{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T15:26:53Z","timestamp":1787412413798,"version":"build-2736575974"},"reference-count":37,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100031478","name":"NextGenerationEU","doi-asserted-by":"publisher","award":["RRF-2.3.1-21-2022-00015"],"award-info":[{"award-number":["RRF-2.3.1-21-2022-00015"]}],"id":[{"id":"10.13039\/100031478","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003825","name":"Magyar Tudom?nyos Akad?mia","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100003825","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012550","name":"Nemzeti Kutat?si, Fejleszt?si ls Innovaci?s Alap","doi-asserted-by":"publisher","award":["FK-143019"],"award-info":[{"award-number":["FK-143019"]}],"id":[{"id":"10.13039\/501100012550","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012550","name":"Nemzeti Kutat?si, Fejleszt?si ls Innovaci?s Alap","doi-asserted-by":"publisher","award":["K-143039"],"award-info":[{"award-number":["K-143039"]}],"id":[{"id":"10.13039\/501100012550","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Inline Raman spectroscopy-based monitoring enables the development of control systems that allow the implementation of Process Analytical Technology (PAT) principles even in chemical reactions, thereby improving quality, efficiency, and safety. There are only a few articles in the literature that discuss such control systems. This may be due to the numerous challenges involved, including the need for robust measurement setups and the development of chemometric algorithms capable of delivering accurate and stable real-time evaluations. Thus, this study presents the Raman spectroscopic monitoring and chemometric-based feedback control of a highly exothermic and potentially hazardous diazotization reaction, namely, the synthesis of phenyldiazonium chloride from aniline, hydrochloric acid, and sodium nitrite. Raman spectra were analyzed offline using Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) and in real-time using Classical Least Squares (CLS) chemometric methods to monitor and control key reaction components. The developed feedback system successfully controlled concentration levels during both acid\u2013base and diazotization phases. The reduction of the Raman signal-to-noise ratio, induced by the decomposition of the diazonium salt, was also observed. This factor significantly affected the monitoring of the diazotization experiment. Furthermore, a calibration was established to quantify the molar concentrations of key components based on Raman spectra. The calibration experiment successfully demonstrated well-fitted linear molar\u2013spectral relationships for both aniline (R2homogeneous = 0.997; R2heterogeneous = 0.9947) and aniline hydrochloride (R2 = 0.9987). For aniline, the molar\u2013spectral relationship exhibited a distinct change in tendency that precisely correlated with its solubility limit in water, marking the transition from homogeneous solution to emulsion.<\/jats:p>","DOI":"10.1021\/acs.oprd.6c00030","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T07:00:37Z","timestamp":1783580437000},"page":"2149-2158","source":"Crossref","is-referenced-by-count":0,"title":["Spectroscopic Monitoring\nand Chemometric-Based Feedback\nControl of the Diazotization Reaction"],"prefix":"10.1021","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9406-0097","authenticated-orcid":true,"given":"Ma\u0301te\u0301","family":"Fent","sequence":"first","affiliation":[{"name":"Budapest University of Technology and Economics , , Mu\u030begyetem rkp. 3 , ,","place":["Budapest, Hungary, H-1111"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8877-2587","authenticated-orcid":true,"given":"Attila","family":"Farkas","sequence":"additional","affiliation":[{"name":"Budapest University of Technology and Economics , , Mu\u030begyetem rkp. 3 , ,","place":["Budapest, Hungary, H-1111"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajnalka","family":"Pataki","sequence":"additional","affiliation":[{"name":"Budapest University of Technology and Economics , , Mu\u030begyetem rkp. 3 , ,","place":["Budapest, Hungary, H-1111"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2651-7756","authenticated-orcid":true,"given":"Zsombor K.","family":"Nagy","sequence":"additional","affiliation":[{"name":"Budapest University of Technology and Economics , , Mu\u030begyetem rkp. 3 , ,","place":["Budapest, Hungary, H-1111"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6858-1388","authenticated-orcid":true,"given":"Istva\u0301n","family":"Csontos","sequence":"additional","affiliation":[{"name":"Budapest University of Technology and Economics , , Mu\u030begyetem rkp. 3 , ,","place":["Budapest, Hungary, H-1111"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"2026082211134617400_cit1","unstructured":"FDA.\n          .  Guidance for Industry\nPAT - A Framework for Innovative Pharmaceutical Development, Manufacturing,\nand Quality Assurance; 2004; https:\/\/www.fda.gov\/media\/71012\/download."},{"issue":"1","key":"2026082211134617400_cit2","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1007\/s00216-010-3781-x","article-title":"Process Analytical\nTechnology (PAT)\nfor Biopharmaceutical Products","volume":"398","author":"Rathore","year":"2010","journal-title":"Anal. Bioanal.\nChem."},{"key":"2026082211134617400_cit3","doi-asserted-by":"publisher","first-page":"114379","DOI":"10.1016\/j.jpba.2021.114379","article-title":"Process Analytical\nTechnologies \u2013\nAdvances in Bioprocess Integration and Future Perspectives","volume":"207","author":"Gerzon","year":"2022","journal-title":"J. Pharm. Biomed. Anal."},{"issue":"3","key":"2026082211134617400_cit4","doi-asserted-by":"publisher","first-page":"221","DOI":"10.3390\/cryst11030221","article-title":"Application\nof PAT-Based Feedback Control Approaches\nin Pharmaceutical Crystallization","volume":"11","author":"Gao","year":"2021","journal-title":"Crystals\n(Basel)."},{"key":"2026082211134617400_cit5","doi-asserted-by":"crossref","DOI":"10.1007\/978-981-99-8034-5","volume-title":"Introduction to\nQuality by Design (QbD)","author":"Jain","year":"2024"},{"key":"2026082211134617400_cit6","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1016\/j.foodcont.2015.08.007","article-title":"Exploiting near\nInfrared Spectroscopy as an Analytical Tool for On-Line Monitoring\nof Acidity during Coffee Roasting","volume":"60","author":"Santos","year":"2016","journal-title":"Food Control"},{"issue":"3","key":"2026082211134617400_cit7","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1021\/op300062t","article-title":"Implementation\nof Raman Signal Feedback\nto Perform Controlled Crystallization of Carvedilol","volume":"17","author":"Pataki","year":"2013","journal-title":"Org. Process Res. Dev."},{"key":"2026082211134617400_cit8","unstructured":"Abu Bakar, M. R.; Saleemi, A. N.; Nagy, Z.; Rielly, C.\n          Direct\nnucleation\ncontrol of crystal size distribution in pharmaceutical crystallization. In  17th International Symposium on Industrial Crystallization, September 14\u201317, 2008, Maastricht, The Netherlands; https:\/\/hdl.handle.net\/2134\/4747."},{"key":"2026082211134617400_cit9","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1016\/j.ces.2017.09.034","article-title":"Systematic\nModel Identification and\nOptimization-Based Active Polymorphic Control of Crystallization Processes","volume":"174","author":"Simone","year":"2017","journal-title":"Chem. Eng. Sci."},{"key":"2026082211134617400_cit10","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1016\/j.powtec.2020.03.027","article-title":"Process Analytical\nTechnology-Based\n(PAT) Model Simulations of a Combined Cooling, Seeded and Antisolvent\nCrystallization of an Active Pharmaceutical Ingredient (API)","volume":"366","author":"Trampuz\u030c","year":"2020","journal-title":"Powder Technol."},{"issue":"2","key":"2026082211134617400_cit11","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1021\/ac048842u","article-title":"Use of\nIn-Line near-Infrared\nSpectroscopy in Combination with Chemometrics for Improved Understanding\nof Pharmaceutical Processes","volume":"77","author":"Rantanen","year":"2005","journal-title":"Anal. Chem."},{"issue":"4","key":"2026082211134617400_cit12","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.1208\/s12249-008-9145-6","article-title":"Monitoring Granulation Rate Processes\nUsing Three PAT Tools in a Pilot-Scale Fluidized Bed","volume":"9","author":"Tok","year":"2008","journal-title":"AAPS PharmSciTech"},{"issue":"7","key":"2026082211134617400_cit13","doi-asserted-by":"publisher","first-page":"822","DOI":"10.3390\/ph15070822","article-title":"Real-Time Monitoring\nof Critical Quality Attributes during High-Shear Wet Granulation Process\nby Near-Infrared Spectroscopy Effect of Water Addition and Stirring\nSpeed on Pharmaceutical Properties of the Granules","volume":"15","author":"Koyanagi","year":"2022","journal-title":"Pharmaceuticals"},{"issue":"2","key":"2026082211134617400_cit14","doi-asserted-by":"publisher","first-page":"452","DOI":"10.3390\/pr13020452","article-title":"NIR-Based Real-Time Monitoring of\nFreeze-Drying Processes: Application to Fault and Endpoint Detection","volume":"13","author":"Massei","year":"2025","journal-title":"Processes"},{"key":"2026082211134617400_cit15","doi-asserted-by":"publisher","first-page":"121689","DOI":"10.1016\/j.ijpharm.2022.121689","article-title":"Comparative Study on\nthe Real-Time Monitoring of a Fluid Bed Drying Process of Extruded\nGranules Using near-Infrared Spectroscopy and Audible Acoustic Emission","volume":"619","author":"Aoki","year":"2022","journal-title":"Int. J. Pharm."},{"key":"2026082211134617400_cit16","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.jpba.2014.07.012","article-title":"NIR Spectroscopic Method for the In-Line Moisture Assessment\nduring Drying in a Six-Segmented Fluid Bed Dryer of a Continuous Tablet\nProduction Line: Validation of Quantifying Abilities and Uncertainty\nAssessment","volume":"100","author":"Fonteyne","year":"2014","journal-title":"J. Pharm. Biomed. Anal."},{"issue":"10","key":"2026082211134617400_cit17","doi-asserted-by":"publisher","first-page":"1721","DOI":"10.1021\/acs.oprd.6b00212","article-title":"Raman-Based\nFeedback Control of the Enzymatic Hydrolysis of Lactose","volume":"20","author":"Hirsch","year":"2016","journal-title":"Org. Process Res. Dev."},{"issue":"1","key":"2026082211134617400_cit18","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1021\/op500015d","article-title":"Feedback Control\nof Oximation Reaction by Inline Raman Spectroscopy","volume":"19","author":"Csontos","year":"2015","journal-title":"Org. Process Res. Dev."},{"issue":"11","key":"2026082211134617400_cit19","doi-asserted-by":"publisher","first-page":"1553","DOI":"10.1021\/ed100129z","article-title":"Demonstration\nof a Runaway Exothermic Reaction: Diels-Alder\nReaction of (2 E,4 E)-2,4-Hexadien-1-Ol and Maleic Anhydride","volume":"88","author":"Parsons","year":"2011","journal-title":"J. Chem. Educ."},{"issue":"1","key":"2026082211134617400_cit20","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1051\/ctv\/ctv2022370179","article-title":"Fourier Transform\nInfrared Spectroscopy\nin Monitoring the Wine Production","volume":"37","author":"Thanasi","year":"2022","journal-title":"Cie\u0302ncia\ne Te\u0301cnica Vitivini\u0301cola"},{"issue":"12","key":"2026082211134617400_cit21","doi-asserted-by":"publisher","first-page":"e12423","DOI":"10.1016\/j.heliyon.2022.e12423","article-title":"In-Situ Monitoring\nof Nitrate in Industrial Wastewater Using Fourier Transform Infrared\nAttenuated Total Reflectance Spectroscopy (FTIR-ATR) Coupled with\nChemometrics Methods","volume":"8","author":"Gan","year":"2022","journal-title":"Heliyon"},{"key":"2026082211134617400_cit22","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.ejpb.2019.05.007","article-title":"Real-Time Monitoring\nof Particle Size Distribution in a Continuous Granulation and Drying\nProcess by near Infrared Spectroscopy","volume":"141","author":"Pauli","year":"2019","journal-title":"Eur.\nJ. Pharm. Biopharm."},{"issue":"1","key":"2026082211134617400_cit23","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1007\/s10404-010-0654-8","article-title":"In Situ Raman Spectroscopy\nto Monitor the Hydrolysis of Acetal in Microreactors","volume":"10","author":"Rinke","year":"2011","journal-title":"Microfluid. Nanofluidics"},{"issue":"9","key":"2026082211134617400_cit24","doi-asserted-by":"publisher","first-page":"17275","DOI":"10.3390\/s140917275","article-title":"Raman Spectroscopy\nfor In-Line Water Quality Monitoring\u2500Instrumentation and Potential","volume":"14","author":"Li","year":"2014","journal-title":"Sensors"},{"issue":"5","key":"2026082211134617400_cit25","doi-asserted-by":"publisher","first-page":"e2848","DOI":"10.1002\/btpr.2848","article-title":"Inline Noninvasive\nRaman Monitoring and Feedback Control\nof Glucose Concentration during Ethanol Fermentation","volume":"35","author":"Hirsch","year":"2019","journal-title":"Biotechnol. Prog."},{"issue":"10","key":"2026082211134617400_cit26","doi-asserted-by":"publisher","first-page":"1698","DOI":"10.3390\/polym11101698","article-title":"In-Line Monitoring\nthe Degradation of Polypropylene under Multiple Extrusions Based on\nRaman Spectroscopy","volume":"11","author":"Guo","year":"2019","journal-title":"Polymers (Basel)."},{"issue":"17","key":"2026082211134617400_cit27","doi-asserted-by":"publisher","first-page":"6068","DOI":"10.1021\/acssuschemeng.1c01518","article-title":"Real-Time\nMonitoring of Aqueous Organic Reduction Reactions Using Ex Situ Fiber\nOptic Raman Spectroscopy","volume":"9","author":"Amberchan","year":"2021","journal-title":"ACS Sustain. Chem.\nEng."},{"key":"2026082211134617400_cit28","doi-asserted-by":"publisher","first-page":"124251","DOI":"10.1016\/j.ijpharm.2024.124251","article-title":"Raman and NIR Spectroscopy-Based\nReal-Time Monitoring\nof the Membrane Filtration Process of a Recombinant Protein for the\nDiagnosis of SARS-CoV-2","volume":"660","author":"Vasko\u0301","year":"2024","journal-title":"Int. J. Pharm."},{"key":"2026082211134617400_cit29","doi-asserted-by":"publisher","first-page":"125976","DOI":"10.1016\/j.matchemphys.2022.125976","article-title":"Raman Spectroscopy\nas Process Analytical\nTechnology Tool for Monitoring Atomic Layer Deposition (ALD) of Drug\nParticles","volume":"282","author":"Mittal","year":"2022","journal-title":"Mater. Chem. Phys."},{"key":"2026082211134617400_cit30","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.aca.2012.12.028","article-title":"Multivariate Curve\nResolution: A Review of Advanced\nand Tailored Applications and Challenges","volume":"765","author":"Ruckebusch","year":"2013","journal-title":"Anal.\nChim. Acta"},{"issue":"1\u20132","key":"2026082211134617400_cit31","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.ijpharm.2011.07.023","article-title":"Characterization\nof Melt Extruded and Conventional Isoptin Formulations Using Raman\nChemical Imaging and Chemometrics","volume":"419","author":"Vajna","year":"2011","journal-title":"Int. J. Pharm."},{"key":"2026082211134617400_cit32","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.aca.2011.10.065","article-title":"Testing the Performance of Pure Spectrum\nResolution\nfrom Raman Hyperspectral Images of Differently Manufactured Pharmaceutical\nTablets","volume":"712","author":"Vajna","year":"2012","journal-title":"Anal. Chim. Acta"},{"key":"2026082211134617400_cit33","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.jlp.2015.09.004","article-title":"Reactive Chemical\nHazards of Diazonium\nSalts","volume":"38","author":"Sheng","year":"2015","journal-title":"J. Loss Prev. Process Ind."},{"key":"2026082211134617400_cit34","doi-asserted-by":"publisher","first-page":"179156","DOI":"10.1016\/j.tca.2022.179156","article-title":"Research on the Decomposition\nKinetics and Thermal Hazards of Aniline Diazonium Salt","volume":"709","author":"Xie","year":"2022","journal-title":"Thermochim. Acta"},{"issue":"2","key":"2026082211134617400_cit35","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1039\/b106889j","article-title":"Comparison of In-Line NIR, Raman\nand UV-Visible Spectrometries, and at-Line NMR Spectrometry for the\nMonitoring of an Esterification Reaction","volume":"127","author":"McGill","year":"2002","journal-title":"Analyst"},{"issue":"18","key":"2026082211134617400_cit36","doi-asserted-by":"publisher","first-page":"20214","DOI":"10.1021\/acsomega.4c00565","article-title":"Real-Time\nMonitoring of Multistep Batch and Flow Synthesis Processes of a Key\nIntermediate of Lifitegrast by a Combined Spectrometer System with\nBoth Near-Infrared and Raman Spectroscopies Coupled to Partial Least-Squares","volume":"9","author":"Liu","year":"2024","journal-title":"ACS Omega"},{"issue":"10","key":"2026082211134617400_cit37","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.1366\/12-06729","article-title":"In-Line\nNear-Infrared (NIR) and Raman Spectroscopy Coupled with Principal\nComponent Analysis (PCA) for in Situ Evaluation of the Transesterification\nReaction","volume":"67","author":"Fontalvo-Go\u0301mez","year":"2013","journal-title":"Appl. Spectrosc."}],"container-title":["Organic Process Research\n&amp; Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.oprd.6c00030","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/oprdfk\/article-pdf\/30\/8\/2149\/65832156\/acs.oprd.6c00030.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/oprdfk\/article-pdf\/30\/8\/2149\/65832156\/acs.oprd.6c00030.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T15:14:19Z","timestamp":1787411659000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/oprdfk\/article\/30\/8\/2149\/5203770\/Spectroscopic-Monitoring-and-Chemometric-Based"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,9]]},"references-count":37,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,7,9]]},"published-print":{"date-parts":[[2026,8,21]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.oprd.6c00030","relation":{},"ISSN":["1083-6160","1520-586X"],"issn-type":[{"value":"1083-6160","type":"print"},{"value":"1520-586X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,9]]}}}