WO2010109490A1 - A method for preparation of enantioselective composite membrane - Google Patents

A method for preparation of enantioselective composite membrane Download PDF

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Publication number
WO2010109490A1
WO2010109490A1 PCT/IN2010/000188 IN2010000188W WO2010109490A1 WO 2010109490 A1 WO2010109490 A1 WO 2010109490A1 IN 2010000188 W IN2010000188 W IN 2010000188W WO 2010109490 A1 WO2010109490 A1 WO 2010109490A1
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Prior art keywords
membrane
enantioselective
minutes
amino acids
mixture
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PCT/IN2010/000188
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French (fr)
Inventor
Kripal Singh
Hari Chand Bajaj
Parvin Ganeshrao Ingole
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Council Of Scientific & Industrial Research
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Priority to KR1020117025333A priority Critical patent/KR101573968B1/en
Priority to JP2012501507A priority patent/JP5619867B2/en
Priority to CN201080022405.5A priority patent/CN102438734B/en
Priority to DE112010001374T priority patent/DE112010001374T5/en
Publication of WO2010109490A1 publication Critical patent/WO2010109490A1/en

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
    • B01D69/12—Composite membranes; Ultra-thin membranes
    • B01D69/125—In situ manufacturing by polymerisation, polycondensation, cross-linking or chemical reaction
    • B01D69/1251—In situ manufacturing by polymerisation, polycondensation, cross-linking or chemical reaction by interfacial polymerisation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
    • B01D71/06—Organic material
    • B01D71/56—Polyamides, e.g. polyester-amides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
    • B01D61/007—Separation by stereostructure, steric separation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
    • B01D67/0002—Organic membrane manufacture
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
    • B01D69/02—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor characterised by their properties
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
    • B01D69/12—Composite membranes; Ultra-thin membranes
    • B01D69/125—In situ manufacturing by polymerisation, polycondensation, cross-linking or chemical reaction
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30—Preparation of optical isomers
    • C07C227/34—Preparation of optical isomers by separation of optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C277/06—Purification or separation of guanidine

Definitions

  • the present invention relates to a method for the preparation of enantioselective composite membrane for separation of amino acids from their aqueous solutions and for optical resolution of racemic mixtures.
  • the present invention particularly relates to a method for the preparation of enantioselective composite nanofiltration membrane useful for separation of optical isomers of amino acids.
  • the enantioselective composite membranes of present invention are useful for separation of enantiomers from their mixture to obtain optical pure isomers.
  • the enantioselective composite membranes of present invention can be used for optical resolution of racemic mixtures of amino acids and chiral compounds to obtain optically pure enantiomers in a pressure driven membrane process such as reverse osmosis, nanofiltration etc.
  • Stereoisomers are those molecules which differ from each other only in the arrangement of their atoms within space. Stereo-isomers are generally classified as diastereomers or enantiomers; the latter embracing those which are mirror-images of each other and former being those which are not mirror images. Enantiomers (the mirror images), also known as optical isomers, have identical physical and chemical properties. Therefore a mixture of enantiomers as a rule can not be separated by ordinary separation methods, such as fractional distillation (boiling points being identical), as conventional crystallization unless the solvent is optically active (due to identical solubilities), as conventional chromatography unless adsorbent is optically active (because they are held equally onto ordinary adsorbent). The problem of separating enantiomers is further exacerbated by the fact that conventional synthetic techniques almost always produce a mixture of enantiomers. Thus separation of a mixture of enantiomers is a most challenging problem in analytical chemistry.
  • enantiomers Separation of enantiomers is very important to organic compounds such as amino acids, drugs, pesticides, insecticides etc. because majority are optically active and exist as a pairs of optical isomers (enantiomers). Enantiomers of many chiral drugs show remarkably differences in their biological & pharmacological properties. One enantiomer may have drug activity, while the other may be inert or even harmful.
  • (S)-verapamil is effective as a calcium channel blocker while (R)-verapamil produces cardiac side effects;
  • 1-enantiomer of j3 -blocker propranolol is ⁇ 100 times more active than d-form;
  • (R)(+)-enantiomer of thalidomide possesses the sleeping action and its (S)(-)-enantiomer possesses teratogenic action, the different in pharmacological action of thalidomide was found responsible for serious malformation in newborn babies of women who took drug during pregnancy, "Thalidomide Tragedy" in 1960 s etc. It is therefore "The United States Food and Drug Administration" has recently issued new regulations governing the marketing of chiral drugs. According to the new regulations, the pharmacological properties of each enantiomer of a chiral drug should be tested separately for therapeutic efficacy and safety,.
  • Chromatographic techniques GC, HPLC, CE etc.
  • Chromatographic methods require an appropriate chiral selector incorporated into the stationary phase (chiral ' stationary phase) or coated onto the surface of the column packing material (chiral coated stationary phases).
  • Enantioselective Chiral columns having chiral stationary phases are costly and have finite working life. Therefore cost of separation is quite high.
  • the contact time for the interfacial reaction is 10 seconds, and the reaction is substantially complete in 1 second.
  • the resulting polysulfone/polyamide composite membrane is then air-dried.
  • the membrane claims to exhibits good flux and salt rejection.
  • various types of additives have been incorporated into the solutions used in the interfacial polycondensation reaction.
  • the drawback of this membrane is that it is not enantioselective.
  • the enantioselective polymer membranes described in prior arts as detailed above are asymmetric and dense membranes fabricated from chiral polymers such as polysaccharides and derivatives, poly ⁇ -amino acids, polyacetylene derivatives etc. Most of these polymers are crystalline in nature and do not have membrane forming ability. Therefore membranes made from such polymers are fragile hence difficult to handle. Poor mechanical properties restricted their use to dialysis mode of separation. In dialysis mode of separation the driving force is solute concentration gradient only, therefore these membranes exhibited very low rate of permeation.
  • enantiomers separation membranes are prepared from non Chiral Polymers having grafted enantiomers recognizing molecules viz.; amino acids, proteins, oligo-peptides etc. These membranes have superior mechanical properties however during permeation recognition sites get saturated quickly being fixed in the polymer matrix therefore selectivity of such membranes decrease sharply with time.
  • Composite membranes are typically prepared by coating a porous support membrane with an aqueous solution of polyfunctional amine, followed by coating with solution of a polyfunctional acyl halide in an organic solvent to prepare thin film discriminating layer of polyamide by interfacial polycondensation reaction between a polyfunctional amine and a polyfunctional acyl halide as described in various patents.
  • the inventive steps involved in the present invention are i) discriminating layer of composite membrane has resulted by interfacial polymerization reaction of chiral amino acids and polyfunctional amine with polyfunctional acyl chloride, ( ⁇ ) the preparation of chiral enantioselective layer by interfacial method, requires very small amount of chiral compound and very large membrane having homo chiral environment can be fabricated, ( ⁇ i) the process minimizes the requirement of optically pure chiral reagent essential for the separation of racemic mixtures and (iv) the process bring chiral micro environment in the polymer membrane in the form of enantioselective thin layer supported on the ultrafiltration layer which results in higher flux and high selectivity.
  • the main object of present invention is to provide a method for the fabrication of a self- supporting and perm-selective membrane for enantiomeric separation by pressure driven membrane processes such as reverse osmosis, nanofiltration, etc.
  • Another object of present invention is to provide a composite membrane based on piperazine and trimesoyl chloride are non-enantioselective hence do not perform enantiomer separation.
  • Another object of present invention is to provide high stability and retention of enantioselectivity with time.
  • Still another object of the present invention is to provide a method for fabricating enantioselective composite nanofiltration membrane for separation of enantiomers of chiral molecules.
  • Yet another object of the present invention to provide a membrane based method for optical resolution of a racemic mixture into optically pure isomers.
  • Figure 1 shows ATR-FTIR spectra for chemical structure of the enantioselective layer of enantioselective composite membrane.
  • the present invention provides a method for the preparation of enantioselective composite membrane useful for the separation of enantiomers from their mixture to obtain optically pure isomers, which comprise of:
  • step (b) dip coating of ultrafiltration membrane as obtained from step (a) with a mixture comprising, 1-2% aqueous solution of amino acid or mixture of amino acids, polyfunctional amine and acid acceptor for a time period of 1 to 5 minutes, maintained the pH in the range of 10 to 13;
  • step (c) removing the coated UF membrane from the mixture as obtained from step (b) and draining the extra solution from the UF membrane for 5 to 30 minutes;
  • step (d) again dipping the coated membrane obtained from step (c) in 0.1-1% solution of triacyl halide in hexane for a time period of 1 to 5 minutes and draining the extra solution for 1 to 5 minutes;
  • step (e) drying the membrane as obtained from step (d) for a time period of 1 to 4 hours;
  • step (f) heating the membrane as obtained from step (e) for a time period of 1 to 15 minutes at a temperature in the range of 70 0 C to 100 0 C, followed by cooling and air drying for 1 to 2 hours;
  • step (g) soaking the membrane as obtained from step (f) in deionized water upto 24 hours to obtain enantioselective composite membrane comprising an enantioselective layer on the ultrafilteration memberane and testing it for separation of amino acids from their aqueous solution.
  • the enantioselective layer of composite " membrane used is enantioselective having thickness in the range of 400 to 1600A.
  • amino acid or mixture of amino acids used is selected from the group consisting of at least two primary amino groups.
  • the enantioselective layer of composite membrane used is of cross linked polyamide polymer having at least one chiral carbon atom.
  • polyfunctional amine used is selected from metaphenylene diamine
  • piperizine and acid acceptor used is selected from triethyl amine or NaOH.
  • polyfiinctional triacyl halide used is trimesoyl chloride.
  • the ultrafiltration membrane used is selected from the group consisting of polysulfone, poly ether sulfone, and polyvinylidienefiuoride having thickness in the range of 20-60 ⁇ m.
  • the enantioselective composite membrane separates 50-70% arginine and 80-90% lysine from aqueous solution.
  • ' a method for enantioseparation of racemic mixture of amino acids, using the enantioselective composite membrane, wherein the said process is carried out ' on a reverse osmosis membrane testing unit at trans membrane pressure ranging between 345 K Pa to 862 K Pa, using aqueous and/or buffered solution of amino acids in the range of 0.1 to 1% as feed at flow rate in the range of 300 to 800 ml per minute at 20- 30 0 C.
  • Enantioselective thin film composite membranes of the present invention are prepared by coating a micro-porous support with basic amino acid (amino acids having two primary amino groups viz., arginine, lysine, etc.) or a mixture of basic amino acid, polyfunctional amine as meta phenylenediamine, piperazine, preferentially piperazine and an acid acceptor triethyl amine, NaOH preferably NaOH and then a polyfunctional acyl halide (having reactivity more than one) preferably trimesoyl chloride stepwise.
  • basic amino acid amino acids having two primary amino groups viz., arginine, lysine, etc.
  • polyfunctional amine as meta phenylenediamine
  • piperazine preferentially piperazine and an acid acceptor triethyl amine
  • NaOH preferably NaOH
  • a polyfunctional acyl halide having reactivity more than one
  • amino acid or a mixture of amino acid, polyfunctional amine and acid acceptor is preferably coated first followed by coating of polyfunctional acyl halide.
  • the amino acid or mixture of amino acid and polyfunctional amine is coated from an aqueous solution and polyfunctional acyl halide is coated from an organic solution.
  • First ultrafiltration membrane is fabricated from polymer materials such as Polysulfone, Polyethersulfone, Polyvinylidieneflouride, etc. preferably polysulfone by phase inversion technique.
  • a solution of above-mentioned polymers of desired concentration 12 to 18 % w/w in aprotic solvents such as dimethylformamide, N, N dimethylacetamide etc (more precisely 18% w/w) is spreaded on non-woven polyester fabric (support) in uniform thickness, the support is then dipped in coagulation bath containing 2% aqueous solution of dimethylformamide after specified time varies from 10- 40 seconds.
  • the membrane is washed with deionised water for several times.
  • Ultrafiltration membrane so prepared is used for the preparation of enantioselective composite nanofiltration membranes of present invention, by preparing a thin enantioselective layer in-situ on the enantioselective layer of ultrafiltration membrane by interfacial polymerization technique by reacting 1-2% aqueous solution of a amino acid or a mixture of amino acid (arginine), polyfiinctional amine preferably piperazine (in ratio of 50-50 % arginine and piperazine) and an acid acceptor viz., triethyl amine, NaOH etc., preferably NaOH.
  • the pH of aqueous solution is maintained at 10-13 preferably 12, with 0.1-1% solution of trimesoyl chloride in hexane.
  • enantioselective layer on the enantioselective layer of ultrafiltration membrane it is first dip coated with aqueous solution of amino acid or a mixture of amino acid, a polyfiinctional amine preferably piperazine (in ratio of 50-50 % arginine and piperazine) and an acid acceptor viz., triethyl amine and NaOH for 1-5 minutes precisely 3 minutes.
  • aqueous solution of amino acid or a mixture of amino acid, a polyfiinctional amine preferably piperazine (in ratio of 50-50 % arginine and piperazine) and an acid acceptor viz., triethyl amine and NaOH viz., triethyl amine and NaOH
  • the UF membrane is then dip coated with 0.1- 1% solution of trimesoyl chloride in hexa ⁇ e precisely €.5%, for a period of about 1-5 minutes precisely 3 minutes.
  • the resultant coated UF membrane is removed from trimesoyl chloride solution mixture and membrane is drained off for 1-5 minutes precisely for 5 minutes to remove excess solution of trimesoyl chloride.
  • the membrane is then air dried for 1-4 hours precisely 4 hours, then cured by heating at a temperature of 70-100 0 C precisely at 90 0 C for 1-15 minutes, precisely for 10 minutes.
  • the resultant membrane is then cooled and dried in air for two hours and then soaked in water upto 24 hours to obtain the desired enantio selective composite membrane.
  • FIGURE 1 The enantioselective composite membrane was characterized by ATR-FTIR spectrophotometer for chemical structure of its the enantioselective layer.
  • ATR-FTIR spectra of polysulfone membrane before coating and after coating were recorded on a Perkin-Elmer spectrometer (Perkin-Elmer Spectrum GX, ATR-FTIR) using a Germanium crystal at a nominal incident angle of 45° at speed of 100 scans at a resolution of 2 cm "1 .
  • ATR-FTIR spectra of polysulfone membrane (A) and after coating (B) it with poly (piperazinecoarginine trimesamide) film in-situ are given below.
  • the peaks at 1487-90 cm '1 , and 1584 cm “1 are characteristics of polysulfone support.
  • the peak at 1667 cm “1 in the spectra of coated membrane is indicative of amide formation.
  • Characteristic absorption at 1731 cm “1 (imide ring C O), 1369 cm “1 (C-N-C, imide in the plane), and 747 cm “1 (C-N-C, out-of-plane bending, imide).
  • the membranes were tested for separation of amino acids preferably arginine, lysine, alanine etc from their aqueous and buffer solution and enantioseparation of racemic mixture of amino acids on reverse osmosis membrane testing unit at trans-membrane pressure in the range of 345 -862 K Pa, precisely at 552 KPa, using 0.1-1%, aqueous solution and buffer solution of amino acids as feed at flow rate varies from 300-800 ml per minute precisely 500 ml per minute at 25 0 C temperature.
  • the concentration of amino acids in permeate was determined by UV-Vis spectrophotomer at 290 nm and the ratio of d and 1-enantiomers in permeate to determine the enantiomeric excess(ee%) was estimated on HPLC fitted with PDA detector, by using Chiral column Chrompack(+) supplied by Diacel Chemical Industries, USA.
  • Enantiomers are chiral molecules having identical molecular formula and chemical structure, but differ only in their spatial orientation. The difference in spatial orientation has many implications as biological and pharmaceutical activities of many chiral compounds are entirely different. Therefore use of such compounds in optically pure form is imminent.
  • the separation of enantiomers presents a difficult problem. Many techniques are known in the art for separation of enantiomers based on different techniques. All enantioseparation techniques are based on the chiral micro environment in the vicinity of the racemic mixture for identifying the paired enantiomers.
  • the presence of homo-chiral environment is essential to discriminate paired enantiomers.
  • the novelty of the membrane of the present invention is to bring chiral micro environment in the polymer membrane in the form of the enantioselective layer thin layer supported on the ultrafiltration layer which results higher flux and higher selectivity.
  • the composite membranes of present invention have enantioselective layer chiral discriminating layer that has been prepared in-situ on the ultrfiltration membrane.
  • the enantioselective layer discriminating layer has resulted by interfacial polymerization reaction of chiral amino acids and polyfunctional amine with polyfunctional acyl chloride.
  • the Preparation of chiral enantioselective layer by interfacial method requires very small amount of chiral compound and very large membrane having homo-chiral environment can be fabricated. Thus minimizes the requirement of optically pure chiral reagent essential for separation of racemic mixtures.
  • Enantioselective composite membrane was prepared by impregnating polysulfone UF membrane in 1% aqueous solution of arginine and Piprazine (50:50) for 3 minutes, pH of solution was maintained to 12 by adding IN NaOH, draining extra solution for 15 minutes and then dipping membrane in 0.5% solution of trimesoyl chloride in hexane for 2 minutes, extra solution was drained for 2 minutes then drying the membrane for 4 hours in air. The membrane was heat cured for 5 minutes at 90 0 C temperature, cooled to 25 0 C temperature, air dried for 2 hours, then soaked in deionized water upto 24 hours.
  • the membrane was tested for separation and enantioselctivity for arginine at standard conditions; 0.1% aqueous solution of racemic arginine as feed at flow rate 500ml per minute at 552 KPa. Membrane exhibited permeation rate 636 l/m 2 /day and 75% rejection for arginine. Enantioselcetivity for d-arginine was observed 65% .
  • Enantioselective composite membrane was prepared by impregnating polysulfone UF membrane in 1% aqueous solution of arginine and Piprazine (50:50) for 3 minutes, pH of solution was maintained to 12 by adding IN NaOH, draining extra solution for 15 minutes and then dipping membrane in 1% solution of trimesoyl chloride in hexane for 2 minutes, extra solution was drained for 5 minutes then drying the membrane for 4 hours in air. The membrane was heat cured for 5 minutes at 90 0 C temperature, cooled to 25 0 C temperature; air dried for 2 hours, then soaked in deionized water upto 24 hours.
  • the membrane was tested for separation and enantioselctivity for arginine at standard conditions; using 0.1% aqueous solution of racemic arginine as feed at flow rate 500ml per minute at 552 KPa. Membrane exhibited permeation rate 734 1/nr/day after 6 hours and 66% rejection for arginine. Enantioselectivity for d arginine was 50%.
  • Enantioselective composite membrane was prepared by impregnating polysulfone UF membrane in 1% aqueous solution of Piprazine for 3 minutes, pH of solution was maintained to 12 by adding IN NaOH, draining extra solution for 15 minutes and then dipping membrane in 0.5% solution of trimesoyl chloride in hexane for 2 minutes, extra solution was drained for 5 minutes then drying the membrane for 4 hours in air.
  • the membrane was heat cured for 5 minutes at 90 0 C temperature, cooled to 25 0 C temperature, air dried for 2 hours, then soaked in deionized water upto 24 hours.
  • the membrane was tested at standard conditions using 0.1% aqueous solution, of racemic arginine as feed with flow rate 500ml per minute at 552 KPa. Membrane exhibited, permeation rate 1125 1/mVday and 60% rejection for arginine. Membrane did not show , enantioselectivity for d arginine.
  • Enantioselective composite membrane was prepared by impregnating polysulfone UF membrane in 1% aqueous solution of arginine at 12 pH by adding IN NaOH for 3 minutes, draining extra solution for 15 minutes and then dipping membrane in 0.5% solution of trimesoyl chloride in hexane for 2 minutes, extra solution was drained for 2 minutes then drying the membrane for 4 hours in air.
  • the membrane was heat cured for 5 minutes at 90 0 C temperature, cooled to 25 0 C temperature, air dried for 2 hours, then soaked in deionized water upto 24 hours.
  • the membrane was tested at standard conditions using 0.1% aqueous solution of racemic arginine as feed with flow rate 500ml per minute at 552 KPa.
  • Membrane exhibited permeation rate 1125 1/mVday and 48% rejection for arginine and Membrane exhibited enantioselectivity for d-arginine 50%.
  • Enantioselective composite membrane was prepared by impregnating polysulfone UF membrane in 1% aqueous solution of lysine and Piprazine (50:50) at 12 pH for 5 minutes, draining extra solution for 15 minutes and then dipping membrane in 0.5% solution of trimesoyl chloride in hexane for 5 minutes, extra solution was drained for 5 minutes then drying the membrane for 4 hours in air.
  • the membrane was heat cured for 5 minutes at 90 0 C temperature, cooled to 25 0 C temperature; air dried for 2 hours and then soaked in deionized water upto 24 hours.
  • the membrane was tested at standard conditions using 0.1% aqueous solution of racemic lysine as feed with flow rate 500ml per minute at 552 KPa.
  • Membrane exhibited permeation rate 587.19 1/mVday and 83% rejection for lysine.
  • Membrane exhibited enantioselectivity for d lysine 90%.
  • the membrane exhibited permeation rate 293.5 ⁇ 1 / m 2 /day, 46% rejection for lysine and enantioselectivity for d-lysine was 60%.
  • the membrane exhibited volumetric flux 342.30 1/mVday and lysine rejection 72%.
  • the enantioselectivity for d-alanine was 56%.
  • the enantioselective polymer membranes described in prior art are asymmetric and dense membranes fabricated from chiral polymers such as polysaccharides and derivatives, poly ⁇ -amino acids, polyacetylene derivatives etc.
  • Most membranes are fragile have poor mechanical properties thus posses difficulties to handle membrane, as a result their use is restricted to dialysis mode of separation. In dialysis mode of separation the driving force is solute concentration across the membrane therefore membranes exhibit very low rate of permeation.
  • Membranes having superior mechanical properties exhibit enantioselectivity in the beginning but selectivity decrease sharply with time due to saturation of recognition sites.
  • the composite membranes of the present invention can be used to perform enantiomers separation at commercial scale.
  • the composite membranes of the present invention exhibits permeation flux of 6-24 gallon/feetVday depending upon trans-membrane pressure.
  • the composite membranes of present invention can be used in pressure driven separation process at pressure varies from 345 to 862 K Pa.
  • the higher trans-membrane pressure result higher flux thereby higher productivity.
  • the composite membranes of present invention are stable and mechanically superior therefore it is to handle and convert into modular form.
  • the enantiomers separation methods described in prior arts are often batch processes even if continuous, could not be adapted for a large scale continuous separation.
  • the enantiomers separation process using membranes of present invention would be a continuous process and can be adapted for a large scale continuous separation.
  • the enantiomers separation process of present invention would exhibit high rate of transport and the degree of separation in a reasonable time period to make feasible for large scale amino acids separation from their aqueous solution and mixture.

Abstract

The present invention provides an enantioselective composite membrane useful for separation of optical isomers and the process for the preparation thereof. The invention further provides a membrane based pressure driven separation process for separation of enantiomers from their mixture to obtain optical pure isomers. The present invention also provides a membrane based method for optical resolution of racemic mixtures of amino acids to obtain optically pure amino acids.

Description

"A method lbr preparation of ■enantioselectlve composite membrane"
FIELD OF THE INVENTION
The present invention relates to a method for the preparation of enantioselective composite membrane for separation of amino acids from their aqueous solutions and for optical resolution of racemic mixtures. The present invention particularly relates to a method for the preparation of enantioselective composite nanofiltration membrane useful for separation of optical isomers of amino acids.
The enantioselective composite membranes of present invention are useful for separation of enantiomers from their mixture to obtain optical pure isomers. The enantioselective composite membranes of present invention can be used for optical resolution of racemic mixtures of amino acids and chiral compounds to obtain optically pure enantiomers in a pressure driven membrane process such as reverse osmosis, nanofiltration etc.
BACKGROUND OF THE INVENTION
Stereoisomers are those molecules which differ from each other only in the arrangement of their atoms within space. Stereo-isomers are generally classified as diastereomers or enantiomers; the latter embracing those which are mirror-images of each other and former being those which are not mirror images. Enantiomers (the mirror images), also known as optical isomers, have identical physical and chemical properties. Therefore a mixture of enantiomers as a rule can not be separated by ordinary separation methods, such as fractional distillation (boiling points being identical), as conventional crystallization unless the solvent is optically active (due to identical solubilities), as conventional chromatography unless adsorbent is optically active (because they are held equally onto ordinary adsorbent). The problem of separating enantiomers is further exacerbated by the fact that conventional synthetic techniques almost always produce a mixture of enantiomers. Thus separation of a mixture of enantiomers is a most challenging problem in analytical chemistry.
Separation of enantiomers is very important to organic compounds such as amino acids, drugs, pesticides, insecticides etc. because majority are optically active and exist as a pairs of optical isomers (enantiomers). Enantiomers of many chiral drugs show remarkably differences in their biological & pharmacological properties. One enantiomer may have drug activity, while the other may be inert or even harmful. For examples, (S)-verapamil is effective as a calcium channel blocker while (R)-verapamil produces cardiac side effects; 1-enantiomer of j3 -blocker propranolol is ~ 100 times more active than d-form; (R)(+)-enantiomer of thalidomide possesses the sleeping action and its (S)(-)-enantiomer possesses teratogenic action, the different in pharmacological action of thalidomide was found responsible for serious malformation in newborn babies of women who took drug during pregnancy, "Thalidomide Tragedy" in 1960 s etc. It is therefore "The United States Food and Drug Administration" has recently issued new regulations governing the marketing of chiral drugs. According to the new regulations, the pharmacological properties of each enantiomer of a chiral drug should be tested separately for therapeutic efficacy and safety,.
Various methods are known for separating enantiomers such as diastereomeric resolutions, enzyme catalyzed reactions, chromatographic methods, the application of liquid membranes, molecular recognition techniques, and inclusion complexation techniques. Preferential crystallization, diastereomeric resolutions, enzyme catalyzed reactions etc. involve coupling of the enantiomers with an auxiliary chiral reagent to convert them into diastereomers, which can then be separated by any conventional separation technique. Reference may be made to Diastereomeric resolutions and are described in "CRC Handbook of Optical Resolutions via Diasteromeric Salt Formation" Kozma D., 2002 ISBN: 0849300193. The major drawback of diastereomeric resolutions is the requirement of large quantities of optically pure derivatizing agent (chiral reagents or solvents) which can be expensive and can often not be recoverable.
References may be made to Chromatographic techniques (GC, HPLC, CE etc.) and are described in "Chiral Separation Techniques — A Practical Approach" Second Edition, Edited by G. Subramanian ISBN 3-527-29875-4, wherein Chromatographic methods require an appropriate chiral selector incorporated into the stationary phase (chiral ' stationary phase) or coated onto the surface of the column packing material (chiral coated stationary phases). Enantioselective Chiral columns having chiral stationary phases are costly and have finite working life. Therefore cost of separation is quite high.
References may be made to Molecular recognition phenomena for enantiomers separation has been reported in "Chiral Separation Techniques - A Practical Approach" Second Edition, Edited by G. Subramanian ISBN 3-527-29875-4. A varying nos. of chiral stationary phases, complexes etc. have been developed based of molecular recognition.
References may be made to U. S. Patent No. 6759488 entitled "Molecularly imprinted polymers grafted on solid supports", wherein the separation of enantiomers is based on molecular recognition phenomenon. The draw back of MIP techniques is that cross- linkable monomers can only be used for fabricating molecularly imprinting membranes.
References may be made to U. S. Patent No. 5,080,795 entitled "Supported chiral liquid membrane for the separation of enantiomers", wherein supported chiral liquid membrane containing chiral carrier selectively complexes with one of the two enantiomers and separates it from other. The major drawbacks of the membrane are poor stability and loss of enantioselectivity with time. References may be made to U. S. Patent No. 6,485,650 entitled "Liquid membrane separation of enantiomers", wherein a method of separating enantiomers in a supported liquid membrane module containing a carrier and a phase transfer agent with a feed fluid containing a racemic mixture describes an enantiomer which is transported into the liquid membrane and thereafter contacting the liquid membrane with a sweep fluid. The enantiomer is then recovered from the sweep fluid. The membrane module is constructed in such a way that the feed fluid and the sweep fluid are adjacent to, but on opposite sides of, the liquid membrane and the feed and sweep fluids have a substantially continuous interfacial contact along the length of the liquid membrane. The drawbacks of the liquid-liquid extraction technique are less productivity and chances of inter-mixing the two solutions at the interface of the membrane.
References may be made to U.S. Patent No. 4,277,344 entitled "Interfacially synthesized reverse osmosis membrane", wherein an aromatic polyamide film which is the interfacial reaction product of an aromatic polyamine having at least two primary amines groups with an aromatic acyl halide having at least three acyl halide groups. According to this patent a porous polysulfone support is coated with m-phenylenediamine in water. After removal of excess m-phenylenediamine solution from the coated support, the coated support is covered with a solution of trimesoyl chloride dissolved in "FREON" TF solvent (trichlorotrifluoroethane). The contact time for the interfacial reaction is 10 seconds, and the reaction is substantially complete in 1 second. The resulting polysulfone/polyamide composite membrane is then air-dried. The membrane claims to exhibits good flux and salt rejection. However in order to improve the membrane performance various types of additives have been incorporated into the solutions used in the interfacial polycondensation reaction. The drawback of this membrane is that it is not enantioselective.
References may be made to U.S. Patent No. 5,205,934 entitled "Silicone-derived solvent stable membranes" wherein methods for producing composite nanofiltration membranes describe, which comprise a layer of silicone immobilized onto a support, preferably a polyacrylonitrile support. These composite membranes are claimed to be solvent stable and are claimed to have utility for separation of high molecular weight solutes, including organometallic catalyst complexes, from organic solvents. The membrane does not have enantioselective character.
References may be made to U. S. Patent No. 6,743,373 entitled "Process for the separation of enantiomers and enantiopure reagent" wherein a mixture comprising the enantiomers is reacted in the basic medium with a reagent based on an enantiopure amino acid and the mixture of diastereomers obtained is subjected to a separation operation. The drawback of the process is that for the separation of enantiomers, enantiomers must have at least one free functional group and the reagent comprises at least one amino group of the amino acid carries an activating group in order to form an active precursor of an isocyanate group, and in which at least one carboxyl group of the amino acid is substituted.
The enantioselective polymer membranes described in prior arts as detailed above are asymmetric and dense membranes fabricated from chiral polymers such as polysaccharides and derivatives, poly α-amino acids, polyacetylene derivatives etc. Most of these polymers are crystalline in nature and do not have membrane forming ability. Therefore membranes made from such polymers are fragile hence difficult to handle. Poor mechanical properties restricted their use to dialysis mode of separation. In dialysis mode of separation the driving force is solute concentration gradient only, therefore these membranes exhibited very low rate of permeation. Other types of enantiomers separation membranes are prepared from non Chiral Polymers having grafted enantiomers recognizing molecules viz.; amino acids, proteins, oligo-peptides etc. These membranes have superior mechanical properties however during permeation recognition sites get saturated quickly being fixed in the polymer matrix therefore selectivity of such membranes decrease sharply with time.
Composite membranes are typically prepared by coating a porous support membrane with an aqueous solution of polyfunctional amine, followed by coating with solution of a polyfunctional acyl halide in an organic solvent to prepare thin film discriminating layer of polyamide by interfacial polycondensation reaction between a polyfunctional amine and a polyfunctional acyl halide as described in various patents.
The inventive steps involved in the present invention are i) discriminating layer of composite membrane has resulted by interfacial polymerization reaction of chiral amino acids and polyfunctional amine with polyfunctional acyl chloride, (ϋ) the preparation of chiral enantioselective layer by interfacial method, requires very small amount of chiral compound and very large membrane having homo chiral environment can be fabricated, (ϋi) the process minimizes the requirement of optically pure chiral reagent essential for the separation of racemic mixtures and (iv) the process bring chiral micro environment in the polymer membrane in the form of enantioselective thin layer supported on the ultrafiltration layer which results in higher flux and high selectivity.
OBJECTIVE OF THE INVENTION
The main object of present invention is to provide a method for the fabrication of a self- supporting and perm-selective membrane for enantiomeric separation by pressure driven membrane processes such as reverse osmosis, nanofiltration, etc.
Another object of present invention is to provide a composite membrane based on piperazine and trimesoyl chloride are non-enantioselective hence do not perform enantiomer separation. Another object of present invention is to provide high stability and retention of enantioselectivity with time.
Still another object of the present invention is to provide a method for fabricating enantioselective composite nanofiltration membrane for separation of enantiomers of chiral molecules.
Yet another object of the present invention to provide a membrane based method for optical resolution of a racemic mixture into optically pure isomers.
BRIEF DESCRIPTION OF DRAWING
Figurel: Figure 1 shows ATR-FTIR spectra for chemical structure of the enantioselective layer of enantioselective composite membrane.
SUMMARY OF INVENTION
Accordingly, the present invention provides a method for the preparation of enantioselective composite membrane useful for the separation of enantiomers from their mixture to obtain optically pure isomers, which comprise of:
(a) providing ultrafiltration (UF) membrane prepared by wet phase inversion method;
(b) dip coating of ultrafiltration membrane as obtained from step (a) with a mixture comprising, 1-2% aqueous solution of amino acid or mixture of amino acids, polyfunctional amine and acid acceptor for a time period of 1 to 5 minutes, maintained the pH in the range of 10 to 13;
(c) removing the coated UF membrane from the mixture as obtained from step (b) and draining the extra solution from the UF membrane for 5 to 30 minutes;
(d) again dipping the coated membrane obtained from step (c) in 0.1-1% solution of triacyl halide in hexane for a time period of 1 to 5 minutes and draining the extra solution for 1 to 5 minutes;
(e) drying the membrane as obtained from step (d) for a time period of 1 to 4 hours;
(f) heating the membrane as obtained from step (e) for a time period of 1 to 15 minutes at a temperature in the range of 700C to 1000C, followed by cooling and air drying for 1 to 2 hours;
(g) soaking the membrane as obtained from step (f) in deionized water upto 24 hours to obtain enantioselective composite membrane comprising an enantioselective layer on the ultrafilteration memberane and testing it for separation of amino acids from their aqueous solution.
In an embodiment of the present invention the enantioselective layer of composite" membrane used is enantioselective having thickness in the range of 400 to 1600A.
Another embodiment of the invention, amino acid or mixture of amino acids used is selected from the group consisting of at least two primary amino groups.
In another embodiment, the enantioselective layer of composite membrane used is of cross linked polyamide polymer having at least one chiral carbon atom.
In another embodiment, polyfunctional amine used is selected from metaphenylene diamine, piperizine and acid acceptor used is selected from triethyl amine or NaOH.
In yet another embodiment, polyfiinctional triacyl halide used is trimesoyl chloride.
In another embodiment, the ultrafiltration membrane used is selected from the group consisting of polysulfone, poly ether sulfone, and polyvinylidienefiuoride having thickness in the range of 20-60 μ m.
In still another embodiment, the enantioselective composite membrane separates 50-70% arginine and 80-90% lysine from aqueous solution.
In yet another embodiment,' a method for enantioseparation of racemic mixture of amino acids, using the enantioselective composite membrane, wherein the said process is carried out' on a reverse osmosis membrane testing unit at trans membrane pressure ranging between 345 K Pa to 862 K Pa, using aqueous and/or buffered solution of amino acids in the range of 0.1 to 1% as feed at flow rate in the range of 300 to 800 ml per minute at 20- 300C.
In yet another embodiment, wherein the concentration of amino acids in permeate was determined by UV-Vis spectrophotometer and the ratio of d and 1- enantiomers in permeate was estimated on HPLC fitted with PDA. detector, by using Chiral column.
DETAILED DESCRIPTION OF THE INVENTION
Enantioselective thin film composite membranes of the present invention are prepared by coating a micro-porous support with basic amino acid (amino acids having two primary amino groups viz., arginine, lysine, etc.) or a mixture of basic amino acid, polyfunctional amine as meta phenylenediamine, piperazine, preferentially piperazine and an acid acceptor triethyl amine, NaOH preferably NaOH and then a polyfunctional acyl halide (having reactivity more than one) preferably trimesoyl chloride stepwise. The coating steps need not be in specific order, however amino acid or a mixture of amino acid, polyfunctional amine and acid acceptor is preferably coated first followed by coating of polyfunctional acyl halide. The amino acid or mixture of amino acid and polyfunctional amine is coated from an aqueous solution and polyfunctional acyl halide is coated from an organic solution.
First ultrafiltration membrane is fabricated from polymer materials such as Polysulfone, Polyethersulfone, Polyvinylidieneflouride, etc. preferably polysulfone by phase inversion technique. In this technique, a solution of above-mentioned polymers of desired concentration 12 to 18 % w/w in aprotic solvents such as dimethylformamide, N, N dimethylacetamide etc (more precisely 18% w/w) is spreaded on non-woven polyester fabric (support) in uniform thickness, the support is then dipped in coagulation bath containing 2% aqueous solution of dimethylformamide after specified time varies from 10- 40 seconds. The membrane is washed with deionised water for several times.
Ultrafiltration membrane so prepared is used for the preparation of enantioselective composite nanofiltration membranes of present invention, by preparing a thin enantioselective layer in-situ on the enantioselective layer of ultrafiltration membrane by interfacial polymerization technique by reacting 1-2% aqueous solution of a amino acid or a mixture of amino acid (arginine), polyfiinctional amine preferably piperazine (in ratio of 50-50 % arginine and piperazine) and an acid acceptor viz., triethyl amine, NaOH etc., preferably NaOH. The pH of aqueous solution is maintained at 10-13 preferably 12, with 0.1-1% solution of trimesoyl chloride in hexane.
To prepare enantioselective layer on the enantioselective layer of ultrafiltration membrane it is first dip coated with aqueous solution of amino acid or a mixture of amino acid, a polyfiinctional amine preferably piperazine (in ratio of 50-50 % arginine and piperazine) and an acid acceptor viz., triethyl amine and NaOH for 1-5 minutes precisely 3 minutes. The coated UF membrane is removed from the solution and excess solution is drained from UF membrane for about 5-30 minutes precisely 15 minutes to retain the desired amount of monomers. The UF membrane is then dip coated with 0.1- 1% solution of trimesoyl chloride in hexaήe precisely €.5%, for a period of about 1-5 minutes precisely 3 minutes. The resultant coated UF membrane is removed from trimesoyl chloride solution mixture and membrane is drained off for 1-5 minutes precisely for 5 minutes to remove excess solution of trimesoyl chloride. The membrane is then air dried for 1-4 hours precisely 4 hours, then cured by heating at a temperature of 70-1000C precisely at 900C for 1-15 minutes, precisely for 10 minutes. The resultant membrane is then cooled and dried in air for two hours and then soaked in water upto 24 hours to obtain the desired enantio selective composite membrane.
FIGURE 1: The enantioselective composite membrane was characterized by ATR-FTIR spectrophotometer for chemical structure of its the enantioselective layer. ATR-FTIR spectra of polysulfone membrane before coating and after coating were recorded on a Perkin-Elmer spectrometer (Perkin-Elmer Spectrum GX, ATR-FTIR) using a Germanium crystal at a nominal incident angle of 45° at speed of 100 scans at a resolution of 2 cm"1. ATR-FTIR spectra of polysulfone membrane (A) and after coating (B) it with poly (piperazinecoarginine trimesamide) film in-situ are given below. The peaks at 1487-90 cm'1, and 1584 cm"1 are characteristics of polysulfone support. The appearance of absorption bands in 1472-1644 cm"1 region can be attributed to the C=O, C=N stretching vibrations. The peak at 1667 cm"1 in the spectra of coated membrane is indicative of amide formation. Characteristic absorption at 1731 cm"1 (imide ring C=O), 1369 cm"1 (C-N-C, imide in the plane), and 747 cm"1 (C-N-C, out-of-plane bending, imide).
The membranes were tested for separation of amino acids preferably arginine, lysine, alanine etc from their aqueous and buffer solution and enantioseparation of racemic mixture of amino acids on reverse osmosis membrane testing unit at trans-membrane pressure in the range of 345 -862 K Pa, precisely at 552 KPa, using 0.1-1%, aqueous solution and buffer solution of amino acids as feed at flow rate varies from 300-800 ml per minute precisely 500 ml per minute at 250C temperature. The concentration of amino acids in permeate was determined by UV-Vis spectrophotomer at 290 nm and the ratio of d and 1-enantiomers in permeate to determine the enantiomeric excess(ee%) was estimated on HPLC fitted with PDA detector, by using Chiral column Chrompack(+) supplied by Diacel Chemical Industries, USA.
Enantiomers are chiral molecules having identical molecular formula and chemical structure, but differ only in their spatial orientation. The difference in spatial orientation has many implications as biological and pharmaceutical activities of many chiral compounds are entirely different. Therefore use of such compounds in optically pure form is imminent. The separation of enantiomers presents a difficult problem. Many techniques are known in the art for separation of enantiomers based on different techniques. All enantioseparation techniques are based on the chiral micro environment in the vicinity of the racemic mixture for identifying the paired enantiomers.
The presence of homo-chiral environment is essential to discriminate paired enantiomers. The novelty of the membrane of the present invention is to bring chiral micro environment in the polymer membrane in the form of the enantioselective layer thin layer supported on the ultrafiltration layer which results higher flux and higher selectivity.
The composite membranes of present invention have enantioselective layer chiral discriminating layer that has been prepared in-situ on the ultrfiltration membrane. The enantioselective layer discriminating layer has resulted by interfacial polymerization reaction of chiral amino acids and polyfunctional amine with polyfunctional acyl chloride. The Preparation of chiral enantioselective layer by interfacial method requires very small amount of chiral compound and very large membrane having homo-chiral environment can be fabricated. Thus minimizes the requirement of optically pure chiral reagent essential for separation of racemic mixtures.
The following examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention.
Enantioselective composite membrane was prepared by impregnating polysulfone UF membrane in 1% aqueous solution of arginine and Piprazine (50:50) for 3 minutes, pH of solution was maintained to 12 by adding IN NaOH, draining extra solution for 15 minutes and then dipping membrane in 0.5% solution of trimesoyl chloride in hexane for 2 minutes, extra solution was drained for 2 minutes then drying the membrane for 4 hours in air. The membrane was heat cured for 5 minutes at 900C temperature, cooled to 25 0C temperature, air dried for 2 hours, then soaked in deionized water upto 24 hours. The membrane was tested for separation and enantioselctivity for arginine at standard conditions; 0.1% aqueous solution of racemic arginine as feed at flow rate 500ml per minute at 552 KPa. Membrane exhibited permeation rate 636 l/m2/day and 75% rejection for arginine. Enantioselcetivity for d-arginine was observed 65% .
EXMiPLE 2
Enantioselective composite membrane was prepared by impregnating polysulfone UF membrane in 1% aqueous solution of arginine and Piprazine (50:50) for 3 minutes, pH of solution was maintained to 12 by adding IN NaOH, draining extra solution for 15 minutes and then dipping membrane in 1% solution of trimesoyl chloride in hexane for 2 minutes, extra solution was drained for 5 minutes then drying the membrane for 4 hours in air. The membrane was heat cured for 5 minutes at 900C temperature, cooled to 25 0C temperature; air dried for 2 hours, then soaked in deionized water upto 24 hours. The membrane was tested for separation and enantioselctivity for arginine at standard conditions; using 0.1% aqueous solution of racemic arginine as feed at flow rate 500ml per minute at 552 KPa. Membrane exhibited permeation rate 734 1/nr/day after 6 hours and 66% rejection for arginine. Enantioselectivity for d arginine was 50%.
Enantioselective composite membrane was prepared by impregnating polysulfone UF membrane in 1% aqueous solution of Piprazine for 3 minutes, pH of solution was maintained to 12 by adding IN NaOH, draining extra solution for 15 minutes and then dipping membrane in 0.5% solution of trimesoyl chloride in hexane for 2 minutes, extra solution was drained for 5 minutes then drying the membrane for 4 hours in air. The membrane was heat cured for 5 minutes at 900C temperature, cooled to 25 0C temperature, air dried for 2 hours, then soaked in deionized water upto 24 hours. The membrane was tested at standard conditions using 0.1% aqueous solution, of racemic arginine as feed with flow rate 500ml per minute at 552 KPa. Membrane exhibited, permeation rate 1125 1/mVday and 60% rejection for arginine. Membrane did not show , enantioselectivity for d arginine.
EXAMPLE 4
Enantioselective composite membrane was prepared by impregnating polysulfone UF membrane in 1% aqueous solution of arginine at 12 pH by adding IN NaOH for 3 minutes, draining extra solution for 15 minutes and then dipping membrane in 0.5% solution of trimesoyl chloride in hexane for 2 minutes, extra solution was drained for 2 minutes then drying the membrane for 4 hours in air. The membrane was heat cured for 5 minutes at 900C temperature, cooled to 250C temperature, air dried for 2 hours, then soaked in deionized water upto 24 hours. The membrane was tested at standard conditions using 0.1% aqueous solution of racemic arginine as feed with flow rate 500ml per minute at 552 KPa. Membrane exhibited permeation rate 1125 1/mVday and 48% rejection for arginine and Membrane exhibited enantioselectivity for d-arginine 50%.
EXAMPLE S
Enantioselective composite membrane was prepared by impregnating polysulfone UF membrane in 1% aqueous solution of lysine and Piprazine (50:50) at 12 pH for 5 minutes, draining extra solution for 15 minutes and then dipping membrane in 0.5% solution of trimesoyl chloride in hexane for 5 minutes, extra solution was drained for 5 minutes then drying the membrane for 4 hours in air. The membrane was heat cured for 5 minutes at 900C temperature, cooled to 250C temperature; air dried for 2 hours and then soaked in deionized water upto 24 hours. The membrane was tested at standard conditions using 0.1% aqueous solution of racemic lysine as feed with flow rate 500ml per minute at 552 KPa. Membrane exhibited permeation rate 587.19 1/mVday and 83% rejection for lysine. Membrane exhibited enantioselectivity for d lysine 90%.
EXAMPLE S
Enantioselective composite membrane prepared as per example No.l, tested at standard conditions using 0.1% aqueous solution of racemic lysine as feed with flow rate 500ml per minute at 552 KPa. The membrane exhibited permeation rate 293.5^ 1 /m2/day, 46% rejection for lysine and enantioselectivity for d-lysine was 60%.
EXAMPLE 7
Enantioselective composite membrane prepared as per example No.l, tested at standard conditions using 0.05% aqueous solution of racemic alanine as feed with flow rate 500ml per minute at 552 KPa. The membrane exhibited volumetric flux 342.30 1/mVday and lysine rejection 72%. The enantioselectivity for d-alanine was 56%. THE MAIN ADVANTAGES OF THE PRESENT INVENTION
1) The enantioselective polymer membranes described in prior art are asymmetric and dense membranes fabricated from chiral polymers such as polysaccharides and derivatives, poly α-amino acids, polyacetylene derivatives etc. Most membranes are fragile have poor mechanical properties thus posses difficulties to handle membrane, as a result their use is restricted to dialysis mode of separation. In dialysis mode of separation the driving force is solute concentration across the membrane therefore membranes exhibit very low rate of permeation. Membranes having superior mechanical properties exhibit enantioselectivity in the beginning but selectivity decrease sharply with time due to saturation of recognition sites.
2) The composite membranes of the present invention obviate the drawbacks of the membrane described in prior arts as mentioned above.
3) The composite membranes of the present invention can be used to perform enantiomers separation at commercial scale.
4) The composite membranes of the present invention exhibits permeation flux of 6-24 gallon/feetVday depending upon trans-membrane pressure.
5) The composite membranes of present invention can be used in pressure driven separation process at pressure varies from 345 to 862 K Pa. The higher trans-membrane pressure result higher flux thereby higher productivity.
6) The composite membranes of present invention are stable and mechanically superior therefore it is to handle and convert into modular form.
7) The enantiomers separation methods described in prior arts are often batch processes even if continuous, could not be adapted for a large scale continuous separation. The enantiomers separation process using membranes of present invention would be a continuous process and can be adapted for a large scale continuous separation.
8) The enantiomers separation process of present invention would exhibit high rate of transport and the degree of separation in a reasonable time period to make feasible for large scale amino acids separation from their aqueous solution and mixture.

Claims

We claim:
1. A method for preparation of enantioselective composite membrane useful for the separation of enantiomers from their mixture to obtain optically pure isomers, wherein the process comprises the step of:
(a) providing ultrafiltration (UF) membrane prepared by wet phase inversion method;
(b) dip coating of ultrafiltration membrane as obtained from step (a) with a mixture comprising, 1-2% aqueous solution of amino acid or mixture of amino acids, polyfunctional amine and acid acceptor for a time period of 1 to 5 minutes, maintained the pH in the range of 10 to 13;
(c) removing the coated UF membrane from the mixture as obtained from step (b) and draining the extra solution from the UF membrane for 5 to 30 minutes;
(d) again dipping the coated membrane obtained from step (c) in 0.1-1% solution of triacyl halide in hexane for a time period of 1 to 5 minutes ^ and draining the extra solution for 1 to 5 minutes;
(e) drying the membrane as obtained from step (d) for a time period of 1 to 4 hours;
(f) heating the membrane as obtained from step (e) for a time period of 1 to 15 minutes at a temperature in the range of 700C to 1000C, followed. by cooling and air drying for 1 to 2 hours; and
(g) soaking the membrane as obtained from step (f) in deionized water up to 24 hours to obtain enantioselective composite membrane comprising an enantioselective layer on the ultrafilteration membrane and testing it for separation of amino acids from their aqueous solution.
2. The method as claimed in claim 1, wherein the enantioselective layer of the composite membrane is having thickness in the range of 400 to 16OθA.
3. The method as claimed in claim 1, wherein amino acid or mixture of amino acids used is selected from the group consisting of at least two primary amino groups.
4. The method as claimed in claim 1, wherein the enantioselective layer of composite membrane is of cross linked poly amide polymer having at least one chiral carbon atom.
5. The method as claimed in claim l(b), wherein polyfunctional amine used is selected from metaphenylene diamine, piperizine and acid acceptor used is selected from triethyl amine or NaOH.
6. The method as claimed in claim l(d), wherein polyfunetional triacyl halide used is trimesoyl chloride.
7. The method as claimed in claim 1, wherein the ultrafiltration membrane usedv for preparation of composite membrane is selected from the group consisting of polysulfone, polyethersulfone, and polyvinylidienefluoride having thickness in the range of 20~60 μ m.
8. The method as claimed in claims 1, wherein enantioselective composite membrane separates 50-70% arginine and 80-90% lysine from aqueous solution.
9. The method for enantioseparation of racemic mixture of amino acids, using the enantioselective composite membrane, obtained by the process as claimed in claim 1, wherein said process is carried out on a reverse osmosis membrane testing unit at trans membrane pressure ranging between 345 to 862 K Pa, using aqueous and/or buffered solution of amino acids in the range of 0.1 to 1% as feed at flow rate in the range of 300 to 800 ml per minute.
0. The method as claimed in claims 9, wherein the concentration of amino acids in permeate was determined by UV-Vis spectrophotometer and the ratio of d and 1- enantiomers in permeate was estimated on HPLC fitted with PDA deteetor, by using Chiral column.
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WO2013118148A1 (en) * 2012-02-06 2013-08-15 Council Of Scientific & Industrial Research "l-enantiomers selective membrane for optical resolution of alpha-amino acids and process for the preparation thereof"
CN103357279A (en) * 2013-07-30 2013-10-23 云南师范大学 Teicoplanin chiral conposite membrane and its application in separation of D,L-p-hydroxyphenylglycine racemates
CN103357279B (en) * 2013-07-30 2015-09-30 云南师范大学 Teicoplanin chiral composite membrane and the application in D, L-D-pHPG racemate resolution thereof
EP3329986A4 (en) * 2015-07-31 2019-04-03 Toray Industries, Inc. Separation membrane, separation membrane element, water purifier and method for producing separation membrane
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CZ308513B6 (en) * 2019-03-24 2020-10-14 Ústav Chemických Procesů Av Čr, V. V. I. Composite chiral membrane, preparation method and methods of enrichment of mixtures of enantiomers

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