SEPARATION OF ENANTIOMERS USING POLYMER MEMBRANES

1. Separation of enantiomers
using polymer membranes
BY UNDER THE GUIDANCE OF
K.LAVANYA, Dr. Y.SOUJANYA MAM,
M.PHARMACY 2ND YEAR SENIOR SCIENTIST, IICT.
(PHARMACEUTICAL CHEMISTRY)

2.  Chiral molecules which are
non superimposable mirror
images
 Have same physical
properties (B.p, m.p, density,
etc.)
 Rotate plane polarized light
the same magnitude but in
opposite directions (+ or -)
 Have significantly different
biological properties
Enantiomers

3. Examples of enantiomers

4. Need for enantiomer seperation
 Preparation of enantiopure (ee~100%) compounds is one of the
most important aims both for industrial practice and research.
 The separation of enantiomers for chiral molecules is crucial,
particularly in the pharmaceutical industry, as enantiomers of
drug substances may have distinct biological interactions and,
consequently different pharmacological, pharmacokinetic, or
toxicological activities.
 The body is highly chiral selective; it will interact with each
racemic drug differently and metabolize each enantiomer by a
separate pathway to produce different pharmacological activity.

5. Need for enantiomer seperation
 One isomer may thus produce the desired therapeutic
activities, while the other may be inactive or produce
unwanted side effects.
 Even when side effects are not serious, the inactive
enantiomer must be metabolized and thus represents an
unnecessary burden for the organism.
 Thalidomide disaster”: thousands of babies were born
with malformed limbs due to misuse of S-thalidomide
for pregnant women.

6. Ibuprofen

7. Thalidomide is now being used to treat plasma cell
cancer, leprosy, and has shown anti-HIV activity

8. • Chromatography
• Asymmetric synthesis
• Resolution of racemic
compounds
• Crystallization
• Capillary electrophoresis
• Polymeric membranes
• Enzymes
CHIRAL SEPERATION
METHODS

9. Role of polymer membranes in chiral
seperation
 These membranes preferentially allow a specific enantiomer
to adsorb to or diffuse into the membrane.
 This specificity is generated by chiral recognition sites in the
membranes such as chiral side chains, chiral backbones, or
immobilized chiral selectors in polymeric chiral separation
membranes.
 They act as selective barriers in the resolution process, and
they preferentially transport one enantiomer due to the
stereospecific interaction between the enantiomer and chiral
recognition sites.

10. Polymeric membranes
 Liquid membranes with immobilized chiral ligand have also been used for chiral
separation although these techniques could be difficult to apply in commercial
systems because of the instability of the liquid membranes
 An alternative approach is to use an affinity ultrafiltration system in which a large
stereo selective ligand is added to the bulk solution to selectively bind, and thus
retain, one of the stereoisomers.
 Polypeptide membranes have shown very high enantiomer permeation rates with
encouraging selectivity for chiral drug separation.

11. Contd..
 Immobilized cyclodextrins are also used.
 CD-functionalized membrane have a lower cost and might have wider applicability
and higher tolerance in various environments.
 However, chiral separation through immobilized CD membranes has the
disadvantage of low selectivity because native cyclodextrins have limited chiral
recognition ability and limited flexibility, which are important to enable interaction
with the enantiomers.

12. Mechanism
 The mechanism of chiral separation on polymeric membranes can be categorized as:
Diffusion-selective membranes: Made of an intrinsically chiral polymer
without specific foreign chiral selectors.
Ex: albumin or other proteins, chiral polysaccharide chains or segments, DNA, crown
ether derivatives, and oligopeptides.
Sorption-selective membranes: Made by embedding or immobilizing chiral
selectors in polymer membranes or on the membrane surfaces and these membranes
have less selective diffusion but show highly selective sorption.
Ex: of chiral selectors include crown ether derivatives,cyclodextrin, albumin and other
proteins, and DNA.

13. Contd..
 The driving force for the permeation and separation is the concentration difference between
feed and permeate solutions for the dialysis method, and a pressure-driven force for
ultrafiltration and nanofiltration.
 Most studies have been performed in dialysis membranes. But disadvantages of dialysis
method are that the concentration of the final product is more dilute than that of the feed
solution, and that permeation is extremely slow.
 Due to these, chiral separation in industrial applications may require ultrafiltration or Nano
filtration through chiral separation membranes.
 In addition to dialysis and filtration, pervaporation via membranes is also useful,where the
driving force of the permeation is a vapor pressure difference.

14. Contd..
 Enantioselective vapor permeation is also effective for chiral separation if the
racemic compounds are more or less volatile
 Several chiral separation membranes were prepared from chiral polymers
 Chiral separation using membranes with immobilized large molecules as chiral
selectors can work by three mechanisms:
(1) affinity membranes
(2) selective sorption membranes and
(3) selective diffusion membranes

15. CHIRAL SEPERATION MEMBRANES
 Several chiral separation membranes were prepared from chiral polymers where
enantioselectivity was generated from chiral carbons in the main chain.
 Poly(γ -methyl-L-glutamate),alginate,chitosan,cellulose,and their derivatives are
typically used as chiral polymers for the preparation of chiral separation membranes.

16. CHIRAL SEPERATION MEMBRANES
 Chiral Separation Membranes are also prepared from polymers with a Chiral Branch
 Chiral Separation Membranes with Immobilized Stereo selective Ligands as Chiral
Selectors and Recognition Sites:
 Cyclodextrins, crown ether derivatives, albumin, and DNA are commonly used as
stereo selective ligands in chiral separation membranes.
 Immobilized Cyclodextrin Membranes: Native cyclodextrins (CD) are cyclic
oligosaccharides consisting of six to eight D-(+)- glucopyranose units that provide
three-point interactions for the chiral recognition of various organic molecules by
hydrophobic interaction with the CD cavity and two hydrogen bonds.
 Immobilized DNA membranes:DNA can also intercalate some enantiomers with a
binding constant that depends on the stereo enantiomer.

18. Immobilised DNA Membranes
 Researchers investigated the effect of the pore size on chiral separation through
immobilized DNA membranes.
 They found that D-phenylalanine preferentially permeated through the immobilized DNA
membranes with pore sizes <2.0 nm (MWCO <5000), while L(S)-phenylalanine
preferentially permeated through the immobilized DNA membranes with a pore size >2.0
nm (MWCO of the base membranes >5000).
 The pore size of the immobilized DNA membranes regulated preferential permeation of the
stereo enantiomer through the membranes.
 The immobilized DNA membranes adsorbed L-phenylalanine preferentially, independent
of the pore size

20. Separation of D,L amino acids
 Chiral ligand exchange membranes were synthesized for potential use in racemic
filtration applicable to the pharmaceutical industry
 RC membrane + 10 mµ epoxy silane for times of 6,12,and 24 hrs followed by reaction
with L-proline for 48 hrs and reaction with copper acetate for 24 hrs — for both single
component D-phe and L-phe diffusion runs. Diffusion of L-phe through membranes is
much slower than that of D-phe.
 For all 3 epoxy silane reaction times ,which determines the no. of available epoxy
groups on the membrane for reaction with proline ,D-phe appears to diffuse through
the membrane at the same rate.
 D-phe first appears in the permeate of diffusion cell at ~500 mins .Since D-phe
diffuses at same rate and L-phe diffusion is much slower,it is reasonable that a retarded
transport mechanism is at work.(D-phe → diffuses ;L-phe → absorbs)

22.  Several researchers have investigated chiral separation by affinity ultrafiltration using
albumin as a large stereo-specific binding agent.
 Albumin has several chiral recognition sites for amino acids and small drugs. The stability
and high cost of these proteins make it difficult to develop a large-scale commercial process
for the chiral separation of pharmaceuticals by affinity ultrafiltration using albumin. DNA
was recently discovered to have several chiral recognition sites for specific enantiomers.
 DNA is much more stable than proteins and is less expensive than albumin when using DNA
isolated from salmon testis. The separation factors of immobilized DNA membranes and
immobilized albumin membranes were both acceptable, although DNA seems to be a more
promising stereo-specific binding agent.
Ultra filtration

23. Multistage chiral separation process
 Most chiral
separation
membranes have
relatively low
separation factors,
except for affinity
membranes.
 One of the solutions
to this problem is to
use a multistage
chiral separation
process.

24. Molecularly imprinted polymers
 It is designed to mimic the recognition site of an enzyme with its shape,
formed by interactions with a “template” target molecule.
 Two basic methods of preparing molecularly imprinted membranes—
covalent and non-covalent molecular imprinting methods.
 In both cases, the template molecules are chosen to allow interactions with
the functional group of the imprinted polymeric membranes.

25. Molecular imprinted polymers
 Advantages
 Robust with high mechanical strength
 Resistant to elevated pressure or temperature
 Stable in the presence of extreme acids,bases or
organic solvents
 Have special recognition sites with predetermined
selectivity for the analyte
 Drawbacks
 Low chromatographic efficiency
 High peak asymmetry

26. Conclusion
 Several polymeric membranes were developed from natural chiral
polymers and synthetic polymers with a chiral main backbone or chiral
side chains. Molecularly imprinted membranes were also prepared from
achiral monomers and/or polymers.
 In conclusion, advanced polymeric materials are playing an important
role in the development of chiral separation membranes for
pharmaceutical applications.