Chiral separation by SMB chromatography

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Pais, L.S., Loureiro,

J

.M., and Rodrigues, A.E. Chiral Separation by SMB Chromatography

in ISCD'98 1oth Intemational Symposiu"' o11 Chiral Dimimination, Vienna, Austria, August 30 - September 2, 1998. (poste1j

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10th International Symposium on

Chiral Discrimination

Vienna Hilton August 30- September 2, 1998

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Chairman: Wolfgang Lindner

Institute of Analytical Chemistry

University of Vienna, Wiihringerstrasse 38 A-1090 Wien, Austria

e-mail: Chira 198@olivin .anc.univie. a c. at

Fax +43-1-315-1826

h ttp:l/www. a ne. u n ivi e. ac.at!Chi r a 198

Bankers: Salzburg er Sparkasse, Bank Code 20404, Account No. 2500 392506

ISCD'98 Secretariat SEMACO Firmianstrasse 3 A-5020 Salzburg, Austria e-mail: [email protected] Fax +43-662-826 878-4 Tel. +43-662-826 878

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16

ORTELLI Didier

Univ. of Geneva 30 quai Emest- Anserment Switzerland

Te/.:41 22 702 6477 Fa1:.: 41 22 781 51 93 E-mail [email protected]

OURYUPIN Andrei

Central Customs Labor. of the State Customs 11/5 Novozavodskaya str. Russia Tel.: Fax.: 7 95 449 83 49 E-mail

PAIS Luis

L.S.R.E.-Laboratory of Separation and Reaction Engineering Rue dos Bragas Portugal Te/.:351 2 2041669 Fax.: 351 2 2041674 E-mai/

PALOMBI Laura

University of Rome "La Sapienza", Dept Chemistry PI. A. Moro 5 Italy

Te/.:39 6 49913638 Fax.: 936 4991 E-mail [email protected]

PE'TER Ma'ria

Albert Szent-Gyorgyi Medical University Eotvos u. 6 POB 121 Hungary

Tel.: 36 62 454 000 Fax.: 36 62 310 604 E-m ail [email protected] _u-szeged. hu

PEARS Robert

REGIS TECHNOLOGIES 8210 Austin Ave USA

Te/.:847 583 7649 Fax.: 847 9671214 E-mail [email protected]

PERRY Robert

Gill Jermings & Every 7 Eldon Street United Kingdom

Te/.:44 1713 7713 77 Fax.: 44171 5771310 E-mail [email protected]

PERSSON Bengt-Arne

Astra Hassle AB Sweden

Te/.:46 31 7761327 Fax.: 46 31 776 3760 E-m ail [email protected]. astra.com

PESCITELLI Gennaro

CNR University ofPisa via Risorgimento 35 Italy

Tel.: Fax.: E-mail

PFEIFFER Jens

Universitat Tuebingen Te/.:49 7071 2976260

Alle der Morgenstelle 18 Germany

Fax.: 49 707129 5538 [email protected]

PIRKLE H. William

University of Illinois, Depart. of Chemistry 600 S. Mathews Street USA

Tel.: Fax.:/2172448068 E-mai/

PRANGLE Anita

University of Sunderland Wahrncliffe street United Kingdom

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ISCD '98 Scientilic Program-Posters 11 http://w\vw.anc.univie.ac.at/Chiral98/posters2.1

I of9

1Oth Intetnational Symposium on Chiral Discrimination, ISCD'98

August 30- September 2 1998 in Vienna (Austria)

[Topics] [[History l] [Pro!!ram] [Exhibition]

Scientific Program - Posters Session 11

Click on the

fiJ

to get the complete abstract in PDF-fonnat. For reading the PDF format you need the Adobe Acrobat Reader, which is available free.

POSTER SESSION I

Topics

Al Fundamental Aspects ofChirality, Molecular Recognition and Molecular Modelling, Suprastructural

Phenomena, Chiral Polymers

B Novel Developments in Asymmetric Synthesis Including Chemocatalysis C Asymmeh·ic Synthesis using Biocatalysis and Enzymatic Methods

D 1 Gas-and Liquid Phase Separation Techniques (LC, CE, CEC, MEKC, GC)

g

Enantioseparation via Crystallographic Techniques

POSTER SESSION II

Topics

A2 Fundamental Aspects of Chirality, Molecular Recognition and Molecular Modelling, Suprastructural

Phenomena, Chiral Polymer

D2 Gas- and Liquid Phase Separation Techniques (LC, CE, CEC, MEKC, GC)

E

Preparative Enantiomer Separation Techniques including Chromatography (LC, GC, CCC) and

Membrane Teclmology

G Chiral Aspects in Pharmacology, Pharmacokinetics, Pharmacodynamics, Drug Binding, etc.

H Chiroptical Spectroscopy, NMR, lnshumentation, etc.

POSTER

SESSION

11 Tuesday/Wednesday, September 1/September 2, 1998

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ISCD '98 Scientific Program- Posters 11 http://www.anc.univie.ac.at!Chira198/postcrs2.t

5 of9

HIGH PERFORMANCE LIQUID CHROMATOGRAPHY OF BINAPHTHYL DERIVATIVES

ENANTIOMERS ON NEW CHOLIC ACID-BASED STATIONARY PHASES. APPROACH OF

THE CHIRAL RECOGNITION MECHANISM

Vaton-Chanvrier L., Combret Y. and Combret J.C.; Mt. St. Aignan (France)

BISBENZYLISOQUINOLINE ALKALOIDS AS COMPLEXA TION AGENTS

Millership J.; Belfast (Northern Ireland)

RESOLUTION OF THE DIASTEREOMERS OF SB-238592-DB BY CAPILLARY

ELECTROPHORESIS USING NONIONIC SURF ACT ANTS

Hadley M.R. and Gilges M.; Tonbridge (UK)

ENANTIOSEPARATION OF SOTALOL ON A CBH-I BASED CHIRAL PHASE: EFFECT OF COLUMN TEMPERATURE

Fulde K. and Frahm A.W.; Freiburg (Ge1many)

SELECTIVITY TUNING IN CHIRAL GAS CHROMATOGRAPHY

Krupcik J., Spanik I. and Sandra P.; Bratislava (Slovak Republik)

ON THE USAGE OF CYCLODEXTRINS IN GC AND CE.

Koppenhoefer B., Wuerthner S., Jakob A., Juvanecz Z. and Szeitli G.; Budapest (Hungary)

CHIRAL KBS: A KNOWLEDGE-BASED SYSTEM FOR CHIRAL SEPARATIONS

!j]

Torres-Lapasio J.R., Maftouh M., Vander Heyden Y., Vargas M.G. and Massart D.L.; Brussels

(Belgium)

F

Preparative Enantiomer Separation Techniques including Chromatography (LC,

GC, CCC) and Membrane Technology

DEVELOPMENT OF ENANTIOSELECTIVE LARGE SCALE PREPARATIVE SEPARATIONS

Cox G., Dapremont 0., Suteu C. and Murakami T.; Illkirch (France)

OPTIMISA TION OF THE PREPARATIVE ENANTIOMERIC SEPARATION OF AN

ALPHA-HYDROXY ACID BY LIQUID CHROMATOGRAPHY ON TWO DERIVATISED

POLYSACCHARIDE (DAICEL TYPE) STATIONARY PHASES Suteu C., Cox G. and Amberg W.; Illkirch (France)

CHIRAL SEPARATION BY SMB CHROMATOGRAPHY

Pais L.S., Loureiro J.M. and Rodrigues A.E.; Porta Codex (Porhtgal)

PRODUCTIVITY OF DIFFERENT CHIRAL STATIONARY PHASES FOR PREPARATIVE

ENANTIOSEPARATION BY SIMULATED MOVING BED (SMB)-CHROMATOGRAPHY

Schulte M. and Ludemann-Homburger 0.; Dannstadt (Gennany)

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Introduction

·Concept of Simulated Moving Bed:

1st UOP patent (1 961)

Sorbex processes.

• Applications:

Petroleum refining and petrochemicals

(Parex and Molex processes)

Carbohydrate industry

(production of fructose from corn syrup) (Sarex process)

·The SMB technology has recently found new applications in the areas of biotechnology, pharmaceuticals and fine chemistry.

lSRf

SMB Principle

·Flow scheme that takes advantages of continuous and countercurrent

movement of liquid and solid without

actual movement of the adsorbent. •The adsorbent bed is divided into a

number of fixed-bed columns, while the

inlet and outlet lines move

simultaneously one column at fixed time ~

intervals in the direction of the liquid phase flow.

•Advantages of SMB chromatography: lt is a continuous process;

Can perform low selectivity separations;

Reduction in eluent consumption and

adsorbent requirements.

LSR£ ₂

- - - -- -· ---· ··-- ---·-~ . --- ----·.

Section I!

Section IV

Schemalic diagram of a Simulated Moving Bed

IS RE 3

Ob.iectives

• Modeling strategies of a Simulated Moving Bed unit • SMB simulation and study of the

influence of operating parameters

on the SMB performance

• Optimization of the SMB operation conditions

• Experimental operation

of a SMB pilot unit

(Licosep 12-26, NOVASEP, France)

lSRE 4

Modeling

·Two main strategies:

The SMB model: considers the real shift of the injection and collection points. The TMB (true moving bed) model: considers liquid and solid flow in opposite directions.

·For practical purposes, optimization and . choice of SMB configuration (length of each section) can be safely carried out on the basis of analogy with TMB mode ling.

Reference: Pais, Lourelro and Rodrigues, 'Modeling

Strategies for Enantiomers Separation by SMB

Chromatography', A/ChE J., 44, 561·569 (1998).

!SHE 5

Model equauons for the steadv-state TMB model

Mass balance in a volume elemerzt of the bedj: d2cij dcij (1-E) •

DL. - - - v·- - --k(q .. -q··)=O

J dz.2 1 dz. E lj IJ 1'vlass balance in the particle:

dq.. • u5- d

11

+k(q .. -qij)=O

Z IJ

Boundary conditions for section j:

:=0: Cij""--T=cij,O DL1 dcij

Vj Z

: = Lj: cij = cij+/,0 extract, raffinate nodes

and IS BE

v,

cij=-cij+l,O v,v !!J1L V F Cij = Cij+l,O _ _f_C. VJI VI/ I qij

=

qij+l,O eluent node feed node

The TMB model considers: • Axial dispersion flow for the bulk fluid phase • lntraparticle mass transfer rate

described by the

linear driving force approximation

• The model can handle

.. any.kind of adsorption isotherm

aolltl ci~ulatlon

Uquid recircultlliOn

Schemauc diagram of a True Moving Bed

lSRE ₆ Global balances: Vf = Vfl' +v£ eluent node vu=vf-VX vm =vu+ vF vw=vm-vR extract node feed node rnffinate node Multicompmze/!t adsorption equilibrium i.wlherm:

q;j

=

f A(cA₁,c₈₁J andq;j = f o(cAj•cBj)

1- E

E

Model parameters

Ratio between solid and fluid volumes

V.

r ₁

=

...1.. Ratio between fluid and solid velocities lis

V·L·

Pe 1 = :..J.::L Peel et number

Dij

kL·

a ₁= - -1 Number of mass transfer units

"•

Adsorption equilibrium parameters have to be added to

the list above.

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Simulation twesults

Ur---~--~~---~ 99% H--~-· Ttn --t.o.ss·' -·k=O.rs"' U 1 _I u _u _To l lJ

lnnuence of IIlo mass llansfer resistance on llle separaUon region ltarget99%J

Optimum operation conditions (99% vertex)

k (s-1) _Oe _Ox _OF _OR

0.5 18.29 17.62 6.80 7.47

0.1 22.70 16.90 2_39 8.19

Sy>tem: bl-naphthol enantiomers

SAIB Op613tion conditions: 0Ft0e=Ox+OR=25.ll9 mllmin

Sv.1lch time Interval: 3 min

Recycling flow rate; 35.38 mllmin

Creed= 2.9 g/1 each enantiomer

v-1 beG. 446 m1 LSRE

'

.

0,1--..1

Separauon region In a lh versus QF plot

Region flll1ited by closed squares:

separation region lor a 95% purity criteria.

9

Open squares: path of equal raffinate and extract purities. (mass lranslercoefficient /r-0.1 s·l)

·Since the objective of the SMB operation is to obtain the two pure enantiomers, the

path of equal purities is the optimum trajectory that must be followed.

•The optimum will result from a trade-off

between solvent consumption and

productivity, purity and recovery

requirements, and system robustness.

ISRE 11

Elfect of the extractllow-rate on llle SMB performance i =a=r-e ~i::-.~ . ; ... ~ , 7 , ··:!·.·- ·· l ·-,--- ·.,

1 =1

E-+

.:

i

\

,

<

~;

..

17 "f:

-

t'"

11 \

lA~ I '"' e ,., t .! .. "'

..

... tl ln u ,.. .~ .. ~

...

.

ll 14 ll u :u u lt !.utanR--.l~l

• The deviation of the extract flow-rate from

its optimum value drastically affects the performance of one or the other enantiomer, depending on which direction Ox is changed.

IS RE

OpUmum purtUes and recoveries as a runcuoa ollbe feed now rate.

~r-~----~--.-~==~·

I •

Q,IMWool

Solvent consumpUon and adsorbent producUv11V

as a runcuoa ollbe reed now rata.

10

References: Pais, Loureiro and Rodrigues

lSRE

Chem. Engng Sci., 52, 245-257 (1997).

J. Chromatog. A, 769, 25-35 (1997). J. Chromatog. A, submitted (1998). 12

Systems studied

Separauon of chlral epoXide enanuomers

CX1

1.1 0 . H

(Sandoz Pharma, Base/, Swi!zerland) ocn ..

Stationary phase: microcrystalline cellulose triacetate (dp=45 J..lm)

Mobile phase: methanol

Temperature: 25

o

c

011 otl

Separauon of hi-naphthol enanuomers

~

(Aidrich, USA, Cat. No. 10, 465-5)

Stationary phase: Pirkle type, DNBPG-Silica (dp=25-40 J..lffi)

Mobile phase: heptane-isopropanol (72!281

Temperature: 25

oc

LSRE

lSOE

comparison between experimental and model results

- ·~ ~

"

bl-naphlbol enanUomers

chlral epoxide enanuomers

13 15

I

Ope1

11

ation

SMB pilot unit:

LICOSEP 12-26 (Novasep, France)

Experimental performance parameters .

System PUX(% PUR(% RCX(% RCR(%

Chlral epaxld• Si-naphthol System Chlral epolldo Bi-nCijl_hthol lSBE 90.0 92.0 94.0 91.1 93.0 96.2 97.3 91.6 SC(mVg) PR (g/day !bed) (Q~+Qf.) _QF(Cd.F cF ₊_I!) QF(CF +C~) _Yb.J 400 52 1200 GB Slll)lllllnaiiUncolllllUoa.

"""'

10122-5 Ui ZI20 or ~.00 1.52 2:05 Bklloh!hel tB 10.5 i 2-2·2·2 25 l!I(ID"""*'' 2.!l V5 35.Ja llis 16.110 ].61 g.og

Conclusions

14

·The SMBITMB packages are important learning and training tools used to predict the

effect of operating variables on the process performance, and so the choice of the best

conditions for the SMB operation.

• The regions for enantiomer separation can be numerically predicted, considering non-linear

competitive adsorption isotherms, dispersion

and mass transfer resislances phenomena. The mass transfer resistance phenomenon affects (reduces) the separation region of

both enantiomers.

• Ox versus OF plot provides a practical tool for choosing the better SMB operating conditions. The optimum will result from a

trade-off between solvent consumption and productivity, purity and recovery requirements, and system robustness.

LSHE 16