Process modelling, design and technoeconomic Liquid–Liquid Extraction (LLE) optimisation for comparative evaluation of batch vs. continuous pharmaceutical manufacturing of atropine

•Upstream plantwide modelling and optimisation of the continuous pharmaceutical manufacturing (CPM) of atropine.•Continuous liquid–liquid extraction (CPM-LLE) design considers ternary phase composition modelling (UNIFAC) and estimated solute partitioning between product LLE phases.•Technoeconomic op...

Full description

Saved in:

Bibliographic Details
Published in	Computers & chemical engineering Vol. 124; pp. 28 - 42
Main Authors	Diab, Samir, Mytis, Nikolaos, Boudouvis, Andreas G., Gerogiorgis, Dimitrios I.
Format	Journal Article
Language	English
Published	Elsevier Ltd 08.05.2019
Subjects	Atropine Continuous pharmaceutical manufacturing (CPM) Liquid–liquid extraction (LLE) Process design Process optimisation Reactor design Process design Atropine Liquid–liquid extraction (LLE) Reactor design Continuous pharmaceutical manufacturing (CPM) Process optimisation
Online Access	Get full text
ISSN	0098-1354 1873-4375
DOI	10.1016/j.compchemeng.2018.12.028

Cover

Abstract	•Upstream plantwide modelling and optimisation of the continuous pharmaceutical manufacturing (CPM) of atropine.•Continuous liquid–liquid extraction (CPM-LLE) design considers ternary phase composition modelling (UNIFAC) and estimated solute partitioning between product LLE phases.•Technoeconomic optimisation for comparative evaluation of separation solvents for CPM-LLE under varying design assumptions (plant capacity, solvent recovery).•Toluene emerges as the most economically viable CPM-LLE solvent choice compared to the batch LLE designs, followed by diethyl ether and n-butyl acetate.•Toluene usage allows acceptable E-factors for pharmaceutical processes. Continuous Pharmaceutical Manufacturing (CPM) can revolutionise industrial efficiency via potential operational and economic benefits over currently dominant batch methods. Process modelling and optimisation are valuable towards rapid design space evaluation and elucidation of optimal process design configurations, without expensive and time-consuming experimental campaigns. This paper pursues total cost minimisation via nonlinear optimisation of different separation design options for atropine, a product of great societal importance. The study considers a demonstrated continuous flow synthesis, presents reaction kinetic parameter estimation towards reactor design, and illustrates a comparative analysis of the subsequent batch vs. continuous liquid–liquid extraction (LLE) for product purification, using published partition coefficient data and UNIFAC-modelled ternary liquid–liquid equilibria. Original optimisation results show that toluene is the best continuous LLE solvent, attaining the lowest total costs at both plant capacities considered and the greatest total cost savings with respect to the batch LLE design for varying solvent recovery, at acceptable material efficiencies.
AbstractList	•Upstream plantwide modelling and optimisation of the continuous pharmaceutical manufacturing (CPM) of atropine.•Continuous liquid–liquid extraction (CPM-LLE) design considers ternary phase composition modelling (UNIFAC) and estimated solute partitioning between product LLE phases.•Technoeconomic optimisation for comparative evaluation of separation solvents for CPM-LLE under varying design assumptions (plant capacity, solvent recovery).•Toluene emerges as the most economically viable CPM-LLE solvent choice compared to the batch LLE designs, followed by diethyl ether and n-butyl acetate.•Toluene usage allows acceptable E-factors for pharmaceutical processes. Continuous Pharmaceutical Manufacturing (CPM) can revolutionise industrial efficiency via potential operational and economic benefits over currently dominant batch methods. Process modelling and optimisation are valuable towards rapid design space evaluation and elucidation of optimal process design configurations, without expensive and time-consuming experimental campaigns. This paper pursues total cost minimisation via nonlinear optimisation of different separation design options for atropine, a product of great societal importance. The study considers a demonstrated continuous flow synthesis, presents reaction kinetic parameter estimation towards reactor design, and illustrates a comparative analysis of the subsequent batch vs. continuous liquid–liquid extraction (LLE) for product purification, using published partition coefficient data and UNIFAC-modelled ternary liquid–liquid equilibria. Original optimisation results show that toluene is the best continuous LLE solvent, attaining the lowest total costs at both plant capacities considered and the greatest total cost savings with respect to the batch LLE design for varying solvent recovery, at acceptable material efficiencies.
Author	Gerogiorgis, Dimitrios I. Mytis, Nikolaos Diab, Samir Boudouvis, Andreas G.
Author_xml	– sequence: 1 givenname: Samir surname: Diab fullname: Diab, Samir organization: Institute for Materials and Processes (IMP), School of Engineering, University of Edinburgh, The Kings Buildings, Edinburgh, EH9 3FB, Scotland, UK – sequence: 2 givenname: Nikolaos surname: Mytis fullname: Mytis, Nikolaos organization: School of Chemical Engineering, National Technical University of Athens, Athens 15780, Greece – sequence: 3 givenname: Andreas G. surname: Boudouvis fullname: Boudouvis, Andreas G. organization: School of Chemical Engineering, National Technical University of Athens, Athens 15780, Greece – sequence: 4 givenname: Dimitrios I. orcidid: 0000-0002-2210-6784 surname: Gerogiorgis fullname: Gerogiorgis, Dimitrios I. email: D.Gerogiorgis@ed.ac.uk organization: Institute for Materials and Processes (IMP), School of Engineering, University of Edinburgh, The Kings Buildings, Edinburgh, EH9 3FB, Scotland, UK
BookMark	eNqNUctu1DAUtVArMW35B7MDiQTbeYyzQmg0FKRIsGjXlnNzM-NRYgfbGZUd_8C_9IP4EjwdFohVV_d5zr1H54pcWGeRkNec5Zzx-v0hBzfNsMcJ7S4XjMuci5wJ-YKsuFwXWVmsqwuyYqyRGS-q8iW5CuHAGBOllCvy-M07wBDo5HocR2N372iPwews1banEWFvHYKzbjJAW_N9Mf3vn7_OCd0-RK8hGmfpm7bdvqVujmYyQT-1Bufp6TvtU31Eikc9LueRG2inI-zpMeRpx0ZjF7cEOu-1nzTgEg3okU7aLkM6sPj02Amko3ezsXhDLgc9Bnz1N16T-0_bu83nrP16-2Xzsc2gqGTMhgoGuWbIuqbgWnDRc93VHArRlQ2v6q7WTOq6FywN044YOt6LUtcwNI2soLgmH8684F0IHgcFJj5JSMLNqDhTJxvUQf1jgzrZoLhQyYbE0PzHMHszaf_jWdjNGYtJ4tGgVwEMWsDeeISoemeewfIHH12zpw
CitedBy_id	crossref_primary_10_1002_aic_16738 crossref_primary_10_1002_aic_18142 crossref_primary_10_1039_D1RE00184A crossref_primary_10_1016_j_cherd_2022_11_012 crossref_primary_10_1016_j_seppur_2021_120384 crossref_primary_10_1016_j_indcrop_2022_115283 crossref_primary_10_1016_j_compchemeng_2021_107541 crossref_primary_10_1007_s41981_024_00342_z crossref_primary_10_1021_acs_iecr_2c04282
Cites_doi	10.1126/scitranslmed.aaf2608 10.1039/c0gc00918k 10.1016/j.apm.2013.09.019 10.1016/j.ijpharm.2017.06.039 10.1016/j.jhealeco.2016.01.012 10.1021/acs.oprd.5b00001 10.1039/c3gc41629a 10.1021/ie0341000 10.1016/j.apsusc.2003.10.035 10.1021/acs.oprd.6b00386 10.1016/j.compchemeng.2017.12.014 10.1021/acs.iecr.6b02146 10.1021/op400245s 10.1161/CIRCULATIONAHA.110.970889 10.1126/science.aaf1337 10.1016/j.bmc.2017.02.002 10.1039/C6RE00091F 10.1016/S0098-1354(98)00059-3 10.1039/C4GC01563K 10.1002/jcc.24764 10.1146/annurev.physchem.58.032806.104637 10.1021/acs.oprd.6b00165 10.1016/j.bmc.2016.12.046 10.1134/S1061934816090094 10.1016/j.compchemeng.2017.02.046 10.3762/bjoc.11.134 10.1016/B978-0-444-63576-1.50063-7 10.1002/jps.24252 10.1016/j.mpmed.2015.11.004 10.1021/ie00107a010 10.1016/j.cej.2015.08.008 10.1021/acs.iecr.7b00434 10.1016/B978-0-444-63433-7.50015-8 10.1002/anie.201305429 10.1016/j.cep.2018.01.015 10.1126/science.aan0745 10.1002/aic.690210607 10.1556/1846.2015.00013 10.1039/C1CS15219J 10.1063/1.4930004 10.1016/B978-0-444-64235-6.50286-2 10.1002/jps.24594 10.1146/annurev-chembioeng-060816-101443 10.1186/s13561-014-0023-5 10.1021/op200347k 10.1007/s12247-015-9215-8 10.13182/NSE16-10 10.1205/cherd.04359 10.1039/C6GC00611F
ContentType	Journal Article
Copyright	2018 Elsevier Ltd
Copyright_xml	– notice: 2018 Elsevier Ltd
DBID	AAYXX CITATION
DOI	10.1016/j.compchemeng.2018.12.028
DatabaseName	CrossRef
DatabaseTitle	CrossRef
DatabaseTitleList
DeliveryMethod	fulltext_linktorsrc
Discipline	Engineering
EISSN	1873-4375
EndPage	42
ExternalDocumentID	10_1016_j_compchemeng_2018_12_028 S0098135418307610
GroupedDBID	--K --M .DC .~1 0R~ 1B1 1~. 1~5 4.4 457 4G. 5GY 5VS 7-5 71M 8P~ 9JN AABNK AACTN AAEDT AAEDW AAIAV AAIKC AAIKJ AAKOC AALRI AAMNW AAOAW AAQFI AAXUO ABJNI ABMAC ABNUV ABYKQ ACDAQ ACGFS ACRLP ADBBV ADEWK ADEZE ADTZH AEBSH AECPX AEKER AENEX AFKWA AFTJW AGHFR AGUBO AGYEJ AHHHB AHJVU AHPOS AIEXJ AIKHN AITUG AJOXV AKURH ALMA_UNASSIGNED_HOLDINGS AMFUW AMRAJ AXJTR BJAXD BKOJK BLXMC CS3 DU5 EBS EFJIC EFLBG EJD ENUVR EO8 EO9 EP2 EP3 F5P FDB FIRID FNPLU FYGXN G-Q GBLVA IHE J1W JJJVA KOM LG9 LX7 M41 MO0 N9A O-L O9- OAUVE OZT P-8 P-9 P2P PC. Q38 RIG ROL RPZ SBC SDF SDG SDP SES SPC SPCBC SSG SST SSZ T5K ~G- 29F AAQXK AATTM AAXKI AAYWO AAYXX ABFNM ABWVN ABXDB ACLOT ACNNM ACRPL ACVFH ADCNI ADMUD ADNMO AEIPS AEUPX AFFNX AFJKZ AFPUW AGQPQ AI. AIGII AIIUN AKBMS AKRWK AKYEP ANKPU APXCP ASPBG AVWKF AZFZN BBWZM CITATION EFKBS FEDTE FGOYB HLY HLZ HVGLF HZ~ NDZJH R2- SCE SEW VH1 WUQ ZY4 ~HD
ID	FETCH-LOGICAL-c358t-f5cf870e0b931a212d1ab61c32b49156b6a08a6d20a21b932fb1d24a6cf9985c3
IEDL.DBID	.~1
ISSN	0098-1354
IngestDate	Thu Apr 24 22:57:16 EDT 2025 Wed Oct 01 04:01:57 EDT 2025 Fri Feb 23 02:26:08 EST 2024
IsPeerReviewed	true
IsScholarly	true
Keywords	Process design Atropine Liquid–liquid extraction (LLE) Reactor design Continuous pharmaceutical manufacturing (CPM) Process optimisation
Language	English
LinkModel	DirectLink
MergedId	FETCHMERGED-LOGICAL-c358t-f5cf870e0b931a212d1ab61c32b49156b6a08a6d20a21b932fb1d24a6cf9985c3
ORCID	0000-0002-2210-6784
PageCount	15
ParticipantIDs	crossref_citationtrail_10_1016_j_compchemeng_2018_12_028 crossref_primary_10_1016_j_compchemeng_2018_12_028 elsevier_sciencedirect_doi_10_1016_j_compchemeng_2018_12_028
ProviderPackageCode	CITATION AAYXX
PublicationCentury	2000
PublicationDate	2019-05-08
PublicationDateYYYYMMDD	2019-05-08
PublicationDate_xml	– month: 05 year: 2019 text: 2019-05-08 day: 08
PublicationDecade	2010
PublicationTitle	Computers & chemical engineering
PublicationYear	2019
Publisher	Elsevier Ltd
Publisher_xml	– name: Elsevier Ltd
References	Dai, Snead, Zhang, Jamison (bib0014) 2015; 5 Eger, Mahlich (bib0022) 2014; 4 Weeranoppanant, Adamo, Saparbaiuly, Rose, Fleury, Schenkel, Jensen (bib0062) 2017; 56 (bib0053) 2015 Poku, Biegler, Kelly (bib0052) 2004; 43 Bana, Örkényi, Lövei, Lakó, Túrós, Éles, Faigl, Greiner (bib0005) 2017; 25 Eldin, Ismaiel, Hassan, Shalaby (bib0023) 2016; 71 Cole-Parmer (bib0010) 2015 Poechlauer, Colberg, Fisher, Jansen, Johnson, Koenig, Lawler, Laporte, Manley, Martin, O'Kearney-McMullan (bib0051) 2013; 17 Lee, O'Connor, Yang, Cruz, Chatterjee, Madurawe, Moore, Yu, Woodcock (bib0043) 2015; 10 Angelopoulos, Gerogiorgis, Paspaliaris (bib0004) 2014; 38 Patrascu, Barton (bib0048) 2018; 125 Escotet-Espinoza, Rogers, Ierapetritou (bib0024) 2016 Grujicic, Chittajallu (bib0035) 2004; 227 Baumann, Baxendale (bib0006) 2015; 11 Bédard, Longstreet, Britton, Wang, Moriguchi, Hicklin, Green, Jamison (bib0008) 2016; 25 Marrs, Rice (bib0045) 2016; 44 Goh, Hodas, Vishnu (bib0032) 2017; 38 Skelland, Moeti (bib0058) 1990; 29 Monbaliu, Stelzer, Revalor, Weeranoppanant, Jensen, Myerson (bib0047) 2016; 20 Sheldon (bib0057) 2012; 41 Gillespie (bib0031) 2007; 58 Plenge (bib0049) 2016; 8 Britton, Raston (bib0009) 2017; 52 Mascia, Heider, Zhang, Lakerveld, Benyahia, Barton, Braatz, Cooney, Evans, Jamison, Jensen, Myerson, Trout (bib0046) 2013; 52 Diab, Gerogiorgis (bib0017) 2018; 111 Anderson (bib0003) 2012; 16 Plumb (bib0050) 2005; 83 Henderson, Jiménez-González, Constable, Alston, Inglis, Fisher, Sherwood, Binks, Curzons (bib0037) 2011; 13 Jolliffe, Gerogiorgis (bib0040) 2017; 103 Roschangar, Sheldon, Senanayake (bib0056) 2015; 17 (bib0061) 2016 Iervolino (bib0038) 2016 (bib0036) 2015 Tryggvason, Ma, Lu (bib0060) 2016; 184 Alder, Hayler, Henderson, Redman, Shukla, Shuster, Sneddon (bib0002) 2016; 18 Drageset, Bjørsvik (bib0020) 2016; 1 Diab, Gerogiorgis (bib0016) 2017; 21 Gross, Roosen (bib0034) 1998; 22 Adamo, Beingessner, Behnam, Chen, Jamison, Jensen, Monbaliu, Myerson, Revalor, Snead, Stelzer, Weeranoppanant, Wong, Zhang (bib0001) 2016; 352 DiMasi, Grabowski, Hansen (bib0019) 2016; 47 Teoh, Rathi, Sharratt (bib0059) 2015; 20 Grom, Stavber, Drnovšek, Likozar (bib0033) 2016; 283 (bib0012) 2015 Cole, Groh, Johnson, Burcham, Campbell, Diseroad, Heller, Howell, Kallman, Koenig, May, Miller, Mitchell, Myers, Myers, Phillips, Polster, White, Cashman, Hurley, Moylan, Sheehan, Spencer, Desmond, Desmond, Gowran (bib0011) 2017; 356 (bib0025) 2018 Diab, Gerogiorgis (bib0018) 2018; 43 Field, Hazinski, Sayre, Chameides, Schexnayder, Hemphill, Samson, Kattwinkel, Berg, Bhanji, Cave, Jauch, Kudenchuk, Neumar, Peberdy, Perlman, Sinz, Travers, Berg, Billi, Eigel, Hickey, Kleinman, Link, Morrison, O'Connor, Shuster, Callaway, Cucchiara, Ferguson, Rea, Vanden Hoek (bib0027) 2010; 122 Ma, Lu, Tryggvason (bib0044) 2015; 27 Dallinger, Kappe (bib0015) 2017; 7 Fredenslund, Jones, Prausnitz (bib0028) 1975; 21 Jolliffe, Gerogiorgis (bib0039) 2016; 37 Kuehn (bib0042) 2015 Zhang, Wang, Teixeira, Jensen, Luo (bib0065) 2017; 8 Jolliffe, Gerogiorgis (bib0041) 2017; 56 Rantanen, Khinast (bib0054) 2015; 104 Yu, Kopcha (bib0064) 2017; 528 Couper (bib0013) 2003 EFPIA, 2018, The Pharmaceutical Industry in Figures, 28. Woods (bib0063) 2007 Gerogiorgis, Jolliffe (bib0030) 2015; 33 Federsel (bib0026) 2013; 15 Rogers, Ierapetritou (bib0055) 2014; 34 Baxendale, Braatz, Hodnett, Jensen, Johnson, Sharratt, Sherlock, Florence (bib0007) 2015; 104 Baxendale (10.1016/j.compchemeng.2018.12.028_bib0007) 2015; 104 Angelopoulos (10.1016/j.compchemeng.2018.12.028_bib0004) 2014; 38 Rogers (10.1016/j.compchemeng.2018.12.028_bib0055) 2014; 34 Couper (10.1016/j.compchemeng.2018.12.028_bib0013) 2003 Field (10.1016/j.compchemeng.2018.12.028_bib0027) 2010; 122 Diab (10.1016/j.compchemeng.2018.12.028_bib0017) 2018; 111 Yu (10.1016/j.compchemeng.2018.12.028_bib0064) 2017; 528 Lee (10.1016/j.compchemeng.2018.12.028_bib0043) 2015; 10 Henderson (10.1016/j.compchemeng.2018.12.028_bib0037) 2011; 13 Bédard (10.1016/j.compchemeng.2018.12.028_bib0008) 2016; 25 DiMasi (10.1016/j.compchemeng.2018.12.028_bib0019) 2016; 47 Zhang (10.1016/j.compchemeng.2018.12.028_bib0065) 2017; 8 Grujicic (10.1016/j.compchemeng.2018.12.028_bib0035) 2004; 227 Alder (10.1016/j.compchemeng.2018.12.028_bib0002) 2016; 18 Eger (10.1016/j.compchemeng.2018.12.028_bib0022) 2014; 4 Jolliffe (10.1016/j.compchemeng.2018.12.028_bib0041) 2017; 56 Tryggvason (10.1016/j.compchemeng.2018.12.028_bib0060) 2016; 184 Roschangar (10.1016/j.compchemeng.2018.12.028_bib0056) 2015; 17 Britton (10.1016/j.compchemeng.2018.12.028_bib0009) 2017; 52 Teoh (10.1016/j.compchemeng.2018.12.028_bib0059) 2015; 20 Rantanen (10.1016/j.compchemeng.2018.12.028_bib0054) 2015; 104 Grom (10.1016/j.compchemeng.2018.12.028_bib0033) 2016; 283 Gillespie (10.1016/j.compchemeng.2018.12.028_bib0031) 2007; 58 Patrascu (10.1016/j.compchemeng.2018.12.028_bib0048) 2018; 125 Jolliffe (10.1016/j.compchemeng.2018.12.028_bib0039) 2016; 37 Federsel (10.1016/j.compchemeng.2018.12.028_bib0026) 2013; 15 Diab (10.1016/j.compchemeng.2018.12.028_bib0016) 2017; 21 Iervolino (10.1016/j.compchemeng.2018.12.028_bib0038) Mascia (10.1016/j.compchemeng.2018.12.028_bib0046) 2013; 52 Woods (10.1016/j.compchemeng.2018.12.028_bib0063) 2007 Ma (10.1016/j.compchemeng.2018.12.028_bib0044) 2015; 27 Poku (10.1016/j.compchemeng.2018.12.028_bib0052) 2004; 43 Jolliffe (10.1016/j.compchemeng.2018.12.028_bib0040) 2017; 103 Adamo (10.1016/j.compchemeng.2018.12.028_bib0001) 2016; 352 Gross (10.1016/j.compchemeng.2018.12.028_bib0034) 1998; 22 Dallinger (10.1016/j.compchemeng.2018.12.028_bib0015) 2017; 7 Kuehn (10.1016/j.compchemeng.2018.12.028_bib0042) Bana (10.1016/j.compchemeng.2018.12.028_bib0005) 2017; 25 Plenge (10.1016/j.compchemeng.2018.12.028_bib0049) 2016; 8 Monbaliu (10.1016/j.compchemeng.2018.12.028_bib0047) 2016; 20 Anderson (10.1016/j.compchemeng.2018.12.028_bib0003) 2012; 16 Drageset (10.1016/j.compchemeng.2018.12.028_bib0020) 2016; 1 Poechlauer (10.1016/j.compchemeng.2018.12.028_bib0051) 2013; 17 Diab (10.1016/j.compchemeng.2018.12.028_bib0018) 2018; 43 Marrs (10.1016/j.compchemeng.2018.12.028_bib0045) 2016; 44 Sheldon (10.1016/j.compchemeng.2018.12.028_bib0057) 2012; 41 Goh (10.1016/j.compchemeng.2018.12.028_bib0032) 2017; 38 Skelland (10.1016/j.compchemeng.2018.12.028_bib0058) 1990; 29 Fredenslund (10.1016/j.compchemeng.2018.12.028_bib0028) 1975; 21 Cole (10.1016/j.compchemeng.2018.12.028_bib0011) 2017; 356 Gerogiorgis (10.1016/j.compchemeng.2018.12.028_bib0030) 2015; 33 Eldin (10.1016/j.compchemeng.2018.12.028_bib0023) 2016; 71 Escotet-Espinoza (10.1016/j.compchemeng.2018.12.028_bib0024) 2016 Baumann (10.1016/j.compchemeng.2018.12.028_bib0006) 2015; 11 10.1016/j.compchemeng.2018.12.028_bib0021 Weeranoppanant (10.1016/j.compchemeng.2018.12.028_bib0062) 2017; 56 Dai (10.1016/j.compchemeng.2018.12.028_bib0014) 2015; 5 Cole-Parmer (10.1016/j.compchemeng.2018.12.028_bib0010) Plumb (10.1016/j.compchemeng.2018.12.028_bib0050) 2005; 83
References_xml	– start-page: 281 year: 2016 end-page: 309 ident: bib0024 article-title: Optimization Methodologies for the Production of Pharmaceutical Products – year: 2015 ident: bib0053 – volume: 10 start-page: 191 year: 2015 end-page: 199 ident: bib0043 article-title: Modernizing pharmaceutical manufacturing: from batch to continuous production publication-title: J. Pharm. Innov. – volume: 125 start-page: 124 year: 2018 end-page: 132 ident: bib0048 article-title: Optimal campaigns in end-to-end continuous pharmaceuticals manufacturing. Part 2: Dynamic optimization publication-title: Chem. Eng. Process – volume: 15 start-page: 3105 year: 2013 end-page: 3115 ident: bib0026 article-title: En route to full implementation: Driving the green chemistry agenda in the pharmaceutical industry publication-title: Green Chem. – volume: 11 start-page: 1194 year: 2015 end-page: 1219 ident: bib0006 article-title: The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry publication-title: Beilstein J. Org. Chem. – volume: 18 start-page: 3879 year: 2016 end-page: 3890 ident: bib0002 article-title: Updating and further expanding GSK's solvent sustainability guide publication-title: Green Chem. – volume: 58 start-page: 35 year: 2007 end-page: 55 ident: bib0031 article-title: Statistical simulation of chemical kinetics publication-title: Ann. Rev. Phys. Chem. – volume: 29 start-page: 2258 year: 1990 end-page: 2267 ident: bib0058 article-title: Mechanism of continuous-phase mass transfer in agitated liquid–liquid systems publication-title: Ind. Eng. Chem. Res. – year: 2016 ident: bib0038 – volume: 56 start-page: 4357 year: 2017 end-page: 4376 ident: bib0041 article-title: Technoeconomic optimization of a conceptual flowsheet for continuous separation of an analgaesic active pharmaceutical ingredient (API) publication-title: Ind. Eng. Chem. Res. – volume: 227 start-page: 56 year: 2004 end-page: 72 ident: bib0035 article-title: Design and optimization of polymer electrolyte membrane (PEM) fuel cells publication-title: Appl. Surf. Sci. – volume: 25 start-page: 6233 year: 2016 end-page: 6241 ident: bib0008 article-title: Minimizing E-factor in the continuous-flow synthesis of diazepam and atropine publication-title: Bioorg. Med. Chem. – volume: 184 start-page: 312 year: 2016 end-page: 320 ident: bib0060 article-title: DNS-assisted modeling of bubbly flows in vertical channels publication-title: Nucl. Sci. Eng. – volume: 25 start-page: 6180 year: 2017 end-page: 6189 ident: bib0005 article-title: The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds publication-title: Bioorg. Med. Chem. – volume: 43 start-page: 6803 year: 2004 end-page: 6812 ident: bib0052 article-title: Nonlinear optimization with many degrees of freedom in process engineering publication-title: Ind. Eng. Chem. Res. – year: 2016 ident: bib0061 – volume: 13 start-page: 854 year: 2011 end-page: 862 ident: bib0037 article-title: Expanding GSK's solvent selection guide—Embedding sustainability into solvent selection starting at medicinal chemistry publication-title: Green Chem. – volume: 34 start-page: 144 year: 2014 end-page: 149 ident: bib0055 article-title: Challenges and opportunities in pharmaceutical manufacturing modelling and optimization publication-title: Comput. Aid. Chem. Eng. – volume: 356 start-page: 1144 year: 2017 end-page: 1151 ident: bib0011 article-title: Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions publication-title: Science – year: 2015 ident: bib0042 – volume: 8 start-page: 1 year: 2016 end-page: 5 ident: bib0049 article-title: Disciplined approach to drug discovery and early development publication-title: Sci. Transl. Med. – volume: 27 year: 2015 ident: bib0044 article-title: Using statistical learning to close two-fluid multiphase flow equations for a simple bubbly system publication-title: Phys. Fluids – volume: 17 start-page: 1472 year: 2013 end-page: 1478 ident: bib0051 article-title: Pharmaceutical roundtable study demonstrates the value of continuous manufacturing in the design of greener processes publication-title: Org. Process Res. Dev. – volume: 104 start-page: 3612 year: 2015 end-page: 3638 ident: bib0054 article-title: The future of pharmaceutical manufacturing sciences publication-title: J. Pharm. Sci. – year: 2018 ident: bib0025 – volume: 21 start-page: 1086 year: 1975 end-page: 1099 ident: bib0028 article-title: Group-contribution estimation of activity-coefficients in nonideal liquid-mixtures publication-title: AIChE J. – volume: 43 start-page: 1643 year: 2018 end-page: 1648 ident: bib0018 article-title: Process modelling, simulation and technoeconomic optimisation for continuous pharmaceutical manufacturing of ( publication-title: Comput.-Aid. Chem. Eng. – volume: 111 start-page: 102 year: 2018 end-page: 114 ident: bib0017 article-title: Process modelling, simulation and technoeconomic evaluation of crystallisation antisolvents for the continuous pharmaceutical manufacturing of rufinamide publication-title: Comput. Chem. Eng. – volume: 22 start-page: S229 year: 1998 end-page: S236 ident: bib0034 article-title: Total process optimization in chemical engineering with evolutionary algorithms publication-title: Comput. Chem. Eng. – volume: 17 start-page: 752 year: 2015 end-page: 768 ident: bib0056 article-title: Overcoming barriers to green chemistry in the pharmaceutical industry—The Green Aspiration Level publication-title: Green Chem. – year: 2007 ident: bib0063 article-title: Rules of Thumb in Engineering Practice – volume: 20 start-page: 414 year: 2015 end-page: 431 ident: bib0059 article-title: Practical assessment methodology for converting fine chemicals processes from batch to continuous publication-title: Org. Process Res. Dev. – volume: 52 start-page: 10159 year: 2017 end-page: 10162 ident: bib0009 article-title: Multi-step continuous-flow synthesis publication-title: Chem. Soc. Rev. – volume: 5 start-page: 133 year: 2015 end-page: 138 ident: bib0014 article-title: Continuous-flow synthesis and purification of atropine with sequential in-line separations of structurally similar impurities publication-title: J. Flow Chem. – reference: EFPIA, 2018, The Pharmaceutical Industry in Figures, 28. – volume: 83 start-page: 730 year: 2005 end-page: 738 ident: bib0050 article-title: Continuous processing in the pharmaceutical industry—Changing the mind set publication-title: Chem. Eng. Res. Des. – volume: 33 start-page: 29 year: 2015 end-page: 32 ident: bib0030 article-title: Continuous pharmaceutical process engineering and economics: Investigating technical efficiency, environmental impact and economic viability publication-title: Chim. Oggi-Chem. Today – volume: 7 start-page: 6 year: 2017 end-page: 12 ident: bib0015 article-title: Why flow means green – Evaluating the merits of continuous processing in the context of sustainability publication-title: Curr. Opin. Green Sust. Chem. – volume: 4 start-page: 23 year: 2014 ident: bib0022 article-title: Pharmaceutical regulation in Europe and its impact on corporate R&D publication-title: Health Econ. Rev. – year: 2003 ident: bib0013 article-title: Process Engineering Economics – volume: 103 start-page: 218 year: 2017 end-page: 232 ident: bib0040 article-title: Technoeconomic optimisation and comparative environmental impact evaluation of continuous crystallisation and antisolvent selection for artemisinin recovery publication-title: Comput. Chem. Eng. – volume: 47 start-page: 20 year: 2016 end-page: 33 ident: bib0019 article-title: Innovation in the pharmaceutical industry: New estimates of R&D costs publication-title: J. Health Econ. – year: 2015 ident: bib0036 – volume: 38 start-page: 1291 year: 2017 end-page: 1307 ident: bib0032 article-title: Deep learning for computational chemistry publication-title: J. Comput. Chem. – volume: 41 start-page: 1437 year: 2012 end-page: 1451 ident: bib0057 article-title: Fundamentals of green chemistry: Efficiency in reaction design publication-title: Chem. Soc. Rev. – volume: 122 start-page: S640 year: 2010 end-page: S656 ident: bib0027 article-title: Part 1: Executive Summary: 2010 American heart association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care publication-title: Circulation – volume: 21 start-page: 924 year: 2017 end-page: 946 ident: bib0016 article-title: Process modeling, simulation, and technoeconomic evaluation of separation solvents for the continuous pharmaceutical manufacturing (CPM) of diphenhydramine publication-title: Org. Process Res. Dev. – volume: 38 start-page: 1799 year: 2014 end-page: 1822 ident: bib0004 article-title: Mathematical modeling and process simulation of perlite grain expansion in a vertical electrical furnace publication-title: App. Math. Model. – volume: 44 start-page: 106 year: 2016 end-page: 108 ident: bib0045 article-title: Chemical terrorism and nerve agents publication-title: Medicine – volume: 37 start-page: 2213 year: 2016 end-page: 2218 ident: bib0039 article-title: Plantwide design and economic evaluation of two continuous pharmaceutical manufacturing (CPM) cases: Ibuprofen and artemisinin publication-title: Comput. Aid. Chem. Eng. – volume: 8 start-page: 285 year: 2017 end-page: 305 ident: bib0065 article-title: Design and scaling up of microchemical systems: a review publication-title: Annu. Rev. Chem. Biomol. – volume: 352 start-page: 61 year: 2016 end-page: 67 ident: bib0001 article-title: On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system publication-title: Science – volume: 1 start-page: 436 year: 2016 end-page: 444 ident: bib0020 article-title: Continuous flow synthesis concatenated with continuous flow liquid–liquid extraction for work-up and purification: selective mono- and di-iodination of the imidazole backbone publication-title: React. Chem. Eng. – volume: 16 start-page: 852 year: 2012 end-page: 869 ident: bib0003 article-title: Using continuous processes to increase production publication-title: Org. Process Res. Dev. – volume: 20 start-page: 1347 year: 2016 end-page: 1353 ident: bib0047 article-title: Compact and integrated approach for advanced end-to-end production, purification, and aqueous formulation of lidocaine hydrochloride publication-title: Org. Process Res. Dev. – volume: 52 start-page: 12359 year: 2013 end-page: 12363 ident: bib0046 article-title: End-to-end continuous manufacturing of pharmaceuticals: integrated synthesis, purification, and final dosage formation publication-title: Angew. Chem.-Int. Ed. – year: 2015 ident: bib0012 – volume: 71 start-page: 861 year: 2016 end-page: 871 ident: bib0023 article-title: Green analytical chemistry: Opportunities for pharmaceutical quality control publication-title: J. Anal. Chem. – volume: 56 start-page: 4095 year: 2017 end-page: 4103 ident: bib0062 article-title: Design of multistage counter-current liquid–liquid extraction for small-scale applications publication-title: Ind. Eng. Chem. Res. – year: 2015 ident: bib0010 – volume: 528 start-page: 354 year: 2017 end-page: 359 ident: bib0064 article-title: The future of pharmaceutical quality and the path to get there publication-title: Int. J. Pharmaceut. – volume: 283 start-page: 703 year: 2016 end-page: 716 ident: bib0033 article-title: Modelling chemical kinetics of a complex reaction network of active pharmaceutical ingredient (API) synthesis with process optimization for benzazepine heterocyclic compound publication-title: Chem. Eng. J. – volume: 104 start-page: 781 year: 2015 end-page: 791 ident: bib0007 article-title: Achieving continuous manufacturing: Technologies and approaches for synthesis, workup, and isolation of drug substance publication-title: J. Pharm. Sci. – volume: 8 start-page: 1 issue: 349 year: 2016 ident: 10.1016/j.compchemeng.2018.12.028_bib0049 article-title: Disciplined approach to drug discovery and early development publication-title: Sci. Transl. Med. doi: 10.1126/scitranslmed.aaf2608 – volume: 13 start-page: 854 issue: 4 year: 2011 ident: 10.1016/j.compchemeng.2018.12.028_bib0037 article-title: Expanding GSK's solvent selection guide—Embedding sustainability into solvent selection starting at medicinal chemistry publication-title: Green Chem. doi: 10.1039/c0gc00918k – volume: 38 start-page: 1799 issue: 5-6 year: 2014 ident: 10.1016/j.compchemeng.2018.12.028_bib0004 article-title: Mathematical modeling and process simulation of perlite grain expansion in a vertical electrical furnace publication-title: App. Math. Model. doi: 10.1016/j.apm.2013.09.019 – volume: 528 start-page: 354 issue: 1–2 year: 2017 ident: 10.1016/j.compchemeng.2018.12.028_bib0064 article-title: The future of pharmaceutical quality and the path to get there publication-title: Int. J. Pharmaceut. doi: 10.1016/j.ijpharm.2017.06.039 – volume: 47 start-page: 20 year: 2016 ident: 10.1016/j.compchemeng.2018.12.028_bib0019 article-title: Innovation in the pharmaceutical industry: New estimates of R&D costs publication-title: J. Health Econ. doi: 10.1016/j.jhealeco.2016.01.012 – volume: 20 start-page: 414 issue: 2 year: 2015 ident: 10.1016/j.compchemeng.2018.12.028_bib0059 article-title: Practical assessment methodology for converting fine chemicals processes from batch to continuous publication-title: Org. Process Res. Dev. doi: 10.1021/acs.oprd.5b00001 – volume: 15 start-page: 3105 issue: 11 year: 2013 ident: 10.1016/j.compchemeng.2018.12.028_bib0026 article-title: En route to full implementation: Driving the green chemistry agenda in the pharmaceutical industry publication-title: Green Chem. doi: 10.1039/c3gc41629a – volume: 43 start-page: 6803 issue: 21 year: 2004 ident: 10.1016/j.compchemeng.2018.12.028_bib0052 article-title: Nonlinear optimization with many degrees of freedom in process engineering publication-title: Ind. Eng. Chem. Res. doi: 10.1021/ie0341000 – volume: 227 start-page: 56 issue: 1–4 year: 2004 ident: 10.1016/j.compchemeng.2018.12.028_bib0035 article-title: Design and optimization of polymer electrolyte membrane (PEM) fuel cells publication-title: Appl. Surf. Sci. doi: 10.1016/j.apsusc.2003.10.035 – volume: 7 start-page: 6 year: 2017 ident: 10.1016/j.compchemeng.2018.12.028_bib0015 article-title: Why flow means green – Evaluating the merits of continuous processing in the context of sustainability publication-title: Curr. Opin. Green Sust. Chem. – volume: 21 start-page: 924 issue: 7 year: 2017 ident: 10.1016/j.compchemeng.2018.12.028_bib0016 article-title: Process modeling, simulation, and technoeconomic evaluation of separation solvents for the continuous pharmaceutical manufacturing (CPM) of diphenhydramine publication-title: Org. Process Res. Dev. doi: 10.1021/acs.oprd.6b00386 – volume: 111 start-page: 102 year: 2018 ident: 10.1016/j.compchemeng.2018.12.028_bib0017 article-title: Process modelling, simulation and technoeconomic evaluation of crystallisation antisolvents for the continuous pharmaceutical manufacturing of rufinamide publication-title: Comput. Chem. Eng. doi: 10.1016/j.compchemeng.2017.12.014 – start-page: 281 year: 2016 ident: 10.1016/j.compchemeng.2018.12.028_bib0024 – volume: 56 start-page: 4357 issue: 15 year: 2017 ident: 10.1016/j.compchemeng.2018.12.028_bib0041 article-title: Technoeconomic optimization of a conceptual flowsheet for continuous separation of an analgaesic active pharmaceutical ingredient (API) publication-title: Ind. Eng. Chem. Res. doi: 10.1021/acs.iecr.6b02146 – ident: 10.1016/j.compchemeng.2018.12.028_bib0042 – volume: 17 start-page: 1472 issue: 12 year: 2013 ident: 10.1016/j.compchemeng.2018.12.028_bib0051 article-title: Pharmaceutical roundtable study demonstrates the value of continuous manufacturing in the design of greener processes publication-title: Org. Process Res. Dev. doi: 10.1021/op400245s – ident: 10.1016/j.compchemeng.2018.12.028_bib0021 – volume: 122 start-page: S640 issue: 18 year: 2010 ident: 10.1016/j.compchemeng.2018.12.028_bib0027 article-title: Part 1: Executive Summary: 2010 American heart association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care publication-title: Circulation doi: 10.1161/CIRCULATIONAHA.110.970889 – volume: 352 start-page: 61 issue: 6281 year: 2016 ident: 10.1016/j.compchemeng.2018.12.028_bib0001 article-title: On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system publication-title: Science doi: 10.1126/science.aaf1337 – volume: 25 start-page: 6233 issue: 23 year: 2016 ident: 10.1016/j.compchemeng.2018.12.028_bib0008 article-title: Minimizing E-factor in the continuous-flow synthesis of diazepam and atropine publication-title: Bioorg. Med. Chem. doi: 10.1016/j.bmc.2017.02.002 – volume: 1 start-page: 436 issue: 4 year: 2016 ident: 10.1016/j.compchemeng.2018.12.028_bib0020 article-title: Continuous flow synthesis concatenated with continuous flow liquid–liquid extraction for work-up and purification: selective mono- and di-iodination of the imidazole backbone publication-title: React. Chem. Eng. doi: 10.1039/C6RE00091F – volume: 22 start-page: S229 year: 1998 ident: 10.1016/j.compchemeng.2018.12.028_bib0034 article-title: Total process optimization in chemical engineering with evolutionary algorithms publication-title: Comput. Chem. Eng. doi: 10.1016/S0098-1354(98)00059-3 – volume: 17 start-page: 752 issue: 2 year: 2015 ident: 10.1016/j.compchemeng.2018.12.028_bib0056 article-title: Overcoming barriers to green chemistry in the pharmaceutical industry—The Green Aspiration LevelTM concept publication-title: Green Chem. doi: 10.1039/C4GC01563K – ident: 10.1016/j.compchemeng.2018.12.028_bib0010 – volume: 38 start-page: 1291 issue: 16 year: 2017 ident: 10.1016/j.compchemeng.2018.12.028_bib0032 article-title: Deep learning for computational chemistry publication-title: J. Comput. Chem. doi: 10.1002/jcc.24764 – year: 2007 ident: 10.1016/j.compchemeng.2018.12.028_bib0063 – volume: 58 start-page: 35 year: 2007 ident: 10.1016/j.compchemeng.2018.12.028_bib0031 article-title: Statistical simulation of chemical kinetics publication-title: Ann. Rev. Phys. Chem. doi: 10.1146/annurev.physchem.58.032806.104637 – volume: 20 start-page: 1347 issue: 7 year: 2016 ident: 10.1016/j.compchemeng.2018.12.028_bib0047 article-title: Compact and integrated approach for advanced end-to-end production, purification, and aqueous formulation of lidocaine hydrochloride publication-title: Org. Process Res. Dev. doi: 10.1021/acs.oprd.6b00165 – ident: 10.1016/j.compchemeng.2018.12.028_bib0038 – volume: 25 start-page: 6180 issue: 23 year: 2017 ident: 10.1016/j.compchemeng.2018.12.028_bib0005 article-title: The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds publication-title: Bioorg. Med. Chem. doi: 10.1016/j.bmc.2016.12.046 – volume: 71 start-page: 861 issue: 9 year: 2016 ident: 10.1016/j.compchemeng.2018.12.028_bib0023 article-title: Green analytical chemistry: Opportunities for pharmaceutical quality control publication-title: J. Anal. Chem. doi: 10.1134/S1061934816090094 – volume: 103 start-page: 218 year: 2017 ident: 10.1016/j.compchemeng.2018.12.028_bib0040 article-title: Technoeconomic optimisation and comparative environmental impact evaluation of continuous crystallisation and antisolvent selection for artemisinin recovery publication-title: Comput. Chem. Eng. doi: 10.1016/j.compchemeng.2017.02.046 – volume: 11 start-page: 1194 year: 2015 ident: 10.1016/j.compchemeng.2018.12.028_bib0006 article-title: The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry publication-title: Beilstein J. Org. Chem. doi: 10.3762/bjoc.11.134 – volume: 37 start-page: 2213 year: 2016 ident: 10.1016/j.compchemeng.2018.12.028_bib0039 article-title: Plantwide design and economic evaluation of two continuous pharmaceutical manufacturing (CPM) cases: Ibuprofen and artemisinin publication-title: Comput. Aid. Chem. Eng. doi: 10.1016/B978-0-444-63576-1.50063-7 – year: 2003 ident: 10.1016/j.compchemeng.2018.12.028_bib0013 – volume: 104 start-page: 781 issue: 3 year: 2015 ident: 10.1016/j.compchemeng.2018.12.028_bib0007 article-title: Achieving continuous manufacturing: Technologies and approaches for synthesis, workup, and isolation of drug substance publication-title: J. Pharm. Sci. doi: 10.1002/jps.24252 – volume: 44 start-page: 106 issue: 2 year: 2016 ident: 10.1016/j.compchemeng.2018.12.028_bib0045 article-title: Chemical terrorism and nerve agents publication-title: Medicine doi: 10.1016/j.mpmed.2015.11.004 – volume: 29 start-page: 2258 issue: 11 year: 1990 ident: 10.1016/j.compchemeng.2018.12.028_bib0058 article-title: Mechanism of continuous-phase mass transfer in agitated liquid–liquid systems publication-title: Ind. Eng. Chem. Res. doi: 10.1021/ie00107a010 – volume: 52 start-page: 10159 issue: 5 year: 2017 ident: 10.1016/j.compchemeng.2018.12.028_bib0009 article-title: Multi-step continuous-flow synthesis publication-title: Chem. Soc. Rev. – volume: 283 start-page: 703 year: 2016 ident: 10.1016/j.compchemeng.2018.12.028_bib0033 article-title: Modelling chemical kinetics of a complex reaction network of active pharmaceutical ingredient (API) synthesis with process optimization for benzazepine heterocyclic compound publication-title: Chem. Eng. J. doi: 10.1016/j.cej.2015.08.008 – volume: 56 start-page: 4095 issue: 14 year: 2017 ident: 10.1016/j.compchemeng.2018.12.028_bib0062 article-title: Design of multistage counter-current liquid–liquid extraction for small-scale applications publication-title: Ind. Eng. Chem. Res. doi: 10.1021/acs.iecr.7b00434 – volume: 33 start-page: 29 issue: 6 year: 2015 ident: 10.1016/j.compchemeng.2018.12.028_bib0030 article-title: Continuous pharmaceutical process engineering and economics: Investigating technical efficiency, environmental impact and economic viability publication-title: Chim. Oggi-Chem. Today – volume: 34 start-page: 144 year: 2014 ident: 10.1016/j.compchemeng.2018.12.028_bib0055 article-title: Challenges and opportunities in pharmaceutical manufacturing modelling and optimization publication-title: Comput. Aid. Chem. Eng. doi: 10.1016/B978-0-444-63433-7.50015-8 – volume: 52 start-page: 12359 issue: 47 year: 2013 ident: 10.1016/j.compchemeng.2018.12.028_bib0046 article-title: End-to-end continuous manufacturing of pharmaceuticals: integrated synthesis, purification, and final dosage formation publication-title: Angew. Chem.-Int. Ed. doi: 10.1002/anie.201305429 – volume: 125 start-page: 124 year: 2018 ident: 10.1016/j.compchemeng.2018.12.028_bib0048 article-title: Optimal campaigns in end-to-end continuous pharmaceuticals manufacturing. Part 2: Dynamic optimization publication-title: Chem. Eng. Process doi: 10.1016/j.cep.2018.01.015 – volume: 356 start-page: 1144 issue: 6343 year: 2017 ident: 10.1016/j.compchemeng.2018.12.028_bib0011 article-title: Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions publication-title: Science doi: 10.1126/science.aan0745 – volume: 21 start-page: 1086 issue: 6 year: 1975 ident: 10.1016/j.compchemeng.2018.12.028_bib0028 article-title: Group-contribution estimation of activity-coefficients in nonideal liquid-mixtures publication-title: AIChE J. doi: 10.1002/aic.690210607 – volume: 5 start-page: 133 issue: 3 year: 2015 ident: 10.1016/j.compchemeng.2018.12.028_bib0014 article-title: Continuous-flow synthesis and purification of atropine with sequential in-line separations of structurally similar impurities publication-title: J. Flow Chem. doi: 10.1556/1846.2015.00013 – volume: 41 start-page: 1437 issue: 4 year: 2012 ident: 10.1016/j.compchemeng.2018.12.028_bib0057 article-title: Fundamentals of green chemistry: Efficiency in reaction design publication-title: Chem. Soc. Rev. doi: 10.1039/C1CS15219J – volume: 27 year: 2015 ident: 10.1016/j.compchemeng.2018.12.028_bib0044 article-title: Using statistical learning to close two-fluid multiphase flow equations for a simple bubbly system publication-title: Phys. Fluids doi: 10.1063/1.4930004 – volume: 43 start-page: 1643 year: 2018 ident: 10.1016/j.compchemeng.2018.12.028_bib0018 article-title: Process modelling, simulation and technoeconomic optimisation for continuous pharmaceutical manufacturing of (S)-warfarin publication-title: Comput.-Aid. Chem. Eng. doi: 10.1016/B978-0-444-64235-6.50286-2 – volume: 104 start-page: 3612 issue: 11 year: 2015 ident: 10.1016/j.compchemeng.2018.12.028_bib0054 article-title: The future of pharmaceutical manufacturing sciences publication-title: J. Pharm. Sci. doi: 10.1002/jps.24594 – volume: 8 start-page: 285 year: 2017 ident: 10.1016/j.compchemeng.2018.12.028_bib0065 article-title: Design and scaling up of microchemical systems: a review publication-title: Annu. Rev. Chem. Biomol. doi: 10.1146/annurev-chembioeng-060816-101443 – volume: 4 start-page: 23 year: 2014 ident: 10.1016/j.compchemeng.2018.12.028_bib0022 article-title: Pharmaceutical regulation in Europe and its impact on corporate R&D publication-title: Health Econ. Rev. doi: 10.1186/s13561-014-0023-5 – volume: 16 start-page: 852 issue: 5 year: 2012 ident: 10.1016/j.compchemeng.2018.12.028_bib0003 article-title: Using continuous processes to increase production publication-title: Org. Process Res. Dev. doi: 10.1021/op200347k – volume: 10 start-page: 191 year: 2015 ident: 10.1016/j.compchemeng.2018.12.028_bib0043 article-title: Modernizing pharmaceutical manufacturing: from batch to continuous production publication-title: J. Pharm. Innov. doi: 10.1007/s12247-015-9215-8 – volume: 184 start-page: 312 year: 2016 ident: 10.1016/j.compchemeng.2018.12.028_bib0060 article-title: DNS-assisted modeling of bubbly flows in vertical channels publication-title: Nucl. Sci. Eng. doi: 10.13182/NSE16-10 – volume: 83 start-page: 730 issue: A6 year: 2005 ident: 10.1016/j.compchemeng.2018.12.028_bib0050 article-title: Continuous processing in the pharmaceutical industry—Changing the mind set publication-title: Chem. Eng. Res. Des. doi: 10.1205/cherd.04359 – volume: 18 start-page: 3879 issue: 13 year: 2016 ident: 10.1016/j.compchemeng.2018.12.028_bib0002 article-title: Updating and further expanding GSK's solvent sustainability guide publication-title: Green Chem. doi: 10.1039/C6GC00611F
SSID	ssj0002488
Score	2.3407977
Snippet	•Upstream plantwide modelling and optimisation of the continuous pharmaceutical manufacturing (CPM) of atropine.•Continuous liquid–liquid extraction (CPM-LLE)...
SourceID	crossref elsevier
SourceType	Enrichment Source Index Database Publisher
StartPage	28
SubjectTerms	Atropine Continuous pharmaceutical manufacturing (CPM) Liquid–liquid extraction (LLE) Process design Process optimisation Reactor design
Title	Process modelling, design and technoeconomic Liquid–Liquid Extraction (LLE) optimisation for comparative evaluation of batch vs. continuous pharmaceutical manufacturing of atropine
URI	https://dx.doi.org/10.1016/j.compchemeng.2018.12.028
Volume	124
hasFullText	1
inHoldings	1
isFullTextHit
isPrint
journalDatabaseRights	– providerCode: PRVESC databaseName: Baden-Württemberg Complete Freedom Collection (Elsevier) customDbUrl: eissn: 1873-4375 dateEnd: 99991231 omitProxy: true ssIdentifier: ssj0002488 issn: 0098-1354 databaseCode: GBLVA dateStart: 20110101 isFulltext: true titleUrlDefault: https://www.sciencedirect.com providerName: Elsevier – providerCode: PRVESC databaseName: Elsevier SD Complete Freedom Collection [SCCMFC] customDbUrl: eissn: 1873-4375 dateEnd: 99991231 omitProxy: true ssIdentifier: ssj0002488 issn: 0098-1354 databaseCode: ACRLP dateStart: 19950101 isFulltext: true titleUrlDefault: https://www.sciencedirect.com providerName: Elsevier – providerCode: PRVESC databaseName: Elsevier SD Freedom Collection customDbUrl: eissn: 1873-4375 dateEnd: 99991231 omitProxy: true ssIdentifier: ssj0002488 issn: 0098-1354 databaseCode: .~1 dateStart: 19950101 isFulltext: true titleUrlDefault: https://www.sciencedirect.com providerName: Elsevier – providerCode: PRVESC databaseName: ScienceDirect Journal Collection customDbUrl: eissn: 1873-4375 dateEnd: 99991231 omitProxy: true ssIdentifier: ssj0002488 issn: 0098-1354 databaseCode: AIKHN dateStart: 19950101 isFulltext: true titleUrlDefault: https://www.sciencedirect.com providerName: Elsevier – providerCode: PRVLSH databaseName: Elsevier Journals customDbUrl: mediaType: online eissn: 1873-4375 dateEnd: 99991231 omitProxy: true ssIdentifier: ssj0002488 issn: 0098-1354 databaseCode: AKRWK dateStart: 19770101 isFulltext: true providerName: Library Specific Holdings
link	http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV3datRAFB5KBdGLUrVibS1H8MJC02Z-kp2AN6VsWXXpVQu9C5nMxEbcZG034pX4Dr5LH6hP4jmTibuCoOBdfuZAmDM5Z87wfd9h7JWxzlSZUZFyUkSKWxmZzNhIZtLGaVbF3Hi0xVk6uVDvLpPLNXYycGEIVhlifx_TfbQOT47CbB7N65o4vpnmMlG4KKkYp7pdqRF1MTj8toR5CKX1oJtJo--zl0uMF8G2cW5mrvlAKC_tTwapMfufctRK3jndZBthwwjH_Tc9YmuuecwersgIPmG3Ae0Pvq0N8csPwHpkBhSNBS_T2rrAQIZp_bmr7d33H_0FjL8urnt2A7yeTsf70GIUmQWUD-CeFsqlQjgs1cGhrcBgIL-CLzeHQJD3uuna7gbmV6vH5DArmo7oE54PSUZ0-j7Hr99iF6fj85NJFPoxRKVM9CKqkrLC39vFJpO8wJxneWFSXkphVIZ1oEmLWBepFTG-xDGiMtwKVaRlhUVdUsqnbL1pG_eM4SRYq5wWI1FgfWgd0WNL69xoZLgxRmwzPXggL4NYOfXM-JQPqLSP-YrzcnJezkWOzttm4pfpvFfs-BejN4Ob89-WX46Z5e_mz__PfIc9wLvM4yj1LltfXHfuBe51FmbPL-Y9du_47fvJ2U-0fgfu
linkProvider	Elsevier
linkToHtml	http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV3datRAFB5KBX8uSq2Kta2eghcKps38JDsBb6RsWW3aqxZ6N2QyExtxk7XdiFel79B38YF8Es9MJu4KgoJ3IZkDw5zJOXOG7_sOIS-1sbrKtIiE5SwS1PBIZ9pEPOMmTrMqptqjLU7SyZn4cJ6cr5CDgQvjYJUh9vcx3Ufr8GY_rOb-rK4dxzeTlCcCN6UrxrFuvyMSNnIV2N71AufBhJSDcKYbfpfsLkBeDreNizO1zUcH85L-atB1Zv9TklpKPIfrZC2cGOFdP6mHZMU2G-TBko7gI_I9wP3B97VxBPM3YDw0A4rGgNdpbW2gIENef-lq8-Pmtn-A8bf5ZU9vgFd5Pn4NLYaRaYD5AB5qoVxIhMNCHhzaCjRG8gv4erUHDvNeN13bXcHsYvmeHKZF0zn-hCdEOiN3_T7D2T8mZ4fj04NJFBoyRCVP5DyqkrLC_9vGOuO0wKRnaKFTWnKmRYaFoE6LWBapYTF-xDGs0tQwUaRlhVVdUvInZLVpG_uU4CIYI6xkI1ZggWis48eWxtrRSFOtNdskcvCAKoNauWua8VkNsLRPasl5yjlPUabQeZuE_TKd9ZId_2L0dnCz-m3_KUwtfzd_9n_mL8i9yelxrvL3J0db5D5-yTyoUm6T1fllZ3fw4DPXz_3G_gmxZQmD
openUrl	ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Process+modelling%2C+design+and+technoeconomic+Liquid%E2%80%93Liquid+Extraction+%28LLE%29+optimisation+for+comparative+evaluation+of+batch+vs.+continuous+pharmaceutical+manufacturing+of+atropine&rft.jtitle=Computers+%26+chemical+engineering&rft.au=Diab%2C+Samir&rft.au=Mytis%2C+Nikolaos&rft.au=Boudouvis%2C+Andreas+G.&rft.au=Gerogiorgis%2C+Dimitrios+I.&rft.date=2019-05-08&rft.issn=0098-1354&rft.volume=124&rft.spage=28&rft.epage=42&rft_id=info:doi/10.1016%2Fj.compchemeng.2018.12.028&rft.externalDBID=n%2Fa&rft.externalDocID=10_1016_j_compchemeng_2018_12_028
thumbnail_l	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=0098-1354&client=summon
thumbnail_m	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=0098-1354&client=summon
thumbnail_s	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=0098-1354&client=summon