https://m2.mtmt.hu/ hun 2026-10-25 00:00 JournalArticle 35435617 VALIDATED true Funding Agency and Grant Number: Egis Pharmaceuticals PLC; Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences; Ministry of Culture and Innovation, from the National Research Development and Innovation Fund [2020-1.1.2-PIACI-KFI-2020-00039]; Ministry of Culture and Innovation, from the National Research Development and Innovation Fund Funding text: The financial support from Egis Pharmaceuticals PLC is gratefully acknowledged. B.S. is thankful for the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences. This work was prepared in the framework of 2020-1.1.2-PIACI-KFI-2020-00039 project with the support of the Ministry of Culture and Innovation, from the National Research Development and Innovation Fund. 0 false 2026-10-22T07:07:31.963+0000 2026-02-10T09:39:23.891+0000 2024-10-04T12:32:55.234+0000 true 10044851 Szilágyi Botond /api/author/10044851 Author true 10044851 2026-02-10T09:39:23.743+0000 2025-03-19T07:25:29.568+0000 true 521 Szuper Admin /api/admin/521 Admin true true false true 24 24 /api/publicationtype/24 PublicationType 1 true 24 JournalArticle true 10000059 Article true 24 24 /api/publicationtype/24 PublicationType 1 true 24 JournalArticle /api/subtype/10000059 Szakcikk SubType 101 true 10000059 true 1 /api/category/1 Category true 1 Borsos, Ákos Derisking Crystallization Process Development and Scale-Up Using a Complementary, “Quick and Dirty” Digital Design true true /api/journal/14406 REVIEWED true false 14406 false 14406 true 1083-6160 1520-586X Journal FOREIGN 28 10 3813 3826 3813 14 2024 Despite the spread of digital (model and AI-based) techniques, the industry-standard pharmaceutical crystallization design and scale-up is still based on experiments’ design (DoE). Many orthogonally designed and usually relatively lightly monitored experiments are performed as a part of it. The final design/scale-up is inherently truncated by experimental and statistical modeling errors and assumptions, compromising the reliability of the calculated design space (DS). This study proposes to apply process modeling in a complementary way: utilize the experiments from the DoE to calibrate an application-driven model, quantify its accuracy, and use it─in parallel with the statistical interpretation of the DoE─to design the process. Both the DoE and model-based DS determination involve workflow-specific assumptions, simplifications, and errors, but the overlap between the independent results may be considered a derisked DS. We demonstrate this workflow on the design of a fed-batch salting-out crystallization for a commercial active pharmaceutical ingredient (API). The model was identified based on product particle size distribution data of a DoE set from a small-scale reactor (0.25 L) and a manufacturing batch (ca. 4000 L). Although reactors with intermediate volumes are also generally applied as a part of scale-up, included in the presented case study, those were not included in the model development and verification. The kinetic equations were taken from our previously developed cooling crystallization model of the same API. After calibration and accuracy evaluation, the critical process parameters were determined using interpretable machine learning via Shapley diagrams, and the DS was mapped and visualized using Monte Carlo sampling-based simulations. The DS was validated for 0.25 L experiments. The model-based DS was somewhat narrower than the DoE-based DS on a small scale. The DS determined for plant-scale crystallization can guide the manufacturing-scale process design and operation. The extrapolation capabilities of the model were stressed by external validation by defining and validating experimentally the DS for a 1 L crystallization. These results indicate that models developed in this application-centric way can enhance the robustness of the processes, and the modeling branch does not add any risk. In the worst-case scenario, if the modeling fails, one still has the results from the traditional design approach. © 2024 The Authors. Published by American Chemical Society. true 2024 true true true false true false GOLD 2026-10-22 true https://doi.org/10.1021/acs.oprd.4c00199 8 0 8 6 3 8 8 6 6 6 6 4 4 6 2 0 8 6 8 6 0 8 8 Folyóiratcikk Journal Article 24 8 Könyvrészlet Chapter in Book 25 0 Könyv Book 23 0 Egyéb konferenciaközlemény Conference paper 31 0 Egyéb konferenciakötet Conference proceedings 32 0 Oltalmi formák Protection forms 26 0 Disszertáció Thesis 28 0 Egyéb Miscellaneous 29 0 Alkotás Achievement 22 0 Kutatási adat Research data 33 0 Folyóiratcikk Journal Article 24 0 0 0 Könyvrészlet Chapter in Book 25 0 0 0 Könyv Book 23 0 0 0 Egyéb konferenciaközlemény Conference paper 31 0 0 0 Egyéb konferenciakötet Conference proceedings 32 0 0 0 Oltalmi formák Protection forms 26 0 0 0 Disszertáció Thesis 28 0 0 0 Egyéb Miscellaneous 29 0 0 0 Alkotás Achievement 22 0 0 0 Kutatási adat Research data 33 0 0 0 2025 0 1 0 1 0 2026 0 7 6 7 6 Q1 false false false false 2025-01-02T13:32:56.159+0000 Egis Gyógyszergyár Zrt.; 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title="Forrásközlemény" style="float: left" src="/frontend/resources/grid/publication-core-icon.png"> <img title="Idézőközlemény" style="float: left" src="/frontend/resources/grid/publication-citation-icon.png"> <div class="autype autype0"> <span class="author-name" mtid="10090493"><a href="/gui2/?type=authors&mode=browse&sel=10090493" target="_blank">Borsos Ákos (<span class="authorship-author-name">Borsos Ákos</span> <span class="authorAux-mtmt"> Vegyészmérnökség, kristályosítás és modellezés</span>) </a> </span> <span class="author-affil">Egis Gyógyszergyár Zrt.</span> ;&nbsp;&nbsp;&nbsp; <span class="author-name" mtid="10099096"><a href="/gui2/?type=authors&mode=browse&sel=10099096" target="_blank">Hámori Csaba (<span class="authorship-author-name">Hámori Csaba</span> <span class="authorAux-mtmt"> gyártástechnológia fejlesztés</span>) </a> </span> <span class="author-affil">Egis Gyógyszergyár Zrt.</span> ;&nbsp;&nbsp;&nbsp; <span class="author-name" >Szilágyi Emőke </span> ;&nbsp;&nbsp;&nbsp; <span class="author-name" >Spaits András </span> ;&nbsp;&nbsp;&nbsp; <span class="author-name" mtid="10099072"><a href="/gui2/?type=authors&mode=browse&sel=10099072" target="_blank">Farkas Ferenc (<span class="authorship-author-name">Farkas Ferenc</span> <span class="authorAux-mtmt"> vegyészet, gyógyszeripar</span>) </a> </span> <span class="author-affil">Egis Gyógyszergyár Zrt.</span> ;&nbsp;&nbsp;&nbsp; <span class="author-name" mtid="10016346"><a href="/gui2/?type=authors&mode=browse&sel=10016346" target="_blank">Százdi László (<span class="authorship-author-name">Százdi László</span> <span class="authorAux-mtmt"> vegyészmérnöki tudományok</span>) </a> </span> <span class="author-affil">Egis Gyógyszergyár Zrt.</span> ;&nbsp;&nbsp;&nbsp; <span class="author-name" mtid="10075363"><a href="/gui2/?type=authors&mode=browse&sel=10075363" target="_blank">Kátainé Fadgyas Katalin (<span class="authorship-author-name">Kátainé Fadgyas Katalin</span> <span class="authorAux-mtmt"> Kémiai tudományok</span>) </a> </span> <span class="author-affil">Egis Gyógyszergyár Zrt.</span> ;&nbsp;&nbsp;&nbsp; <span class="author-name" mtid="10012714"><a href="/gui2/?type=authors&mode=browse&sel=10012714" target="_blank">Volk Balázs (<span class="authorship-author-name">Volk Balázs</span> <span class="authorAux-mtmt"> Hatóanyag gyártóeljárás-fejlesztés, heterociklu...</span>) </a> </span> <span class="author-affil">Egis Gyógyszergyár Zrt.</span> ;&nbsp;&nbsp;&nbsp; <span class="author-name" mtid="10044851"><a href="/gui2/?type=authors&mode=browse&sel=10044851" target="_blank">Szilágyi Botond ✉ (<span class="authorship-author-name">Szilágyi Botond</span> <span class="authorAux-mtmt"> Folyamatmérnök, vegyészmérnök</span>) </a> </span> <span class="author-affil"><span title="Budapesti Műszaki és Gazdaságtudományi Egyetem">BME</span>/Vegyészmérnöki és Biomérnöki Kar</span> </div> </div> <div class="title"><a href="/gui2/?mode=browse&params=publication;35435617" target="_blank">Derisking Crystallization Process Development and Scale-Up Using a Complementary, “Quick and Dirty” Digital Design</a></div> <div> <span class="journal-title">ORGANIC PROCESS RESEARCH & DEVELOPMENT</span> <span class="journal-issn">(<a target="_blank" href="https://portal.issn.org/resource/ISSN/1083-6160">1083-6160</a> <a target="_blank" href="https://portal.issn.org/resource/ISSN/1520-586X">1520-586X</a>)</span>: <span class="journal-volume">28</span> <span class="journal-issue">10</span> <span class="page"> pp 3813-3826 </span> <span class="year">(2024)</span> </div> <div class="pub-footer"> <span class="language" xmlns="http://www.w3.org/1999/html">Nyelv: Angol | </span> <span class="identifiers"> <span class="id identifier oa_GOLD" title=" Gold "> <a style="color:blue" title="10.1021/acs.oprd.4c00199" target="_blank" href="https://doi.org/10.1021/acs.oprd.4c00199"> DOI </a> </span> <span class="id identifier oa_none" title="none"> <a style="color:blue" title="001328669800001" target="_blank" href="https://www.webofscience.com/wos/woscc/full-record/001328669800001"> WoS </a> </span> <span class="id identifier oa_none" title="none"> <a style="color:blue" title="85205910851" target="_blank" href="http://www.scopus.com/record/display.url?origin=inward&eid=2-s2.0-85205910851"> Scopus </a> </span> <span class="id identifier oa_none" title="none"> <a style="color:black" title="https://pubs.acs.org/doi/10.1021/acs.oprd.4c00199" target="_blank" href="https://pubs.acs.org/doi/10.1021/acs.oprd.4c00199"> Egyéb URL </a> </span> </span> <OnlyViewableByAuthor><div class="ratings"> <div class="journal-subject">Folyóirat szakterülete: Scopus - Organic Chemistry&nbsp;&nbsp;&nbsp;SJR indikátor:&nbsp;Q1</div> <div class="journal-subject">Folyóirat szakterülete: Scopus - Physical and Theoretical Chemistry&nbsp;&nbsp;&nbsp;SJR indikátor:&nbsp;Q1</div> </div></OnlyViewableByAuthor> <div class="publication-citation" style="margin-left: 0.5cm;"> <span title="Nyilvános idézőközlemények összesen, említések nélkül" class="citingPub-count">Nyilvános idéző összesen: 8</span> | Független: 6 | Függő: 2 | Nem jelölt: 0 | WoS jelölt: 6 | Scopus jelölt:&nbsp;6 | WoS/Scopus jelölt:&nbsp;6 | DOI jelölt:&nbsp;8 </div> <div class="publication-citation"> <a target="_blank" href="/api/publication?cond=citations.related;eq;35435617&sort=publishedYear,desc&sort=title"> Idézett közlemények száma: 8 </a> </div> <div class="mtid"><span class="long-pub-mtid">Közlemény: 35435617</span> | <span class="status-data status-VALIDATED"> Egyeztetett </span> Forrás Idéző | <span class="type-subtype">Folyóiratcikk ( Szakcikk ) </span> | <span class="pub-category">Tudományos</span> | <span class="publication-sourceOfData">kézi felvitel</span> </div> <div class="lastModified">Utolsó módosítás: 2026.02.10. 10:39 Szatmári Erika (BME admin4) </div> <pre class="comment" style="margin-top: 0; margin-bottom: 0;"><u>Megjegyzés</u>: Funding Agency and Grant Number: Egis Pharmaceuticals PLC; Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences; Ministry of Culture and Innovation, from the National Research Development and Innovation Fund [2020-1.1.2-PIACI-KFI-2020-00039]; Ministry of Culture and Innovation, from the National Research Development and Innovation Fund Funding text: The financial s...</pre> </div></div>