[en] Crystallization of active pharmaceutical ingredients (APIs) is sometimes constrained by solvent selection and undesired solvate formation with challenging solid-form control. This study presents a crystallization and solid-form transformation strategy that exploits, rather than avoids, a solvate intermediate to access the two commercially relevant forms of nitrofurantoin (NIFU), anhydrate β and monohydrate II, thereby extending the known form map for this API. Solubility screening across biobased and green solvents identified dimethyl sulfoxide (DMSO) as the only viable Class 3 solvent providing solubility ≥20 mg/mL while generating an undesired NIFU DMSO hemisolvate. Batch and continuous antisolvent crystallization processes in a DMSO-water system at 25 °C were studied with high yields (≥92%) supported by process analytical technology. Thermal desolvation resulted in complete conversion to anhydrate β between 170 and 180 °C within ≤40 min without detectable degradation (HPLC). Slurry crystallization in water between 10 and 40 °C enabled solvent-mediated phase transformation (SMPT) to monohydrate II within ≤15 min. The semiempirical Avrami–Erofeev equation fits the TGA (R2 ≥ 0.986) and Raman (R2 ≥ 0.947) data well, allowing qualitative assessment of the temperature effect on the desolvation and SMPT processes. Both generated NIFU forms meet US Pharmacopeia critical quality attributes. Based on the NIFU-specific work, the showcased strategy may be relevant for APIs, exhibiting similarly solubility limitations and strong solvation propensity.
Disciplines :
Chemical engineering
Author, co-author :
Lee, Hung Lin ; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, United States
Molajafari, Fateme; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, United States
Koishybay, Aibolat ; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, United States
Miyai, Yuma; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, United States
Zimmermann, Lennart ; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, United States ; Bioseparation Engineering Group, Technical University of Munich, Garching, Germany
Monbaliu, Jean-Christophe ; Université de Liège - ULiège > Molecular Systems (MolSys) ; WEL Research Institute, Wavre, Belgium
Vlaar, Cornelis ; Department of Pharmaceutical Sciences, University of Puerto Rico - Medical Sciences Campus, San Juan, United States
Romañach, Rodolfo J. ; Department of Chemistry, University of Puerto Rico - Mayagüez, Mayagüez, United States
Noor-E-Alam, Md. ; Department of Mechanical and Industrial Engineering, College of Engineering, Center for Health Policy and Healthcare Research, Northeastern University, Boston, United States
Myerson, Allan S. ; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, United States
Stelzer, Torsten ; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, United States ; Department of Pharmaceutical Sciences, University of Puerto Rico - Medical Sciences Campus, San Juan, United States ; Crystallization Design Institute, Molecular Sciences Research Center, University of Puerto Rico, San Juan, United States
Language :
English
Title :
Exploiting Undesired Solvate for Continuous Crystallization of Nitrofurantoin with Solid Form Transformation Process
Polymorphism in the Pharmaceutical Industry: solid Form and Drug Development, Hilfiker, R.; von Raumer, M., Eds.; Wiley: Weinheim, 2019.
Lee, A. Y.; Erdemir, D.; Myerson, A. S. Crystal polymorphism in chemical process development. Annu. Rev. Chem. Biomol. Eng. 2011, 2, 259–280, 10.1146/annurev-chembioeng-061010-114224
Di Martino, P.; Guyot-Hermann, A. M.; Conflant, P.; Drache, M.; Guyot, J. C. A new pure paracetamol for direct compression: the orthorhombic form. Int. J. Pharm. 1996, 128, 1–8, 10.1016/0378-5173(95)04127-3
Nicoud, L.; Licordari, F.; Myerson, A. S. Estimation of the solubility of metastable polymorphs: a critical review. Cryst. Growth Des. 2018, 18, 7228–7237, 10.1021/acs.cgd.8b01200
Lee, T.; Yang, C. L.; Lee, H. L. Saving energy upon water removal in drying by making the α-polymorph of L-glutamic acid. Sep. Sci. Technol. 2022, 57, 1948–1965, 10.1080/01496395.2021.2009514
Bernstein, J. Polymorphism – A perspective. Cryst. Growth Des. 2011, 11, 632–650, 10.1021/cg1013335
Samas, B.; Seadeek, C.; Campeta, A. M.; Chekal, B. P. A thermodynamic-based approach to analyzing a highly solvating polymorphic system: The desolvation window method. J. Pharm. Sci. 2011, 100, 186–194, 10.1002/jps.22265
Tian, F.; Qu, H.; Zimmermann, A.; Munk, T.; Jørgensen, A. C.; Rantanen, J. Factors affecting crystallization of hydrates. J. Pharm. Pharmacol. 2010, 62, 1534–1546, 10.1111/j.2042-7158.2010.01186.x
Byrn, S. R. Solid-State Chemistry of Drugs; Academic Press: New York, 1982.
Dette, S. S.; Stelzer, T.; Jones, M. J.; Ulrich, J. Dehydration behaviour of hydrates. Cryst. Res. Technol. 2010, 45, 697–702, 10.1002/crat.201000188
Adamson, J.; Faiber, N.; Gottlieb, A.; Hamsmith, L.; Hicks, F.; Mitchell, C.; Mittal, B.; Mukai, K.; Papageorgiou, C. D. Development of suitable plant-scale drying conditions that prevent API agglomeration and dehydration. Org. Process Res. Dev. 2016, 20, 51–58, 10.1021/acs.oprd.5b00327
Brittain, H. G. Paroxetine hydrochloride: Polymorphs and solvatomorphs. Profiles Drug Subst. Excip. Relat. Methodol. 2013, 38, 407–421, 10.1016/B978-0-12-407691-4.00009-5
Legendre, A.O.; Silva, L.R.; Silva, D.M.; Rosa, I.M.; Azarias, L.C.; de Abreu, P.J.; de Araújo, M.B.; Neves, P.P.; Torres, C.; Martins, F.T. et al. Solid state chemistry of the antibiotic doxycycline: structure of the neutral monohydrate and insights into its poor water solubility. CrystEngcomm 2012, 14, 2532–2540, 10.1039/C1CE06181J
Zheng, Z.; Hou, B.; Cheng, X.; Liu, W.; Huang, X.; Bao, Y.; Wang, T.; Wang, Z.; Hao, H. The mechanism of solvent-mediated desolvation transformation of lenvatinib mesylate from dimethyl sulfoxide solvate to form D. Acta Crystallogr. 2020, B76, 343–352, 10.1107/S2052520620003935
Myerson, A. S.; Erdemir, D.; Lee, A. Y. Handbook of Industrial Crystallization; Cambridge University Press: Cambridge, 2019.
FDA. Q3C(R8) Impurities: Guidance for Residual Solvents Guidance for Industry 2021 https://www.fda.gov/vaccines-bloodbiologics/guidance-compliance-regulatory-information-biologics/biologics-guidances.
Rogers, L.; Briggs, N.; Achermann, R.; Adamo, A.; Azad, M.; Brancazio, D.; Capellades, G.; Hammersmith, G.; Hart, T.; Imbrogno, J.; Kelly, L. P.; Liang, G.; Neurohr, C.; Rapp, K.; Russell, M. G.; Salz, C.; Thomas, D. A.; Weimann, L.; Jamison, T. F.; Myerson, A. S.; Jensen, K. F. Continuous production of five active pharmaceutical ingredients in flexible plug-and-play modules: A demonstration campaign. Org. Process Res. Dev. 2020, 24, 2183–2196, 10.1021/acs.oprd.0c00208
Silva-Brenes, D. V.; Agrawal, S.; López-Mejías, V.; Duconge, J.; Vlaar, C. P.; Monbaliu, J. C. M.; Stelzer, T. Continuous flow synthesis and crystallization of modafinil: a novel approach for integrated manufacturing. React. Chem. Eng. 2024, 9, 2728–2739, 10.1039/D4RE00273C
Wirth, D. D.; Stephenson, G. A. Purification of dirithromycin. Impurity reduction and polymorph manipulation. Org. Process Res. Dev. 1997, 1, 55–60, 10.1021/op960033s
Black, S. N.; Cuthbert, M. W.; Roberts, R. J.; Stensland, B. Increased chemical purity using a hydrate. Cryst. Growth Des. 2004, 4, 539–544, 10.1021/cg034222v
Maini, L.; Braga, D.; Farinella, F.; Melotto, E.; Verzini, M.; Brescello, R.; Michieletto, I.; Munari, I. Crystal forms of enzalutamide and a crystal engineering route to drug purification. Cryst. Growth Des. 2018, 18, 3774–3780, 10.1021/acs.cgd.7b01613
Chekal, B. P.; Campeta, A. M.; Abramov, Y. A.; Feeder, N.; Glynn, P. P.; McLaughlin, R. W.; Meenan, P. A.; Singer, R. A. The challenges of developing an API crystallization process for a complex polymorphic and highly solvating system. Part I. Org. Process Res. Dev. 2009, 13, 1327–1337, 10.1021/op9001559
World Health Organization. WHO Model List of Essential Medicines - 22nd list, 2021. https://iris.who.int/server/api/core/bitstreams/285bb318-3177-4ed6-8fc9-5d1106220fa4/content (accessed 3 March, 2026).
Pienaar, E. W.; Caira, M. R.; Lötter, A. P. Polymorphs of nitrofurantoin. 2. Preparation and X-ray crystal structures of two anhydrous forms of nitrofurantoin. J. Crystallogr. Spectrosc. Res. 1993, 23, 785–790, 10.1007/BF01247241
Pienaar, E. W.; Caira, M. R.; Lötter, A. Polymorphs of nitrofurantoin. I. Preparation and X-ray crystal structures of two monohydrated forms of nitrofurantoin. J. Crystallogr. Spectrosc. Res. 1993, 23, 739–744, 10.1007/BF01187276
Vangala, V. R.; Chow, P. S.; Tan, R. B. Nitrofurantoin methanol monosolvate. Acta Crystallogr. 2011, E67, o550–o551, 10.1107/S1600536811003679
Tutughamiarso, M.; Bolte, M.; Wagner, G.; Egert, E. Five pseudopolymorphs and a cocrystal of nitrofurantoin. Acta Crystallogr. 2011, C67, o18–o25, 10.1107/S0108270110046755
Tian, F.; Qu, H.; Louhi-Kultanen, M.; Rantanen, J. Insight into crystallization mechanisms of polymorphic hydrate systems. Chem. Eng. Technol. 2010, 33, 833–838, 10.1002/ceat.200900572
Wang, X.; Ji, X.; Cai, T.; Guo, M. Mechanistic insight of polymer effects on the kinetic of solution-mediated phase transformation of nitrofurantoin anhydrate to monohydrate. Pharm. Res 2023, 40, 1587–1598, 10.1007/s11095-023-03513-0
US Patent. JPH 0,212,156 A1. 2023
India Patent IN. 3941/CHE/2011.
Koradia, V.; de Diego, H. L.; Elema, M. R.; Rantanen, J. Integrated approach to study the dehydration kinetics of nitrofurantoin monohydrate. J. Pharm. Sci. 2010, 99, 3966–3976, 10.1002/jps.22244
Crawford, D. E.; Porcheddu, A.; McCalmont, A. S.; Delogu, F.; James, S. L.; Colacino, E. Solvent-free, continuous synthesis of hydrazone-based active pharmaceutical ingredients by twin-screw extrusion. ACS Sustainable Chem. Eng. 2020, 8, 12230–12238, 10.1021/acssuschemeng.0c03816
Yu, L. X.; Amidon, G.; Khan, M. A.; Hoag, S. W.; Polli, J.; Raju, G. K.; Woodcock, J. Understanding pharmaceutical quality by design. AAPS J. 2014, 16, 771–783, 10.1208/s12248-014-9598-3
United States Pharmacopeia. Nitrofurantoin; United States Pharmacopeia, 2020. DOI: 10.31003/USPNF_M56770_03_01.
Scott, D.; Briggs, N. E.; Formosa, A.; Burnett, A.; Desai, B.; Hammersmith, G.; Rapp, K.; Capellades, G.; Myerson, A. S.; Roper, T. D. Impurity purging through systematic process development of a continuous two-stage crystallization. Org. Process Res. Dev. 2023, 27, 148–158, 10.1021/acs.oprd.2c00317
Hellwig, H.; Bovy, L.; Van Hecke, K.; Vlaar, C. P.; Romañach, R. J.; Noor-E-Alam, M.; Myerson, A. S.; Stelzer, T. M.; Jean-Christophe, M. M. Continuous Flow Synthesis of Nitrofuran Pharmaceuticals Using Acetyl Nitrate. Angew. Chem., Int. Ed. 2025, 64, e202501660 10.1002/anie.202501660
Zorrilla-Veloz, R. I.; Stelzer, T.; López-Mejías, V. Measurement and Correlation of the Solubility of 5-Fluorouracil in Pure and Binary Solvents. J. Chem. Eng. Data 2018, 63, 3809–3817, 10.1021/acs.jced.8b00425
George De La Rosa, M. V.; Santiago, R.; Malavé Romero, J.; Duconge, J.; Monbaliu, J. C.; López-Mejías, V.; Stelzer, T. Solubility Determination and Correlation of Warfarin Sodium 2-Propanol Solvate in Pure, Binary, and Ternary Solvent Mixtures. J. Chem. Eng. Data 2019, 64, 1399–1413, 10.1021/acs.jced.8b00977
Vázquez Marrero, V. R.; Piñero Berriós, C.; De Dios Rodríguez, L.; Stelzer, T.; López-Mejiás, V. In the context of polymorphism: Accurate measurement, and validation of solubility data. Cryst. Growth Des. 2019, 19, 4101–4108, 10.1021/acs.cgd.9b00529
Jiménez Cruz, J. M.; Vlaar, C. P.; López-Mejías, V.; Stelzer, T. Solubility measurements and correlation of mbq-167 in neat and binary solvent mixtures. J. Chem. Eng. Data 2021, 66, 832–839, 10.1021/acs.jced.0c00908
Zimmermann, L.; Lee, H. L.; Koishybay, A.; Vlaar, C. P.; Monbaliu, J. C. M.; Romañach, R. J.; Noor-E-Alam, M.; Myerson, A. S.; Stelzer, T. Measurements and correlation of timolol maleate solubility in biobased neat and binary solvent mixtures. J. Chem. Eng. Data 2024, 69, 2369–2379, 10.1021/acs.jced.4c00060
Smallwood, I. M. Handbook of Organic Solvent Properties; Elsevier: Arnold, 1996.
Vellema, J.; Hunfeld, N. G. M.; Van Den Akker, H. E. A.; Ter Horst, J. H. Avoiding Crystallization of lorazepam during infusion. Eur. J. Pharm. Sci. 2011, 44, 621–626, 10.1016/j.ejps.2011.10.010
Reus, M. A.; Van Der Heijden, A. E. D. M.; Ter Horst, J. H. Solubility determination from clear points upon solvent addition. Org. Process Res. Dev. 2015, 19, 1004–1011, 10.1021/acs.oprd.5b00156
Aprile, G.; Pandit, A. V.; Albertazzi, J.; Eren, A.; Capellades, G.; Thorat, A. A.; Gamekkanda, J.; Vetter, T.; Skovby, T.; Sin, G.; Wu, H.; Dam-Johansen, K.; Myerson, A. S. Loop-configuration for plug flow crystallization process development. Cryst. Growth Des. 2023, 23, 8052–8064, 10.1021/acs.cgd.3c00819
Aprile, G.; Pandit, A. V.; Albertazzi, J.; Vetter, T.; Viano, R.; Milani, L.; Adamo, A.; Myerson, A. S.; Stelzer, T. Residence time distribution characterization and proof-of-concept of a novel stacked 7-stage continuous crystallizer cascade with diaphragm-driven slurry transfer. Ind. Eng. Chem. Res. 2024, 63, 18199–18211, 10.1021/acs.iecr.4c02153
Pal, K.; Radocea, A. Gravity as a Knob for Tuning Particle Size Distributions of Small Molecules. Cryst. Growth Des. 2024, 24, 2370–2383, 10.1021/acs.cgd.3c01274
Stelzer, T.; Lakerveld, R.; Myerson, A. S. Process Intensification in Continuous Crystallization. In Handbook of Continuous Crystallization; RSC Publishing: Cambridge, 2020,pp. 266–299.
Li, J.; Lai, T. T. C.; Trout, B. L.; Myerson, A. S. Continuous crystallization of cyclosporine: Effect of operating conditions on yield and purity. Cryst. Growth Des. 2017, 17, 1000–1007, 10.1021/acs.cgd.6b01212
Mo, Y.; Jensen, K. F. A miniature CSTR Cascade for continuous flow of reactions containing solids. React. Chem. Eng. 2016, 1, 501–507, 10.1039/C6RE00132G
Blaze Metrics, LLC. Gen 1 through Gen 2.5 BlazeBasic and BlazePlatform Manual: blaze UI and Office Software 148.03.10.; Quil Ceda Village: WA, USA 2023.
Pataki, H.; Markovits, I.; Vajna, B.; Nagy, Z. K.; Marosi, G. In-line monitoring of carvedilol crystallization using Raman spectroscopy. Cryst. Growth Des. 2012, 12, 5621–5628, 10.1021/cg301135z
Beckmann, W. Crystallization: basic Concepts and Industrial Applications; John Wiley & Sons: Hoboken, NJ, 2013.
Ottoboni, S.; Simurda, M.; Wilson, S.; Irvine, A.; Ramsay, F.; Price, C. J. Understanding effect of filtration and washing on dried product: paracetamol case study. Powder Technol. 2020, 366, 305–323, 10.1016/j.powtec.2020.02.064
Wong, S. Y.; Tatusko, A. P.; Trout, B. L.; Myerson, A. S. Development of continuous crystallization processes using a single-stage mixed-suspension, mixed-product removal crystallizer with recycle. Cryst. Growth Des. 2012, 12, 5701–5707, 10.1021/cg301221q
Li, J.; Trout, B. L.; Myerson, A. S. Multistage continuous mixed-suspension, mixed-product removal (MSMPR) crystallization with solids recycle. Org. Process Res. Dev. 2016, 20, 510–516, 10.1021/acs.oprd.5b00306
Cole, K. P.; Campbell, B. M.; Forst, M. B.; McClary Groh, J.; Hess, M.; Johnson, M. D.; Miller, R. D.; Mitchell, D.; Polster, C. S.; Reizman, B. J.; Rosemeyer, M. An automated intermittent flow approach to continuous Suzuki coupling. Org. Process Res. Dev. 2016, 20, 820–830, 10.1021/acs.oprd.6b00030
Remoto, P. I. J.; Be̅rziņš, K.; Fraser-Miller, S. J.; Korter, T. M.; Rades, T.; Rantanen, J.; Gordon, K. C. Elucidating the dehydration mechanism of nitrofurantoin monohydrate II using low-frequency raman spectroscopy. Cryst. Growth Des. 2022, 22, 2733–2741, 10.1021/acs.cgd.2c00121
Avrami, M. Kinetics of phase change. I. General theory. J. Chem. Phys. 1939, 7, 1103–1112, 10.1063/1.1750380
Avrami, M. Kinetics of phase change. II. Transformation-time relations for random distribution of nuclei. J. Chem. Phys. 1940, 8, 212–224, 10.1063/1.1750631
Avrami, M. Granulation, phase change, and microstructure kinetics of phase change. III. J. Chem. Phys. 1941, 9, 177–184, 10.1063/1.1750872
Joshi, V.; Stowell, J. G.; Byrn, S. R. Solid-state stability of indomethacin solvates. Mol. Cryst. Liq. Cryst. Sci. Technol. A 1998, 313, 265–270, 10.1080/10587259808044286
Brittain, H. G. Polymorphism in Pharmaceutical Solids; Informa Healthcare: USA, Inc., 2009.
Ahuja, S.; Scypinski, S. Handbook of Modern Pharmaceutical Analysis; Academic Press: Amsterdam, 2011.
Giron, D. Thermal Analysis and Calorimetric Methods in the Characterisation of Polymorphs and Solvates. Thermochim. Acta 1995, 248, 1–59, 10.1016/0040-6031(94)01953-E
Stone, M. L.; Webber, M. S.; Mounfield, W. P.; Bell, D. C.; Christensen, E.; Morais, A. R.; Li, Y.; Anderson, E. M.; Heyne, J. S.; Beckham, G. T.; Román-Leshkov, Y. Continuous Hydrodeoxygenation of lignin to jet-range aromatic hydrocarbons. Joule 2022, 6, 2324–2337, 10.1016/j.joule.2022.08.005
McNair, H. M.; Miller, J. M. Basic Gas Chromatography; John Wiley & Sons, Inc.: Hoboken, NJ, 2009.
Yaseen, G.; Ahmad, M.; Zafar, M.; Akram, A.; Sultana, S.; Kilic, O.; Sonmez, G. D. Current status of solvents used in the pharmaceutical industry. Green Sustainable Process for Chemical and Environmental Engineering and Science; Elsevier: Amsterdam. 2021, pp. 195–219.
Duereh, A.; Sato, Y.; Smith, R. L., Jr; Inomata, H. Methodology for replacing dipolar aprotic solvents used in API processing with safe hydrogen-bond donor and acceptor solvent-pair mixtures. Org. Process Res. Dev. 2017, 21, 114–124, 10.1021/acs.oprd.6b00401
FDA. Guidance for Industry. Q3C - Tables and List; 2017. https://www.fda.gov/downloads/drugs/guidances/ucm073395.pdf (accessed 3 March 2026).
Cardew, P. T.; Davey, R. J. The kinetics of solvent-mediated phase transformations. Proc. R. Soc. London A Math. Phys. Sci. 1815, 398, 415–428, 10.1098/rspa.1985.0043
O’Mahony, M. A.; Maher, A.; Croker, D. M.; Rasmuson, Å. C.; Hodnett, B. K. Examining solution and solid state composition for the solution-mediated polymorphic transformation of carbamazepine and piracetam. Cryst. Growth Des. 2012, 12, 1925–1932, 10.1021/cg201665z
Hernández Espinell, J. R.; Toro, V.; Yao, X.; Yu, L.; Lopéz-Mejías, V.; Stelzer, T. Solvent-mediated polymorphic transformations in molten polymers: The account of acetaminophen. Mol. Pharmaceutics 2022, 19, 2183–2190, 10.1021/acs.molpharmaceut.2c00035
American Chemical Society Crystallisation, 4th Edition By J. W. Mullin. 2001. Butterworth Heinemann: Oxford, UK. 600 pp. £75.00. ISBN 075-064-833-3. Org. Proc. Res. Dev., 2002 6 201–202. 10.1021/op0101005.
Groom, C. R.; Bruno, I. J.; Lightfoot, M. P.; Ward, S. C. The Cambridge structural database. Acta Crystallogr. 2016, B72, 171–179, 10.1107/S2052520616003954
Cullity, B. D.; Stock, S. R. Elements of X-Ray Diffraction, 3rd ed.; Pearson Prentice Hall: Upper Saddle River, NJ, 2001.
Caira, M. R.; Pienaar, E. W.; Lötter, A. P. Polymorphism and pseudopolymorphism of the antibacterial nitrofurantoin. Mol. Cryst. Liq. Cryst. Sci. Technol. A 1996, 279, 241–264, 10.1080/10587259608042194
Nagy, Z. K.; Fujiwara, M.; Braatz, R. D. Modelling and control of combined cooling and antisolvent crystallization processes. J. Process Contr. 2008, 18, 856–864, 10.1016/j.jprocont.2008.06.002
Bueno, A.; Viar, N.; Barredo, A.; Gandarias, I.; Requies, J. M. Integrated process for 2,5-furandicarboxylic acid production from fructose via NaCl-promoted dehydration and Au/HT-catalyzed oxidation. J. Ind. Eng. Chem. 2025, 147, 696–704, 10.1016/j.jiec.2024.12.060
Sheldon, R. A. The E factor: fifteen years on. Green Chem. 2007, 9, 1273–1283, 10.1039/b713736m
Xie, W.; Li, T.; Chen, C.; Wu, H.; Liang, S.; Chang, H.; Liu, B.; Drioli, E.; Wang, Q.; Crittenden, J. C. Using the green solvent dimethyl sulfoxide to replace traditional solvents partly and fabricating PVC/PVC-g-PEGMA blended ultrafiltration membranes with high permeability and rejection. Ind. Eng. Chem. Res. 2019, 58, 6413–6423, 10.1021/acs.iecr.9b00370
O’Grady, D.; Barrett, M.; Casey, E.; Glennon, B. The effect of mixing on the metastable zone width and nucleation kinetics in the anti-solvent crystallization of benzoic acid. Chem. Eng. Res. Des. 2007, 85, 945–952, 10.1205/cherd06207
Yu, Z. Q.; Tan, R. B. H.; Chow, P. S. Effects of operating conditions on agglomeration and habit of paracetamol crystals in anti-solvent crystallization. J. Cryst. Growth 2005, 279, 477–488, 10.1016/j.jcrysgro.2005.02.050
O’Mahony, M.; Ferguson, S.; Stelzer, T.; Myerson, A. Separation and Purification in the Continuous Synthesis of Fine Chemicals and Pharmaceuticals. In Science of Synthesis: Flow Chemistry in Organic Synthesis; Thieme, 2018, pp. 51–102.
Yu, X. Y.; Lionberger, R. A.; Raw, A. S.; D’Costa, R.; Wu, H.; Hussain, A. S. Applications of process analytical technology to crystallization processes. Adv. Drug Delivery Rev. 2004, 56, 349–369, 10.1016/j.addr.2003.10.012
Feng Báez, J. P.; Soto-Bibiloni, A.; Stelzer, T. Real-Time Monitoring of Crystallization Processes Using a Novel Compact Composite Sensor Array. Org. Process Res. Dev. 2023, 27, 2174–2182, 10.1021/acs.oprd.3c00330
Liu, J.; Benyahia, B. Optimal start-up strategies of a combined cooling and antisolvent multistage continuous crystallization process. Comput. Chem. Eng. 2022, 159, 107671, 10.1016/j.compchemeng.2022.107671
Yang, Y.; Nagy, Z. K. Combined cooling and antisolvent crystallization in continuous mixed suspension, mixed product removal cascade crystallizers: Steady-state and startup optimization. Ind. Eng. Chem. Res. 2015, 54, 5673–5682, 10.1021/ie5034254
Dufour, F.; Stichel, B.; Grayson, J. I. Control of crystal modification and crystal shape by control of solid–solid transitions during crystallization and drying: Two industrial case studies. Org. Process Res. Dev. 2013, 17, 568–577, 10.1021/op300333h
Cambridge Crystallographic Data Centre. New Functionality for the Geometry Optimization of Crystal and Molecular Structures. https://www.ccdc.cam.ac.uk/discover/blog/new-functionality-for-the-geometry-optimization-of-crystal-and-molecular-structures/ (accessed 26 February 2026).
Joshi, V.; Morris, K. R.; Byrn, S. R.; Carvajal, M. T. Evaluation of the use of Ea(activation energy) as a quantitative indicator of physical stability of indomethacin solvates: Methanolate and tertiary butyl alcohol solvate. Cryst. Growth Des. 2009, 9, 3359–3366, 10.1021/cg800750g
Nordhoff, S.; Ulrich, J. Solvent-induced phase transformations of hydrates. J. Thermal Anal Calorim. 1999, 57, 181–192, 10.1023/A:1010159222264
Bechtloff, B.; Nordhoff, S.; Ulrich, J. Pseudopolymorphs in industrial use. Cryst. Res. Technol. 2001, 36, 1315–1328, 10.1002/1521-4079(200112)36:12<1315::AID-CRAT1315>3.0.CO;2-R
Shirzad, K.; Viney, C. A critical review on applications of the Avrami equation beyond materials science. J. R. Soc. Interface 2023, 20, 20230242, 10.1098/rsif.2023.0242
Chanda, A.; Daly, A. M.; Foley, D. A.; La Pack, M. A.; Mukherjee, S.; Orr, J. D.; Reid, G. L.; Thompson, D. R.; Ward, H. W. Industry perspectives on process analytical technology: tools and applications in API development. Org. Process Res. Dev. 2015, 19, 63–83, 10.1021/op400358b
Hu, Y.; Liang, J. K.; Myerson, A. S.; Taylor, L. S. Crystallization monitoring by Raman spectroscopy: simultaneous measurement of desupersaturation profile and polymorphic form in flufenamic acid systems. Ind. Eng. Chem. Res. 2005, 44, 1233–1240, 10.1021/ie049745u
Nguyen, D. L. T.; Kim, K. J. Solvent-mediated polymorphic transformation of α-taltirelin by seeded crystallization. Chem. Eng. Technol. 2016, 39, 1281–1288, 10.1002/ceat.201600043
Pan, B.; Wei, H.; Jiang, J.; Zong, S.; Lv, P.; Dang, L. Solution-mediated polymorphic transformation of CL-20: An approach to prepare purified form ε particles. J. Mol. Liq. 2018, 265, 216–225, 10.1016/j.molliq.2018.05.121
Otsuka, M.; Matsuda, Y. Effect of environmental humidity on the transformation pathway of nitrofurantoin modifications during grinding and the physicochemical properties of ground products. J. Pharm. Pharmacol. 1993, 45, 406–413, 10.1111/j.2042-7158.1993.tb05566.x
Raijada, D.; Arnfast, L.; Bond, A. D.; Aho, J.; Bøtker, J.; Sandler, N.; Rantanen, J. Dehydration of nitrofurantoin monohydrate during melt extrusion. Cryst. Growth Des. 2017, 17, 3707–3715, 10.1021/acs.cgd.7b00316
Berzins, A.; Trimdale-Deksne, A.; Belyakov, S.; Ter Horst, J. H. Switching nitrofurantoin polymorphic outcome in solvent-mediated phase transformation and crystallization using solvent and additives. Cryst. Growth Des. 2023, 23, 5469–5476, 10.1021/acs.cgd.3c00033
