{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T09:04:15Z","timestamp":1780131855885,"version":"3.54.0"},"reference-count":20,"publisher":"IMR Press","issue":"5","license":[{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmazie"],"abstract":"<jats:p>Background: Switching from branded to generic extended-release (ER) metoprolol formulations is common practice due to cost considerations. Although generics are approved as bioequivalent, subtle differences in formulation, such as coating composition, may influence drug release under real-life conditions across patients. Objective: This study aimed to evaluate potential differences in drug release between the originator product Beloc-Zok 95 mg and randomly selected generic ER metoprolol succinate formulations available on the German market. Methods: Formulations were assessed under variable, interindividual, physiologically relevant in vitro conditions simulating gastrointestinal transit. Results: All formulations demonstrated controlled drug release; however, the release profiles were not fully overlapping. One generic formulation consistently exhibited slightly slower release across all test scenarios. These findings indicate that minor differences in release behavior can occur even among bioequivalent ER formulations. While such variations are generally clinically negligible, they may contribute to pharmacokinetic and pharmacodynamic differences in sensitive individuals, potentially explaining reported adverse effects such as bradycardia, hypotension, chest pain, or increased blood pressure when switching to generic products. Conclusions: The results underscore the importance of considering patient-specific variability when switching from branded to generic formulations. Incorporating physiologically relevant in vitro studies combined with physiologically based pharmacokinetic and pharmacodynamic modeling in future research may improve predictions of in vivo performance and support safer therapeutic decisions.<\/jats:p>","DOI":"10.31083\/pharmazie51859","type":"journal-article","created":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T08:35:36Z","timestamp":1780130136000},"source":"Crossref","is-referenced-by-count":0,"title":["Comparative In Vitro Release Profiling of Brand and Generic Metoprolol Extended-Release Formulations in the Context of Product Switching"],"prefix":"10.31083","volume":"81","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9164-5407","authenticated-orcid":true,"given":"Frank","family":"Karkossa","sequence":"first","affiliation":[{"name":"Institute of Biopharmaceutics and Pharmaceutical Technology, Department of Pharmacy, Center of Drug Absorption and Transport (C_DAT), University of Greifswald, 17489 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7356-5780","authenticated-orcid":true,"given":"Sandra","family":"Klein","sequence":"additional","affiliation":[{"name":"Institute of Biopharmaceutics and Pharmaceutical Technology, Department of Pharmacy, Center of Drug Absorption and Transport (C_DAT), University of Greifswald, 17489 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,5,19]]},"reference":[{"key":"ref1","unstructured":"Morris J, Awosika AO, Dunham A. Metoprolol [Updated 2024 Feb 29]. StatPearls. StatPearls Publishing: Treasure Island (FL). 2025."},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Wikstrand J. Achieving optimal beta1-blockade with metoprolol CR\/Zok. Basic Research in Cardiology. 2000; 95 Suppl 1: I46\u2013I51.","DOI":"10.1007\/s003950070009"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Sandberg A, Abrahamsson B, Reg\u00e5rdh CG, Wieselgren I, Bergstrand R. Pharmacokinetic and biopharmaceutic aspects of once daily treatment with metoprolol CR\/ZOK: a review article. Journal of Clinical Pharmacology. 1990; 30: S2\u2013S16.","DOI":"10.1002\/j.1552-4604.1990.tb03490.x"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Tangeman HJ, Patterson JH. Extended-release metoprolol succinate in chronic heart failure. The Annals of Pharmacotherapy. 2003; 37: 701\u2013710.","DOI":"10.1345\/aph.1C286"},{"key":"ref5","unstructured":"Notheis C, Z\u00f6ller T, Dressman J, Klein S. Perorale Metoprolol-Arzneiformen: Sind unterschiedliche Retardformulierungen austauschbar? Deutsche Apotheker Zeitung. 2003; 143: 48\u201355. (In German)"},{"key":"ref6","unstructured":"Graedon J. Generic Metoprolol Reveals Flaws with FDA\u2019s Approval Process. The People\u2019s Pharmacy. 2024. Available at: https:\/\/www.peoplespharmacy.com\/articles\/metoprolol-mess-toprol-xl-reveals-serious-flaws-with-fdas-generic-process (Accessed: 12 November 2025)."},{"key":"ref7","unstructured":"United States Pharmacopeial Convention. United States Pharmacopeia-National Formulary (USP-NF 2021). Buffer Solutions. 2021."},{"key":"ref8","unstructured":"United States Pharmacopeial Convention. United States Pharmacopeia-National Formulary (USP-NF 2021). Monograph: Metoprolol Succinate Extended-Release Tablets, Test 1. 2021."},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Karkossa F, Klein S. Individualized in vitro and in silico methods for predicting in vivo performance of enteric-coated tablets containing a narrow therapeutic index drug. European Journal of Pharmaceutics and Biopharmaceutics. 2019; 135: 13\u201324.","DOI":"10.1016\/j.ejpb.2018.12.004"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Koziolek M, Grimm M, Becker D, Iordanov V, Zou H, Shimizu J, et al. Investigation of pH and Temperature Profiles in the GI Tract of Fasted Human Subjects Using the Intellicap(\u00ae) System. Journal of Pharmaceutical Sciences. 2015; 104: 2855\u20132863.","DOI":"10.1002\/jps.24274"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Klein S, Shah VP. A standardized mini paddle apparatus as an alternative to the standard paddle. AAPS PharmSciTech. 2008; 9: 1179\u20131184.","DOI":"10.1208\/s12249-008-9161-6"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Garbacz G, Ko\u0142odziej B, Koziolek M, Weitschies W, Klein S. A dynamic system for the simulation of fasting luminal pH-gradients using hydrogen carbonate buffers for dissolution testing of ionisable compounds. European Journal of Pharmaceutical Sciences. 2014; 51: 224\u2013231.","DOI":"10.1016\/j.ejps.2013.09.020"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Wollmer E, Klein S. Patient-specific in vitro drug release testing coupled with in silico PBPK modeling to forecast the in vivo performance of oral extended-release levodopa formulations in Parkinson\u2019s disease patients. European Journal of Pharmaceutics and Biopharmaceutics. 2022; 180: 101\u2013118.","DOI":"10.1016\/j.ejpb.2022.09.015"},{"key":"ref14","unstructured":"Voegele D, Von Hattingberg HM, Brockmeier D. Ein einfaches Verfahren zur. Ermittlung von in-vitro\/in-vivo Zusammenh\u00e4ngen in der Galenik. Acta Pharmaceutica Technologica. 1981; 27: 115\u2013120. (In German)"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Karkossa F, Klein S. Assessing the influence of media composition and ionic strength on drug release from commercial immediate-release and enteric-coated aspirin tablets. The Journal of Pharmacy and Pharmacology. 2017; 69: 1327\u20131340.","DOI":"10.1111\/jphp.12777"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Klein S. The use of biorelevant dissolution media to forecast the in vivo performance of a drug. The AAPS Journal. 2010; 12: 397\u2013406.","DOI":"10.1208\/s12248-010-9203-3"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Klein S, Dressman JB. Comparison of Drug Release From Metoprolol Modified Release Dosage Forms in Single Buffer versus a pH-Gradient Dissolution Test. Dissolution Technologies. 2006; 13: 6\u201312.","DOI":"10.14227\/dt130106p6"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Basu S, Yang H, Fang L, Gonzalez-Sales M, Zhao L, Trame MN, et al. Physiologically Based Pharmacokinetic Modeling to Evaluate Formulation Factors Influencing Bioequivalence of Metoprolol Extended-Release Products. Journal of Clinical Pharmacology. 2019; 59: 1252\u20131263.","DOI":"10.1002\/jcph.1017"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Brown JD, Henriksen C, Vozmediano V, Schmidt S. Real-World Data Approaches for Early Detection of Potential Safety and Effectiveness Signals for Generic Substitution: A Metoprolol Extended-Release Case Study. Journal of Clinical Pharmacology. 2019; 59: 1275\u20131284.","DOI":"10.1002\/jcph.1436"},{"key":"ref20","unstructured":"Graedon J. Another Metoprolol Recall Reveals the Dark Side of Generic Drugs. The People\u2019s Pharmacy. 2017. Available at: https:\/\/www.peoplespharmacy.com\/articles\/another-metoprolol-recall-reveals-the-dark-side-of-generic-drugs (Accessed: 12 November 2025)."}],"container-title":["Die Pharmazie"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/Pharmazie\/81\/5\/10.31083\/Pharmazie51859","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T08:35:41Z","timestamp":1780130141000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/Pharmazie\/81\/5\/10.31083\/Pharmazie51859"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,19]]},"references-count":20,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026]]}},"alternative-id":["S0031-7144(26)02830-0"],"URL":"https:\/\/doi.org\/10.31083\/pharmazie51859","relation":{},"ISSN":["0031-7144","3053-691X"],"issn-type":[{"value":"0031-7144","type":"print"},{"value":"3053-691X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,19]]},"article-number":"51859"}}