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Chiral resolution concepts and their adaptation to membrane technology to produce stereoisomers of high added value

Objective


In the initial phase of the project, extensive HPLC studies with a broad assortment of chiral stationary phases were carried out to identify ideal chiral selectors (SOs) for the racemic target compounds (SAs). These efforts revealed excellent stereodiscrimination capabilities of cinchona type selectors for various types of N-acylated amino acids, suggesting this SO/SA combination as an ideal system for the development of membrane based enantioseparation processes. Structure optimisation of cinchona type SOs using combinatorial synthesis approaches in combination with mechanistic information gained in dedicated spectroscopic, X-ray crystal and computational studies gave access to SOs with receptor-like enantioselectivities. These SOs were further modified to allow their incorporation into liquid supported membranes (SLM) and fixed site membranes (FSM). For SLM applications, the SOs was attached to hydrophobic aliphatic scaffolds or polysiloxanes to provide highly lipophilic enantioselective carrier systems. The strategies to create FSM included immobilization of SO units to prefunctionalized membrane-forming polymers (polyphenylenoxides) and the development of supported membranes based on molecularly imprinted polymers. Characterization and evaluation of the various types of membranes revealed promising results for the SLM approach in terms of enantioselectivity and productivity, while the FSMs generally suffered from slow transport rates and low enantioselectivities. In lab-scale studies, SLM enantioseparations for N-acylated amino acids were systematically optimised in terms of operational conditions, supporting membrane materials and membrane stability.
In pharmaceutical, agrochemical and food industries many
complex isomeric compounds are of a chiral or asymmetric
structure, and thus optically active. Molecules of this
class are called stereoisomers or enantiomers. Often one
of these stereoisomers is beneficially bioactive whereas
the other is may be inactive, unwanted, or possibly
toxic, and must be separated.

The production of pure enantiomers is presently achieved
by diastereomeric crystallization, asymmetric synthesis,
or preparative chromatography. These processes are often
costly, low yield and industrial impractical.

The objective of this project is to develop more
efficient separation and purification methods by use of
enantioselective transport through carrier containing
membranes, the application of optically active chiral
cationic and anionic ion pair formation, inclusion
complexation, and molecularly imprinted fixed bed
membranes.

The project furthermore involves the development of
chiral recognition methodology and discrimination models
in order to achieve separation methods for different
types of products which are important in the above
mentioned industries. The performance of these processes
must be optimized, and the results compared with existing
processes.

Principle tasks of the work program include the choice of
representative compounds from participating industrial
partners, definition and choice of adequate chiral
selector and solvent systems, and determination of
critical parameters of membrane transport systems. The
developed technology will also be applicable to other
industrial products such as amino acids. Further
important aspect will be the targeted design of new
chiral cationic and anionic exchangers and molecularly
imprinted membranes in order to achieve efficient and
economic separation of chiral compounds.

The economic benefits of the project will be
stereochemically high purity products at lower cost, more
efficient production technology, lower investment and an
environmentally friendly process consuming low amounts of
organic solvents.

It is the intention of the US FDA as well as other
national authorities to define limits for the content of
undesired enantiomers in drug or food products. It is the
aim of this project to develop methods fully compliant
with planned FDA and future standards.

The consortium will establish research cooperation among
a German research organization the Universities of
Vienna, Lund, Calabria and a manufacturers in the food
and pharmaceutical industries as well as a membrane
manufacturer.

The successful completion of this project will help
overcome the lead in this technology presently enjoyed by
US and Japan and will result in enhanced competitivity of
European industry.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

INSITUTE FOR ENVIRONMENTALLY COMPATIBLE PROCESS TECHNOLOGY LTD
Address
47,Im Stadtwald, Geb. 47
66123 Saarbruecken
Germany

Participants (6)

Astra Hässle AB
Sweden
Address

431 83 Mölndal
FUMA-TECH GESELLSCHAFT FUER FUNKTIONELLE MEMBRANEN UND ANLAGENTECHNOLOGIE MBH
Germany
Address
Am Grubenstollen 11
1327 St Ingbert
LUND UNIVERSITY
Sweden
Address
60,Getingevaegen, 60
221 00 Lund
Perlarom S.A.
Belgium
Address
9,Rue Jean Lenoir 9
1348 Louvain-la-neuve
UNIVERSITY OF VIENNA
Austria
Address
38,Wahringer Strasse 38
1010 Wien
Università degli Studi della Calabria
Italy
Address
Via Pietro Bucci
87030 Arcavacata Di Rende