Please wait a minute...
Submit  |   Chinese  | 
Advanced Search
   Home  |  Online Now  |  Current Issue  |  Focus  |  Archive  |  For Authors  |  Journal Information   Open Access  
Submit  |   Chinese  | 
Engineering    2017, Vol. 3 Issue (3) : 343 -353
Research |
Recent Developments in the Crystallization Process: Toward the Pharmaceutical Industry
Zhenguo Gao1,2,Sohrab Rohani1(),Junbo Gong2,Jingkang Wang2
1. Department of Chemical and Biochemical Engineering, The University of Western Ontario, London, ON N6A 5B9, Canada
2. School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China

Crystallization is one of the oldest separation and purification unit operations, and has recently contributed to significant improvements in producing higher-value products with specific properties and in building efficient manufacturing processes. In this paper, we review recent developments in crystal engineering and crystallization process design and control in the pharmaceutical industry. We systematically summarize recent methods for understanding and developing new types of crystals such as co-crystals, polymorphs, and solvates, and include several milestones such as the launch of the first co-crystal drug, Entresto (Novartis), and the continuous manufacture of Orkambi (Vertex). Conventional batch and continuous processes, which are becoming increasingly mature, are being coupled with various control strategies and the recently developed crystallizers are thus adapting to the needs of the pharmaceutical industry. The development of crystallization process design and control has led to the appearance of several new and innovative crystallizer geometries for continuous operation and improved performance. This paper also reviews major recent progress in the area of process analytical technology.

Keywords Crystallization      Crystal engineering      Polymorphism      Crystallization process design and control      Crystal size distribution     
Corresponding Authors: Sohrab Rohani   
Just Accepted Date: 08 June 2017   Issue Date: 30 June 2017
E-mail this article
E-mail Alert
Articles by authors
Zhenguo Gao
Sohrab Rohani
Junbo Gong
Jingkang Wang
Cite this article:   
Zhenguo Gao,Sohrab Rohani,Junbo Gong, et al. Recent Developments in the Crystallization Process: Toward the Pharmaceutical Industry[J]. Engineering, 2017, 3(3): 343 -353 .
URL:     OR
1   D’Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 1994;91(9):4082–5
doi: 10.1073/pnas.91.9.4082
2   Wnendt S, Finkam M, Winter W, Ossig J, Raabe G, Zwingenberger K. Enantioselective inhibition of TNF-α release by thalidomide and thalidomide-analogues. Chirality 1996;8(5):390–6
doi: 10.1002/(SICI)1520-636X(1996)8:5<390::AID-CHIR6>3.0.CO;2-I
3   Bauer JF, Saleki-Gerhardt A, Narayanan BA, Chemburkar SR, Patel KM, Spiwek HO, et al., inventors; Abbott Laboratories, assignee. Polymorph of a pharmaceutical. United States patent US 8193367 B2. 2012 Jun 5.
4   Bauer J, Spanton S, Henry R, Quick J, Dziki W, Porter W, et al.Ritonavir: An extraordinary example of conformational polymorphism. Pharm Res 2001;18(6):859–66
doi: 10.1023/A:1011052932607
5   Huang LF, Tong WQ. Impact of solid state properties on developability assessment of drug candidates. Adv Drug Deliv Rev 2004;56(3):321–34
doi: 10.1016/j.addr.2003.10.007
6   Lee AY, Erdemir D, Myerson AS. Crystal polymorphism in chemical process development. Annu Rev Chem Biomol Eng 2011;2:259–80
doi: 10.1146/annurev-chembioeng-061010-114224
7   Sood J, Sapra B, Bhandari S, Jindal M, Tiwary AK. Understanding pharmaceutical polymorphic transformations I: Influence of process variables and storage conditions. Ther Deliv 2014;5(10):1123–42
doi: 10.4155/tde.14.68
8   Wu JX, Xia D, van den Berg F, Amigo JM, Rades T, Yang M, et al.A novel image analysis methodology for online monitoring of nucleation and crystal growth during solid state phase transformations. Int J Pharm 2012;433(1–2):60–70
doi: 10.1016/j.ijpharm.2012.04.074
9   Wallace AF, Hedges LO, Fernandez-Martinez A, Raiteri P, Gale JD, Waychunas GA, et al.Microscopic evidence for liquid-liquid separation in supersaturated CaCO3 solutions. Science 2013;341(6148):885–9
doi: 10.1126/science.1230915
10   Kuhs M, Zeglinski J, Rasmuson ÅC. Influence of history of solution in crystal nucleation of fenoxycarb: Kinetics and mechanisms. Cryst Growth Des 2014;14(3):905–15
doi: 10.1021/cg4007795
11   Ito F, Suzuki Y, Fujimori J, Sagawa T, Hara M, Seki T, et al.Direct visualization of the two-step nucleation model by fluorescence color changes during evaporative crystallization from solution. Sci Rep 2016;6:22918
doi: 10.1038/srep22918
12   Srisanga S, Flood AE, Galbraith SC, Rugmai S, Soontaranon S, Ulrich J. Crystal growth rate dispersion versus size-dependent crystal growth: Appropriate modeling for crystallization processes. Cryst Growth Des 2015;15(5):2330–6
doi: 10.1021/acs.cgd.5b00126
13   Mascia S, Heider PL, Zhang H, Lakerveld R, Benyahia B, Barton PI, et al.End-to-end continuous manufacturing of pharmaceuticals: Integrated synthesis, purification, and final dosage formation. Angew Chem Int Ed 2013;52(47):12359–63
doi: 10.1002/anie.201305429
14   Myerson AS, Krumme M, Nasr M, Thomas H, Braatz RD. Control systems engineering in continuous pharmaceutical manufacturing. May 20–21, 2014 Continuous Manufacturing Symposium. J Pharm Sci 2015;104(3):832–9
doi: 10.1002/jps.24311
15   Adamo A, Beingessner RL, Behnam M, Chen J, Jamison TF, Jensen KF, et al.On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system. Science 2016;352(6281):61–7
doi: 10.1126/science.aaf1337
16   Woo XY, Tan RB, Braatz RD. Precise tailoring of the crystal size distribution by controlled growth and continuous seeding from impinging jet crystallizers. CrystEngComm 2011;13(6):2006–14
doi: 10.1039/c0ce00637h
17   Kee NC, Tan RB, Braatz RD. Selective crystallization of the metastable α-form of L-glutamic acid using concentration feedback control. Cryst Growth Des 2009;9(7):3044–51
doi: 10.1021/cg800546u
18   Singh MR. Towards the control of crystal shape and morphology distributions in crystallizers [dissertation]. West Lafayette: Purde University; 2013.
19   Wang Y, Chen A. Crystallization-based separation of enantiomers. In: Andrushko V, Andrushko N, editors Stereoselective synthesis of drugs and natural products, two volume set. 1st ed. Hoboken: John Wiley & Sons, Inc.; 2013. p. 1663–82
doi: 10.1002/9781118596784.ssd056
20   Nagy ZK, Fevotte G, Kramer H, Simon LL. Recent advances in the monitoring, modelling and control of crystallization systems. Chem Eng Res Des 2013;91(10):1903–22
doi: 10.1016/j.cherd.2013.07.018
21   US Food and Drug Administration. Pharmaceutical cGMPs for the 21st century—A risk based approach. Final report. US Food and Drug Administration; 2004 Sep.
22   Chew W, Sharratt P. Trends in process analytical technology. Anal Methods 2010;2(10):1412–38
doi: 10.1039/c0ay00257g
23   Nagy ZK, Braatz RD. Advances and new directions in crystallization control. Annu Rev Chem Biomol Eng 2012;3:55–75
doi: 10.1146/annurev-chembioeng-062011-081043
24   Yang Y, Nagy ZK. Advanced control approaches for combined cooling/antisolvent crystallization in continuous mixed suspension mixed product removal cascade crystallizers. Chem Eng Sci 2015;127:362–73
doi: 10.1016/j.ces.2015.01.060
25   Yang Y, Song L, Nagy ZK. Automated direct nucleation control in continuous mixed suspension mixed product removal cooling crystallization. Cryst Growth Des 2015;15(12):5839–48
doi: 10.1021/acs.cgd.5b01219
26   Raphael M, Rohani S. Sunflower protein precipitation in a tubular precipitator. Can J Chem Eng 1999;77(3):540–54
doi: 10.1002/cjce.5450770315
27   Alvarez AJ, Myerson AS. Continuous plug flow crystallization of pharmaceutical compounds. Cryst Growth Des 2010;10(5):2219–28
doi: 10.1021/cg901496s
28   Brown CJ, Ni XW. Evaluation of growth kinetics of antisolvent crystallization of paracetamol in an oscillatory baffled crystallizer utilizing video imaging. Cryst Growth Des 2011;11(9):3994–4000
doi: 10.1021/cg200560b
29   McGlone T, Briggs NE, Clark CA, Brown CJ, Sefcik J, Florence AJ. Oscillatory flow reactors (OFRs) for continuous manufacturing and crystallization. Org Process Res Dev 2015;19(9):1186–202
doi: 10.1021/acs.oprd.5b00225
30   Jiang X, Lu D, Wu X, Ruan X, Fang J, He G. Membrane assisted cooling crystallization: Process model, nucleation, metastable zone, and crystal size distribution. AIChE J 2016;62(3):829–41
doi: 10.1002/aic.15069
31   Lakerveld R, van Krochten JJ, Kramer HJ. An air-lift crystallizer can suppress secondary nucleation at a higher supersaturation compared to a stirred crystallizer. Cryst Growth Des 2014;14(7):3264–75
doi: 10.1021/cg500090g
32   Liu WJ, Ma CY, Wang XZ. Novel impinging jet and continuous crystallizer design for rapid reactive crystallization of pharmaceuticals. Procedia Eng 2015;102:499–507
doi: 10.1016/j.proeng.2015.01.199
33   Yazdanpanah N, Ferguson ST, Myerson AS, Trout BL. Novel technique for filtration avoidance in continuous crystallization. Cryst Growth Des 2016;16(1):285–96
doi: 10.1021/acs.cgd.5b01231
34   Schmidt GM. Photodimerization in the solid state. Pure Appl Chem 1971;27(4):647–78
doi: 10.1351/pac197127040647
35   Mahata G, Dey S, Chanda J. Crystal engineering: A powerful tool towards designing pharmaceutical solids with desirable physicochemical properties. Am J Drug Dis 2014;1(1):1–9.
36   Cherukuvada S, Nangia A. Eutectics as improved pharmaceutical materials: Design, properties and characterization. Chem Commun 2014;50(8):906–23
doi: 10.1039/C3CC47521B
37   Desiraju GR. Crystal engineering: A holistic view. Angew Chem Int Ed 2007;46(44):8342–56
doi: 10.1002/anie.200700534
38   LlinàsA, Goodman JM. Polymorph control: Past, present and future. Drug Discov Today 2008;13(5–6):198–210
doi: 10.1016/j.drudis.2007.11.006
39   Mirmehrabi M, Rohani S. An approach to solvent screening for crystallization of polymorphic pharmaceuticals and fine chemicals. J Pharm Sci 2005;94(7):1560–76
doi: 10.1002/jps.20371
40   Allesø M, van den Berg F, Cornett C, Jørgensen FS, Halling-Sørensen B, de Diego HL, et al.Solvent diversity in polymorph screening. J Pharm Sci 2008;97(6):2145–59
doi: 10.1002/jps.21153
41   Pfund LY, Matzger AJ. Towards exhaustive and automated high-throughput screening for crystalline polymorphs. ACS Comb Sci 2014;16(7):309–13
doi: 10.1021/co500043q
42   Storey R, Docherty R, Higginson P, Dallman C, Gilmore C, Barr G, et al.Automation of solid form screening procedures in the pharmaceutical industry—How to avoid the bottlenecks. Crystallogr Rev 2004;10(1):45–56
doi: 10.1080/08893110410001664846
43   Kralj D, Brečević L, Kontrec J. Vaterite growth and dissolution in aqueous solution III. Kinetics of transformation. J Cryst Growth 1997;177(3–4):248–57
doi: 10.1016/S0022-0248(96)01128-1
44   Sheikholeslamzadeh E, Rohani S. Modeling and optimal control of solution mediated polymorphic transformation of L-glutamic acid. Ind Eng Chem Res 2013;52(7):2633–41
doi: 10.1021/ie302683u
45   Trifkovic M, Rohani S, Sheikhzadeh M. Kinetics estimation and polymorphic transformation modeling of buspirone hydrochloride. J Cryst Process Technol 2012;2(2):31–43
doi: 10.4236/jcpt.2012.22006
46   Simone E, Saleemi AN, Nagy ZK. In situ monitoring of polymorphic transformations using a composite sensor array of Raman, NIR, and ATR-UV/vis spectroscopy, FBRM, and PVM for an intelligent decision support system. Org Process Res Dev 2015;19(1):167–77
doi: 10.1021/op5000122
47   Takeguchi K, Obitsu K, Hirasawa S, Orii R, Ieda S, Okada M, et al.Effect of temperature and solvent of solvent-mediated polymorph transformation on ASP3026 polymorphs and scale-up. Org Process Res Dev 2016;20(5):970–6
doi: 10.1021/acs.oprd.6b00068
48   US Food and Drug Administration. Guidance for industry: ANDAs: Pharmaceutical solid polymorphism: Chemistry, manufacturing, and controls information. Silver Spring: Center for Drug Evaluation and Research, US Food and Drug Administration; 2007 Jul.
49   Kawabata Y, Wada K, Nakatani M, Yamada S, Onoue S. Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: Basic approaches and practical applications. Int J Pharm 2011;420(1):1–10
doi: 10.1016/j.ijpharm.2011.08.032
50   Lindenberg M, Kopp S, Dressman JB. Classification of orally administered drugs on the World Health Organization Model list of Essential Medicines according to the biopharmaceutics classification system. Eur J Pharm Biopharm 2004;58(2):265–78
doi: 10.1016/j.ejpb.2004.03.001
51   Amidon GL, Lennernäs H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 1995;12(3):413–20
doi: 10.1023/A:1016212804288
52   Lin SY. Molecular perspectives on solid-state phase transformation and chemical reactivity of drugs: Metoclopramide as an example. Drug Discov Today 2015;20(2):209–22
doi: 10.1016/j.drudis.2014.10.001
53   Almeida e Sousa L, Reutzel-Edens SM, Stephenson GA, Taylor LS. Assessment of the amorphous “solubility” of a group of diverse drugs using new experimental and theoretical approaches. Mol Pharm 2015;12(2):484–95
doi: 10.1021/mp500571m
54   Skrdla PJ, Floyd PD, Dell’orco PC. Practical estimation of amorphous solubility enhancement using thermoanalytical data: Determination of the amorphous/crystalline solubility ratio for pure indomethacin and felodipine. J Pharm Sci 2016;105(9):2625–30
doi: 10.1016/j.xphs.2016.03.036
55   Yu L. Amorphous pharmaceutical solids: Preparation, characterization and stabilization. Adv Drug Deliv Rev 2001;48(1):27–42
doi: 10.1016/S0169-409X(01)00098-9
56   Dengale SJ, Grohganz H, Rades T, Löbmann K. Recent advances in co-amorphous drug formulations. Adv Drug Deliv Rev 2016;100:116–25
doi: 10.1016/j.addr.2015.12.009
57   Löbmann K, Grohganz H, Laitinen R, Strachan C, Rades T. Amino acids as co-amorphous stabilizers for poorly water soluble drugs—Part 1: Preparation, stability and dissolution enhancement. Eur J Pharm Biopharm 2013;85(3 Pt B):873–81
doi: 10.1016/j.ejpb.2013.03.014
58   US Food and Drug Administration. Naming of drug products containing salt drug substances; guidance for industry; availability. Silver Spring: Center for Drug Evaluation and Research, US Food and Drug Administration; 2015 Jun.
59   Fernández Casares A, Nap WM, Ten Figás G, Huizenga P, Groot R, Hoffmann M. An evaluation of salt screening methodologies. J Pharm Pharmacol 2015;67(6):812–22
doi: 10.1111/jphp.12377
60   Serajuddin AT. Salt formation to improve drug solubility. Adv Drug Deliv Rev 2007;59(7):603–16
doi: 10.1016/j.addr.2007.05.010
61   Saal C, Becker A. Pharmaceutical salts: A summary on doses of salt formers from the Orange Book. Eur J Pharm Sci 2013;49(4):614–23
doi: 10.1016/j.ejps.2013.05.026
62   Prohotsky DL, Zhao F. A survey of top 200 drugs—Inconsistent practice of drug strength expression for drugs containing salt forms. J Pharm Sci 2012;101(1):1–6
doi: 10.1002/jps.22735
63   Thackaberry EA. Non-clinical toxicological considerations for pharmaceutical salt selection. Expert Opin Drug Metab Toxicol 2012;8(11):1419–33
doi: 10.1517/17425255.2012.717614
64   Bolla G, Nangia A. Pharmaceutical cocrystals: Walking the talk. Chem Commun 2016;52(54):8342–60
doi: 10.1039/C6CC02943D
65   Remenar JF, Morissette SL, Peterson ML, Moulton B, MacPhee JM, Guzmán HR, et al.Crystal engineering of novel cocrystals of a triazole drug with 1,4-dicarboxylic acids. J Am Chem Soc 2003;125(28):8456–7
doi: 10.1021/ja035776p
66   Wang JR, Yu Q, Dai W, Mei X. Drug-drug co-crystallization presents a new opportunity for the development of stable vitamins. Chem Commun 2016;52(17):3572–5
doi: 10.1039/C5CC10297A
67   Aitipamula S, Banerjee R, Bansal AK, Biradha K, Cheney ML, Choudhury AR, et al.Polymorphs, salts, and cocrystals: What’s in a name? Cryst Growth Des 2012;12(5):2147–52
doi: 10.1021/cg3002948
68   US Food and Drug Administration. Guidance for industry: Regulatory classification of pharmaceutical co-crystals. Silver Spring: Center for Drug Evaluation and Research, US Food and Drug Administration; 2013 Apr.
69   Chen Y, Li L, Yao J, Ma YY, Chen JM, Lu TB. Improving the solubility and bioavailability of apixaban via apixaban-oxalic acid cocrystal. Cryst Growth Des 2016;16(5):2923–30
doi: 10.1021/acs.cgd.6b00266
70   Chattoraj S, Shi L, Chen M, Alhalaweh A, Velaga S, Sun CC. Origin of deteriorated crystal plasticity and compaction properties of a 1:1 cocrystal between piroxicam and saccharin. Cryst Growth Des 2014;14(8):3864–74
doi: 10.1021/cg500388s
71   Weyna DR, Cheney ML, Shan N, Hanna M, Zaworotko MJ, Sava V, et al.Improving solubility and pharmacokinetics of meloxicam via multiple-component crystal formation. Mol Pharm 2012;9(7):2094–102
doi: 10.1021/mp300169c
72   Aakeröy CB, Forbes S, Desper J. Using cocrystals to systematically modulate aqueous solubility and melting behavior of an anticancer drug. J Am Chem Soc 2009;131(47):17048–9
doi: 10.1021/ja907674c
73   Steed JW. The role of co-crystals in pharmaceutical design. Trends Pharmacol Sci 2013;34(3):185–93
doi: 10.1016/
74   Duggirala NK, Perry ML, Almarsson Ö, Zaworotko MJ. Pharmaceutical cocrystals: Along the path to improved medicines. Chem Commun 2016;52(4):640–55
doi: 10.1039/C5CC08216A
75   Wu TK, Lin SY, Lin HL, Huang YT. Simultaneous DSC-FTIR microspectroscopy used to screen and detect the co-crystal formation in real time. Bioorg Med Chem Lett 2011;21(10):3148–51
doi: 10.1016/j.bmcl.2011.03.001
76   Thipparaboina R, Kumar D, Chavan RB, Shastri NR. Multidrug co-crystals: Towards the development of effective therapeutic hybrids. Drug Discov Today 2016;21(3):481–90
doi: 10.1016/j.drudis.2016.02.001
77   Fábián L. Cambridge structural database analysis of molecular complementarity in cocrystals. Cryst Growth Des 2009;9(3):1436–43
doi: 10.1021/cg800861m
78   Hilfiker R, editor. Polymorphism: In the pharmaceutical industry. Hoboken: John Wiley & Sons, Inc.; 2006.
79   Berziņš A, Skarbulis E, Rekis T, Actiņš A. On the formation of droperidol solvates: Characterization of structure and properties. Cryst Growth Des 2014;14(5):2654–64
doi: 10.1021/cg5003447
80   Ulrich J, Frohberg P. Problems, potentials and future of industrial crystallization. Front Chem Sci Eng 2013;7(1):1–8
doi: 10.1007/s11705-013-1304-y
81   Ismail SZ, Anderton CL, Copley RC, Price LS, Price SL. Evaluating a crystal energy landscape in the context of industrial polymorph screening. Cryst Growth Des 2013;13(6):2396–406
doi: 10.1021/cg400090r
82   Reilly AM, Cooper RI, Adjiman CS, Bhattacharya S, Boese AD, Brandenburg JG, et al.Report on the sixth blind test of organic crystal structure prediction methods. Acta Crystallogr B Struct Sci Cryst Eng Mater 2016;72(Pt 4 ):439–59
doi: 10.1107/S2052520616007447
83   Price SL, Braun DE, Reutzel-Edens SM. Can computed crystal energy landscapes help understand pharmaceutical solids? Chem Commun 2016;52(44):7065–77
doi: 10.1039/C6CC00721J
84   Myerson AS, Trout BL. Chemistry. Nucleation from solution. Science 2013;341(6148):855–6
doi: 10.1126/science.1243022
85   Dandekar P, Kuvadia ZB, Doherty MF. Engineering crystal morphology. Annu Rev Mater Res 2013;43:359–86
doi: 10.1146/annurev-matsci-071312-121623
86   Shtukenberg AG, Lee SS, Kahr B, Ward MD. Manipulating crystallization with molecular additives. Annu Rev Chem Biomol Eng 2014;5:77–96
doi: 10.1146/annurev-chembioeng-061312-103308
87   Diao Y, Harada T, Myerson AS, Hatton TA, Trout BL. The role of nanopore shape in surface-induced crystallization. Nat Mater 2011;10(11):867–71
doi: 10.1038/nmat3117
88   Diao Y, Myerson AS, Hatton TA, Trout BL. Surface design for controlled crystallization: The role of surface chemistry and nanoscale pores in heterogeneous nucleation. Langmuir 2011;27(9):5324–34
doi: 10.1021/la104351k
89   Diao Y, Whaley KE, Helgeson ME, Woldeyes MA, Doyle PS, Myerson AS, et al.Gel-induced selective crystallization of polymorphs. J Am Chem Soc 2012;134(1):673–84
doi: 10.1021/ja210006t
90   Kacker R, Salvador PM, Sturm GS, Stefanidis GD, Lakerveld R, Nagy ZK, et al.Microwave assisted direct nucleation control for batch crystallization: Crystal size control with reduced batch time. Cryst Growth Des 2016;16(1):440–6
doi: 10.1021/acs.cgd.5b01444
91   Ouyang JB, Wang JK, Huang X, Gao Y, Bao Y, Wang YL, et al.Gel formation and phase transformation during the crystallization of valnemulin hydrogen tartrate. Ind Eng Chem Res 2014;53(43):16859–63
doi: 10.1021/ie5031826
92   Gao ZG, Li L, Bao Y, Wang Z, Hao HX, Yin QX, et al.From jellylike phase to crystal: Effects of solvent on self-assembly of cefotaxime sodium. Ind Eng Chem Res 2016;55(11):3075–83
doi: 10.1021/acs.iecr.5b03678
93   Zhou G, Moment A, Cuff J, Schafer W, Orella C, Sirota E, et al.Process development and control with recent new FBRM, PVM, and IR. Org Process Res Dev 2015;19(1):227–35
doi: 10.1021/op5000978
94   Simone E, Saleemi AN, Nagy ZK. Raman, UV, NIR, and Mid-IR spectroscopy with focused beam reflectance measurement in monitoring polymorphic transformations. Chem Eng Technol 2014;37(8):1305–13
doi: 10.1002/ceat.201400203
95   Simon LL, Pataki H, Marosi G, Meemken F, Hungerbühler K, Baiker A, et al.Assessment of recent process analytical technology (PAT) trends: A multiauthor review. Org Process Res Dev 2015;19(1):3–62
doi: 10.1021/op500261y
96   Simon LL, Merz T, Dubuis S, Lieb A, Hungerbuhler K. In-situ monitoring of pharmaceutical and specialty chemicals crystallization processes using endoscopy—Stroboscopy and multivariate image analysis. Chem Eng Res Des 2012;90(11):1847–55
doi: 10.1016/j.cherd.2012.03.023
97   El Arnaout T, Cullen PJ, Sullivan C. A novel backlight fiber optical probe and image algorithms for real time size-shape analysis during crystallization. Chem Eng Sci 2016;149:42–50
doi: 10.1016/j.ces.2016.04.025
98   Pertig D, Buchfink R, Petersen S, Stelzer T, Ulrich J. Inline analyzing of industrial crystallization processes by an innovative ultrasonic probe technique. Chem Eng Technol 2011;34(4):639–46
doi: 10.1002/ceat.201000558
99   Gherras N, Serris E, Févotte G. Monitoring industrial pharmaceutical crystallization processes using acoustic emission in pure and impure media. Int J Pharm 2012;439(1–2):109–19
doi: 10.1016/j.ijpharm.2012.09.048
100   Nagy ZK, Chew JW, Fujiwara M, Braatz RD. Comparative performance of concentration and temperature controlled batch crystallizations. J Process Contr 2008;18(3–4):399–407
doi: 10.1016/j.jprocont.2007.10.006
101   Duffy D, Barrett M, Glennon B. Novel, calibration-free strategies for supersaturation control in antisolvent crystallization processes. Cryst Growth Des 2013;13(8):3321–32
doi: 10.1021/cg301673g
102   Abu Bakar MR, Nagy ZK, Saleemi AN, Rielly CD. The impact of direct nucleation control on crystal size distribution in pharmaceutical crystallization processes. Cryst Growth Des 2009;9(3):1378–84
doi: 10.1021/cg800595v
103   Nagy ZK, Fujiwara M, Braatz RD. Modelling and control of combined cooling and antisolvent crystallization processes. J Process Contr 2008;18(9):856–64
doi: 10.1016/j.jprocont.2008.06.002
104   Mesbah A, Landlust J, Huesman AE, Kramer HJ, Jansens PJ, Van den Hof PM. A model-based control framework for industrial batch crystallization processes. Chem Eng Res Des 2010;88(9):1223–33
doi: 10.1016/j.cherd.2009.09.010
105   Aamir E, Rielly CD, Nagy ZK. Experimental evaluation of the targeted direct design of temperature trajectories for growth-dominated crystallization processes using an analytical crystal size distribution estimator. Ind Eng Chem Res 2012;51(51):16677–87
doi: 10.1021/ie301610z
106   Nagy ZK. Model based robust control approach for batch crystallization product design. Comput Chem Eng 2009;33(10):1685–91
doi: 10.1016/j.compchemeng.2009.04.012
107   Trifkovic M, Sheikhzadeh M, Rohani S. Kinetics estimation and single and multi-objective optimization of a seeded, anti-solvent, isothermal batch crystallizer. Ind Eng Chem Res 2008;47(5):1586–95
doi: 10.1021/ie071125g
108   Sheikhzadeh M, Trifkovic M, Rohani S. Real-time optimal control of an anti-solvent isothermal semi-batch crystallization process. Chem Eng Sci 2008;63(3):829–39
doi: 10.1016/j.ces.2007.09.049
109   Moldoványi N, Lakatos BG, Szeifert F. Model predictive control of MSMPR crystallizers. J Cryst Growth 2005;275(1–2):e1349–54
doi: 10.1016/j.jcrysgro.2004.11.170
110   Chianese A, Kramer HJ, editors. Industrial crystallization process monitoring and control. Hoboken: John Wiley & Sons, Inc.; 2012
111   Lu J, Li YP, Wang J, Ren GB, Rohani S, Ching CB. Crystallization of an active pharmaceutical ingredient that oils out. Separ Purif Tech 2012;96:1–6
doi: 10.1016/j.seppur.2012.05.015
112   De Albuquerque I, Mazzotti M. Crystallization process design using thermodynamics to avoid oiling out in a mixture of vanillin and water. Cryst Growth Des 2014;14(11):5617–25
doi: 10.1021/cg500904v
113   Takasuga M, Ooshima H. Control of crystal aspect ratio and size by changing solvent composition in oiling out crystallization of an active pharmaceutical ingredient. Cryst Growth Des 2015;15(12):5834–8
doi: 10.1021/acs.cgd.5b01192
114   Yin YH, Gao ZG, Bao Y, Hou BH, Hao HX, Liu D, et al.Gelation phenomenon during antisolvent crystallization of cefotaxime sodium. Ind Eng Chem Res 2013;53(3):1286–92
doi: 10.1021/ie403539d
115   Yang JX, Wang YL, Hao HX, Xie C, Bao Y, Yin QX, et al.Spherulitic crystallization of L-tryptophan: Characterization, growth kinetics, and mechanism. Cryst Growth Des 2015;15(10):5124–32
doi: 10.1021/acs.cgd.5b01089
116   Paroli F. Industrial crystallizers design and control. In: Chianese A, Kramer HJ, editors Industrial crystallization process monitoring and control. Weinheim: Wiley-VCH; 2012. p. 203–24
doi: 10.1002/9783527645206.ch17
117   Sultana M, Jensen KF, inventors; Massachusetts Institute of Technology, assignee. Systems and methods for microfluidic crystallization. United States patent US 20100298602 A1. 2010 Nov 25.
118   Teychené S, Biscans B. Crystal nucleation in a droplet based microfluidic crystallizer. Chem Eng Sci 2012;77:242–8
doi: 10.1016/j.ces.2012.01.036
119   Ildefonso M, Candoni N, Veesler S. A cheap, easy microfluidic crystallization device ensuring universal solvent compatibility. Org Process Res Dev 2012;16(4):556–60
doi: 10.1021/op200291z
120   Ildefonso M, Revalor E, Punniam P, Salmon JB, Candoni N, Veesler S. Nucleation and polymorphism explored via an easy-to-use microfluidic tool. J Cryst Growth 2012;342(1):9–12
doi: 10.1016/j.jcrysgro.2010.11.098
121   Liu WJ, Ma CY, Liu JJ, Zhang Y, Wang XZ. Analytical technology aided optimization and scale-up of impinging jet mixer for reactive crystallization process. AIChE J 2015;61(2):503–17
doi: 10.1002/aic.14662
122   Woo XY, Tan RB, Braatz RD. Modeling and computational fluid dynamics–population balance equation–micromixing simulation of impinging jet crystallizers. Cryst Growth Des 2009;9(1):156–64
doi: 10.1021/cg800095z
123   Liu WJ, Ma CY, Liu JJ, Zhang Y, Wang XZ. Continuous reactive crystallization of pharmaceuticals using impinging jet mixers. AIChE J 2017;63(3):967−74
doi: 10.1002/aic.15438
124   Kaur Bhangu S, Ashokkumar M, Lee J. Ultrasound assisted crystallization of paracetamol: Crystal size distribution and polymorph control. Cryst Growth Des 2016;16(4):1934–41
doi: 10.1021/acs.cgd.5b01470
125   Soare A, Lakerveld R, van Royen J, Zocchi G, Stankiewicz AI, Kramer HJ. Minimization of attrition and breakage in an airlift crystallizer. Ind Eng Chem Res 2012;51(33):10895–909
doi: 10.1021/ie300432w
126   Leonelli C, Mason TJ. Microwave and ultrasonic processing: Now a realistic option for industry. Chem Eng Process: Process Intensification. 2010;49(9):885–900
doi: 10.1016/j.cep.2010.05.006
127   Soare A, Lakerveld R, van Royen J, Zocchi G, Stankiewicz AI, Kramer HJ. Minimization of attrition and breakage in an airlift crystallizer. Ind Eng Chem Res 2012;51(33):10895–909
doi: 10.1021/ie300432w
128   Eder RJ, Radl S, Schmitt E, Innerhofer S, Maier M, Gruber-Woelfler H, et al.Continuously seeded, continuously operated tubular crystallizer for the production of active pharmaceutical ingredients. Cryst Growth Des 2010;10(5):2247–57
doi: 10.1021/cg9015788
129   Lawton S, Steele G, Shering P. Continuous crystallization of pharmaceuticals using a continuous oscillatory baffled crystallizer. Org Process Res Dev 2009;13(6):1357–63
doi: 10.1021/op900237x
[1] Dejiang Zhang, Shijie Xu, Shichao Du, Jingkang Wang, Junbo Gong. Progress of Pharmaceutical Continuous Crystallization[J]. Engineering, 2017, 3(3): 354 -364 .
Copyright © 2015 Higher Education Press & Engineering Sciences Press, All Rights Reserved.