Appendix A Pharma Mod. UNIFAC - Técnico Lisboa

142 Pages·2013·3.07 MB·English

by  Sara A. Febra

Implementation and evaluation of two models for solubility
of active pharmaceutical ingredients (APIs)
Application on solvent selection in process design
Sara Antunes Febra
Thesis to obtain the Master of Science Degree in
Chemical Engineering
Examination Committee
Chairperson: Prof. Dr. João Manuel Nunes Alvarinhas Fareleira
Supervisors: Prof. Dr. Benilde de Jesus Vieira Saramago
Dr.-Ing. Thoralf Hartwig
Members of the Committee: Prof. Dr. Edmundo José Simões Gomes de Azevedo
November 2013

Tomyfamily. Foryourunconditionallove.

Acknowledgments
I would like to thank many people who have helped me throughout the completion of this dissertation.
In first place, a very special thanks to Franc¸ois Ricard and Luisa Freitas dos Santos for welcoming me
into GSK, since without their approval it would not have been possible to carry out this thesis. I would
like to express my sincere gratitude to my supervisor Dr.-Ing. Thoralf Hartwig, the true embodiment of
a mentor. I appreciate his vast knowledge and skill, but especially the inspiring nature that helped me
to figure out what I wanted out of my career. Moreover, his encouragement made me feel supported
and capable of succeeding all times. One simply could not wish for a better supervisor both at the
professional and the personal level. I also feel very grateful for all the effort and availability my IST
supervisor Prof. Dr. Benilde Saramago put into reading and improving my written thesis. It was a
privilege to have her as my supervisor. On the GSK side, it was an absolute fantastic experience to
meet such great scientists and engineers and to have the opportunity to work closely with some of
them,namelyNoraPataut,IzabelaPhillips,RobWillacy,HughClark,PeteSzeto,JeremyProdger,Ugo
Cocchini,IgorPereira,FranckMallet,MaheshSanganeeandJanFiedler. OnthePSEside,Iwouldlike
tothankSeanBerminghamtohavefacilitatedthecollaborationofPSEthatwascrucialforanimportant
section of the work. I would like to show my appreciation for the contact that Mark Pinto made to find
meaninternshipinGSK,Icannotthankhimenough. CompletingthegPROMSpartoftheworkwould
havebeenmuchmoredifficultwithoutthesupportandfriendshipofFrancesPereira. OntheAspenTech
side, I want to thank Russel Schofield for being so helpful and collaborative, as well as AspenTech
support. On the DDBST side, I thank Wilfried Cordes for reviewing the PMUNIFAC code, as well as
Prof. Ju¨rgen Gmehling and Dr. Dana Constantinescu for giving me theopportunity to present my work
attheUNIFACConsortiummeetingof2013. IappreciateallthehelpDr. AnjaDiedrichsgavemeinthe
understandingofthefundamentalsofthemodelPharmaMod. UNIFAC.Iwouldalsoliketoacknowledge
theopportunityProf. Dr. EdmundoAzevedoprovidedme,byallowingmetospendsometimeinhislab
with researchers, so I could get up to speed with the solubility reality before beginning my internship. I
wanttothankmyboyfriendE´lton,whoexperiencedalltheupsanddownsofmywork,forhislove. Any
challengeisjusteasiertoovercomeandthehappinessfrommyachievementsisexpandedwhenheis
around. Last but not least, I would like to thank my parents for their unconditional support at all levels
throughoutmydegree. Inparticular,theirpatienceandunderstanding.
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Resumo
A selec¸a˜o do solvente o´timo e, eventualmente, o desenho do processo o´timo, sera´ apenas poss´ıvel
a partir da previsa˜o de solubilidade. O modelo Pharma. mod. UNIFAC (PMUNIFAC)[1], criado espe-
cialmente para o efeito, surgiu como um potencial candidato na aplicac¸a˜o em soluc¸o˜es orgaˆnicas de
princ´ıpios ativos. Ao contra´rio de NRTL-SAC[2,3] (modelo emp´ırico que se tem mostrado superior a
outrosmodelosdesolubilidade),estetemavantagemdeserummodelopreditivo,na˜oexigindodados
experimentaisporpartedoutilizador,masapenasestruturamolecular,temperaturaeentalpiadefusa˜o.
Na primeira parte deste trabalho, a implementac¸a˜o dos modelos NRTL-SAC e PMUNIFAC foi efetu-
ada com sucesso nos softwares gPROMS ModelBuilder e Excel/Visual Basic for Applications (VBA),
ferramentas que ficaram acess´ıveis na GlaxoSmithKline (GSK). De seguida, os dois modelos foram
avaliados com base na solubilidade experimental de oito mole´culas da GSK. Apenas o NRTL-SAC
mostrou previso˜es precisas (ordem de magnitude de discrepaˆncia (OMD) = 0.27 e OMD ma´xima =
1.63), ja´ o modelo PMUNIFAC, mostrou-se aque´m das expetativas, exceto quando se consideraram
apenasossistemasquetinhamtodososparaˆmetrosdispon´ıveis(OMDme´dia=0.40eOMDma´xima=
2.05). FoiconclusivoqueomodeloPMUNIFACaindatemmuitosparaˆmetrosemfaltaparaterutilidade
em procedimentos de selec¸a˜o de solventes, mas os resultados observados encorajam a continuac¸a˜o
do desenvolvimento do modelo. Por u´ltimo, o modelo NRTL-SAC foi aplicado na selec¸a˜o de solventes
em dois casos de cristalizac¸a˜o da GSK onde foram identificadas e validadas alternativas, contribuindo
positivamenteparaodesenvolvimentodosprocedimentosdeselec¸a˜odesolventesdaempresa.
Palavras-chave:
Solubilidade;Modelac¸a˜otermodinaˆmica;NRTL-SAC;Pharma. Mod. UNIFAC;
Selec¸a˜odesolventes;Equil´ıbroso´lido-l´ıquido.
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Abstract
Havinganoptimalsolventselection,andultimatelydesigningtheoptimalprocess,canonlybeachieved
withasuitablesolubilitymodel. TheempiricalNRTL-SACmodel[2,3] hasproventobesuperiortoother
solubility models. Pharma mod. UNIFAC (PMUNIFAC)[1], specially designed for application in API or-
ganic solutions, has arisen as a powerful candidate for the application. Unlike NRTL-SAC, it has the
advantage of being a predictive model, i.e., does not require experimental data, but only molecular
structure,meltingtemperatureandmeltingenthalpyasuserinput.
In the first stage of this study, the implementations of NRTL-SAC and PMUNIFAC were accomplished
withsuccessinthesoftwaresgPROMSModelBuilderandExcel/VisualBasicforApplications(VBA)and
becameavailableastoolsinternallyinGlaxoSmithKline(GSK).Inthesecondstage,thetwomodelswere
evaluatedagainstexperimentaldatafrom8GSKAPIs. OnlyNRTL-SACprovedtobefitforpurpose(av-
erage orderof magnitude of discrepancy(OMD) = 0.27and maximum OMD =1.63), since PMUNIFAC
predictionswerepooruntilonlysystemswithallparametersavailablebeingconsidered,whichresulted
in an average OMD = 0.40 and a maximum OMD = 2.05. It was conclusive that PMUNIFAC still has
too many missing parameters to be applied in solubility modelling, but its results were encouraging to
support its further development. In the last stage of the study, NRTL-SAC was successfully applied in
the solvent selection of two GSK crystallisation cases. Alternative solvent systems were identified and
validated,addingvaluetothesolventselectionprocedureofthecompany.
Keywords:
Solubility;Molecularmodelling;NRTL-SAC;Pharma. Mod. UNIFAC;Solventselection;
Solid-liquidequilibria.
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