet in a Blister Package by Finite Difference Method: Program Development","volume":"14","author":"Kim","year":"1998","journal-title":"J. Plast. Film. Sheeting"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/S0378-5173(03)00089-9","article-title":"A new model for predicting moisture uptake by packaged solid pharmaceuticals","volume":"255","author":"Chen","year":"2003","journal-title":"Int. J. Pharm."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.ijpharm.2012.11.025","article-title":"A mechanistic model for the prediction of in-use moisture uptake by packaged dosage forms","volume":"441","author":"Remmelgas","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_17","first-page":"44","article-title":"Predicting Moisture Uptake in Solid-Dosage Packaging","volume":"41","author":"Remmelgas","year":"2017","journal-title":"Pharm. Technol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1007\/s11095-006-9201-4","article-title":"Improved protocol and data analysis for accelerated shelf-life estimation of solid dosage forms","volume":"24","author":"Waterman","year":"2007","journal-title":"Pharm. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1002\/jps.2600660517","article-title":"Effect of temperature and relative humidity on nitrazepam stability in solid state","volume":"66","author":"Genton","year":"1977","journal-title":"J. Pharm. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4437","DOI":"10.1002\/jps.22161","article-title":"Package Selection for Moisture Protection for Solid, Oral Drug Products","volume":"99","author":"Waterman","year":"2010","journal-title":"J. Pharm. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.ejps.2008.09.007","article-title":"Predicting drug hydrolysis based on moisture uptake in various packaging designs","volume":"35","author":"Naversnik","year":"2008","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_22","unstructured":"Pech, J., Kaminski, C., Markus, M., Hoheisel, W., Heumann, R., Winck, J., and Thommes, M. (2024, January 17\u201321). Modeling of Moisture Uptake of Drug Products in Sustainable Blister Packs. Proceedings of the 24th IAPRI World Packaging Conference 2024, Valencia, Spain."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Baehr, H.D., and Kabelac, S. (2012). Thermodynamik, Springer. [15th ed.].","DOI":"10.1007\/978-3-642-24161-1"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1208\/pt040459","article-title":"A study on moisture isotherms of formulations: The Use of polynomial equations to predict the moisture isotherms of tablet products","volume":"4","author":"Li","year":"2003","journal-title":"AAPS PharmSciTech"},{"key":"ref_25","unstructured":"PubChem (2025, May 02). Cilazapril, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/Cilazapril."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/s11144-013-0558-1","article-title":"Cilazapril decomposition kinetics and mechanism in the solid state versus stability of the other ester pro-drug angiotensin converting enzyme inhibitors","volume":"109","author":"Paszun","year":"2013","journal-title":"React. Kinet. Mech. Catal."},{"key":"ref_27","unstructured":"Crank, J. (1975). The Mathematics of Diffusion, Oxford University Press. [2nd ed.]."},{"key":"ref_28","unstructured":"(2020). Standard Test Method for Water Vapor Transmission Rate Through Plastic Film and Sheeting Using a Modulated Infrared Sensor (Standard No. ASTM E1249-20)."},{"key":"ref_29","unstructured":"(2019). Plastics\u2014Film and Sheeting\u2014Determination of Water Vapour Transmission Rate\u2014Part 2: Infrared Detection Sensor Method (Standard No. ISO 15106-2:2019)."},{"key":"ref_30","unstructured":"Liveo Research GmbH (2025, May 02). Liveo Aclar\u00ae. Available online: https:\/\/www.liveoresearch.com\/en\/product\/aclar\/."},{"key":"ref_31","unstructured":"Ametek Mocon (2022). PERMATRAN-W Model 3\/34 Operator\u2019s Manual, Ametek Mocon."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1007\/s11947-007-0012-3","article-title":"GAB Generalized Equation for Sorption Phenomena","volume":"1","author":"Blahovec","year":"2008","journal-title":"Food Bioprocess. Technol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1248\/cpb.53.662","article-title":"Evaluation of the Moisture Sorption Behaviour of Several Excipients by BET, GAB and Microcalorimetric Approaches","volume":"53","author":"Roskar","year":"2005","journal-title":"Chem. Pharm. Bull."},{"key":"ref_34","first-page":"4049","article-title":"Water Sorption of Drugs and Dosage Forms","volume":"Volume 6","author":"Swarbrick","year":"2007","journal-title":"Encyclopedia of Pharmaceutical Technology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1208\/s12249-021-02121-8","article-title":"Accelerated Stability Assessment Program to Predict Long-term Stability of Drugs: Application to Ascorbic Acid and to a Cyclic Hexapeptide","volume":"22","author":"Legrand","year":"2021","journal-title":"AAPS PharmSciTech"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Gonz\u00e1lez-Gonz\u00e1lez, O., Ballesteros, M.P., Torrado, J.J., and Serrano, D.R. (2023). Application of Accelerated Predictive Stability Studies in Extemporaneously Compounded Formulations of Chlorhexidine to Assess the Shelf Life. Molecules, 28.","DOI":"10.3390\/molecules28237925"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"119218","DOI":"10.1016\/j.ijpharm.2020.119218","article-title":"Insights on the role of excipients and tablet matrix porosity on aspirin stability","volume":"580","author":"Veronica","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Kang, C.Y.X., Chow, K.T., Lui, Y.S., Salome, A., Boit, B., Lefevre, P., Hiew, T.N., Gokhale, R., and Heng, P.W.S. (2024). Mannitol-Coated Hydroxypropyl Methylcellulose as a Directly Compressible Controlled Release Excipient for Moisture-Sensitive Drugs: A Stability Perspective. Pharm., 17.","DOI":"10.3390\/ph17091167"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/9\/1233\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:47:04Z","timestamp":1760035624000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/9\/1233"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,22]]},"references-count":38,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["pharmaceutics17091233"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics17091233","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,22]]}}}