https://m2.mtmt.hu/ hun 2026-10-25 00:14 JournalArticle 37018173 VALIDATED true This research was supported by Hungarian National Scientific Research Fund (OTKA) grant FK-138475. 0 false 2026-09-24T14:44:39.852+0000 2026-07-17T09:28:46.228+0000 2026-03-18T14:06:03.109+0000 true 10044851 Szilágyi Botond /api/author/10044851 Author true 10044851 2026-07-17T09:28:46.615+0000 2026-07-17T09:28:46.615+0000 2026-04-24T07:25:13.072+0000 true 10072271 Andódy Katalin /api/admin/10072271 Admin true 2026-05-18T17:13:04.814+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 Bereczki-Horváth, Lili Virág Automatic Design of Wet-Milling-Integrated Batch Crystallization Processes by Process Analytical Technology-Based Split-Range Direct Nucleation Control true true /api/journal/14406 REVIEWED true false 14406 false 14406 true 1083-6160 1520-586X Journal FOREIGN 30 4 861 871 861 11 2026 Wet milling is increasingly employed as a process-intensification tool in pharmaceutical batch crystallization, not only as a terminal particle-size reduction step but also as an integrated unit operation synchronized with the crystallizer to enhance process robustness and expand the attainable range of particle-size and shape distributions. Designing a high-performance batch crystallization process is challenging because of the large number of design variables that often require repeated crystallization and dissolution cycles. Synchronizing the crystallizer and wet-milling operations adds further complexity. Direct nucleation control (DNC) is widely used to automatically design cycles of crystal growth and dissolution for single-input, single-output systems─for example, adjusting the temperature to maintain the relative number density within a predefined range. This study extends the DNC principle to handle an integrated system. We propose a sequential split-range controller that regulates the relative number density by employing cooling and heating as the primary manipulated variables. When the target particle count cannot be achieved by cooling alone, a wet-milling cycle is automatically initiated to increase the count through high shear, thereby enhancing the nucleation, attrition, and breakage. Experimental results indicate that this control strategy can drive the process beyond the limits of conventional DNC, producing repeated cycles of growth and nucleation (by cooling or sequential cooling and milling) and dissolution (by heating). In addition to generating larger crystals, the automatic milling cycles also reduced the aspect ratio of rod-like particles, demonstrating the potential for simultaneous crystal-shape control. Repeated implementation of the integrated operation discovered by split-range DNC exhibited high reproducibility, underscoring the potential of the method not only as a control strategy but also as a rapid process-design tool. true true NATIONAL 2026 true true true false true false NONE 2026-09-24 false 1 0 1 1 0 1 1 1 1 1 1 1 1 1 0 0 1 1 1 1 0 14 14 Folyóiratcikk Journal Article 24 1 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 2026 0 1 1 1 1 Q1 false false false false 2026-03-31T12:33:37.012+0000 Kémiai és Környezeti Folyamatmérnöki Tanszék (BME / VBK) 1 4 1 2 0 true Language 10002 /api/language/10002 Angol English true 2 true PersonAuthorship 135043571 /api/authorship/135043571 1 0.5 true false false Bereczki-Horváth Lili Virág true false false AuthorshipType 1 /api/authorshiptype/1 0 true 0 true false true PersonAuthorship 135043572 /api/authorship/135043572 2 0.5 false true true Author 10044851 /api/author/10044851 Szilágyi Botond true 10044851 true Szilágyi Botond true false false AuthorshipType 1 /api/authorshiptype/1 0 true 0 true false true PublicationIdentifier 31669657 /api/publicationidentifier/31669657 PlainSource 6 /api/publicationsource/6 PublicationSourceType 10001 /api/publicationsourcetype/10001 true true true DOI DOI https://doi.org/@@@ true true 6 true IDENTICAL 10.1021/acs.oprd.5c00402 https://doi.org/10.1021/acs.oprd.5c00402 false 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10.1021/acs.iecr.5b04956 false true Reference 73781241 /api/reference/73781241 34 10.1016/j.jprocont.2020.05.001 false true Reference 73781242 /api/reference/73781242 35 10.1016/j.arabjc.2023.105362 false true Reference 73781243 /api/reference/73781243 36 10.1016/0022-0248(89)90049-3 false true Reference 73781244 /api/reference/73781244 37 10.1021/acs.cgd.2c00141 false true Reference 73781245 /api/reference/73781245 38 10.1021/acs.cgd.0c00295 false true Reference 73781246 /api/reference/73781246 39 10.1021/acs.oprd.0c00307 false true Reference 73781247 /api/reference/73781247 40 10.1021/acs.iecr.8b03349 false true Reference 73781248 /api/reference/73781248 41 10.1016/j.ultsonch.2025.107668 false true /api/publication/37018173 <div class="JournalArticle Publication long-list"> <div class="authors"> <img 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" >Bereczki-Horváth Lili Virág </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>/<span title="Vegyészmérnöki és Biomérnöki Kar">VBK</span>/Kémiai és Környezeti Folyamatmérnöki Tanszék</span> </div> </div> <div class="title"><a href="/gui2/?mode=browse&params=publication;37018173" target="_blank">Automatic Design of Wet-Milling-Integrated Batch Crystallization Processes by Process Analytical Technology-Based Split-Range Direct Nucleation Control</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">30</span> <span class="journal-issue">4</span> <span class="page"> pp 861-871 </span> <span class="year">(2026)</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_none" title="none"> <a style="color:blue" title="10.1021/acs.oprd.5c00402" target="_blank" href="https://doi.org/10.1021/acs.oprd.5c00402"> DOI </a> </span> <span class="id identifier oa_none" title="none"> <a style="color:blue" title="001717867200001" target="_blank" href="https://www.webofscience.com/wos/woscc/full-record/001717867200001"> WoS </a> </span> <span class="id identifier oa_none" title="none"> <a style="color:blue" title="105036693387" target="_blank" href="http://www.scopus.com/record/display.url?origin=inward&eid=2-s2.0-105036693387"> Scopus </a> </span> <span class="id identifier oa_none" title="none"> <a style="color:blue" title="https://pubs.acs.org/doi/10.1021/acs.oprd.5c00402" target="_blank" href="https://pubs.acs.org/doi/10.1021/acs.oprd.5c00402"> 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: 1</span> | Független: 1 | Függő: 0 | Nem jelölt: 0 | WoS jelölt: 1 | Scopus jelölt:&nbsp;1 | WoS/Scopus jelölt:&nbsp;1 | DOI jelölt:&nbsp;1 </div> <div class="publication-citation"> <a target="_blank" href="/api/publication?cond=citations.related;eq;37018173&sort=publishedYear,desc&sort=title"> Idézett közlemények száma: 14 </a> </div> <div class="mtid"><span class="long-pub-mtid">Közlemény: 37018173</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">DOI XML</span> </div> <div class="lastModified">Utolsó módosítás: 2026.07.17. 11:28 Szatmári Erika (BME admin4) </div> <pre class="comment" style="margin-top: 0; margin-bottom: 0;"><u>Megjegyzés</u>: This research was supported by Hungarian National Scientific Research Fund (OTKA) grant FK-138475.</pre> </div></div>