{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T08:07:38Z","timestamp":1789373258104,"version":"build-2803163510"},"reference-count":49,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100004326","name":"Bayer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004326","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Angew Chem Int Ed"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Understanding the chemical degradation of active pharmaceutical ingredients is critical for formulation development and regulatory compliance, yet computational tools either rely on predefined reaction rules that limit discovery of unanticipated pathways or cannot distinguish energetically accessible products from formally possible ones. We present an automated workflow requiring no predefined reaction rules that explores degradation networks from the potential energy surface. The approach combines metadynamics for reaction discovery, energy\u2010 and count\u2010based filtering, density functional theory refinement, and microkinetic modelling to calculate time\u2010 and temperature\u2010dependent product distributions. Applied to the acid\u2010catalysed degradation of BMS\u2010644950, the workflow constructs a network of 1720 species and 2471 elementary steps, reduced to 8 degradation products. Microkinetic simulations identify the two observed lactone products as dominant and propose a tentative structure for a previously uncharacterised 466 Da impurity (R. Hemingway et\u00a0al.,\n                    <jats:italic>Organic Process Research &amp; Development<\/jats:italic>\n                    28 (2024): 674\u2013692). The calculations reveal that several thermodynamically favourable products remain unobserved because activation barriers of 36\u201340\u00a0kcal\u00a0 render them kinetically inaccessible on the experimental timescale, a distinction reaction\u2010rule\u2010based methods cannot make. The exploration finishes within 3 days on a compute cluster, demonstrating that automated, physics\u2010based degradation modelling is tractable for drug\u2010like molecules at industrially relevant\u00a0scales.\n                  <\/jats:p>","DOI":"10.1002\/anie.4407622","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T07:21:05Z","timestamp":1789370465000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Practical Computational Exploration of Chemical Reaction Space: Assessing the Chemical Stability of Active Pharmaceutical Ingredients Under Acidic Conditions"],"prefix":"10.1002","author":[{"given":"Julius","family":"Seumer","sequence":"first","affiliation":[{"name":"Department of Chemistry University of Copenhagen Copenhagen Denmark"},{"name":"Janssen Research &amp; Development A Division of Janssen Pharmaceutica NV (a Johnson &amp; Johnson company) Beerse 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R&amp;D Structural Biology &amp; Computational Design Wuppertal Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1465-1010","authenticated-orcid":false,"given":"Jan H.","family":"Jensen","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Copenhagen Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"crossref","DOI":"10.1007\/978-0-387-85627-8","volume-title":"Handbook of Stability Testing in Pharmaceutical Development: Regulations, Methodologies, and Best Practices","author":"Huynh\u2010Ba K.","year":"2009"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpha.2013.09.003"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.13040\/ijpsr.0975\u20108232.7(6"},{"key":"e_1_2_8_5_1","unstructured":"International Conference on 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