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WO2018211389A1 - Polymères à empreinte moléculaire pour l'adsorption sélective d'urée pour la dialyse - Google Patents

Polymères à empreinte moléculaire pour l'adsorption sélective d'urée pour la dialyse Download PDF

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Publication number
WO2018211389A1
WO2018211389A1 PCT/IB2018/053308 IB2018053308W WO2018211389A1 WO 2018211389 A1 WO2018211389 A1 WO 2018211389A1 IB 2018053308 W IB2018053308 W IB 2018053308W WO 2018211389 A1 WO2018211389 A1 WO 2018211389A1
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Prior art keywords
urea
adsorbent
alkene
dialysate
molecularly imprinted
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PCT/IB2018/053308
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English (en)
Inventor
Dmytro TYMOSHENKO
Kalsang THARPA
Mahabala Panyam Subramanya SHASTRY
Sudha TANTRY
Ramesha GANGANAHALLI
Ranjith CHOORIKKAT
Suryajois Channarayapatna GURUNATH
Jinto JOSE
Arun Kumar
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Sabic Global Technologies B.V.
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Publication of WO2018211389A1 publication Critical patent/WO2018211389A1/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
    • B01J20/26—Synthetic macromolecular compounds
    • B01J20/261—Synthetic macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
    • B01J20/26—Synthetic macromolecular compounds
    • B01J20/265—Synthetic macromolecular compounds modified or post-treated polymers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
    • B01J20/26—Synthetic macromolecular compounds
    • B01J20/268—Polymers created by use of a template, e.g. molecularly imprinted polymers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28002—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their physical properties
    • B01J20/28011—Other properties, e.g. density, crush strength
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/305—Addition of material, later completely removed, e.g. as result of heat treatment, leaching or washing, e.g. for forming pores
    • B01J20/3057—Use of a templating or imprinting material ; filling pores of a substrate or matrix followed by the removal of the substrate or matrix

Definitions

  • the invention generally concerns molecular imprinted polymers (MIPs) that can be used as urea adsorbents.
  • MIPs molecular imprinted polymers
  • the MIPs of the present invention can have a plurality of urea recognition sites imprinted in a polymerized matrix that includes an alkene monomer crosslinked with a multi-alkene molecule.
  • Hemodialysis is a process by which toxins and other molecules, such as urea, are removed from the blood.
  • the hemodialysis processes can be generally classified as: (1) single pass or (2) sorbent-based.
  • Single pass methods for dialysis can use a dialyzer.
  • the dialyzer can have a large number of semi-permeable hollow fibers bundled together and placed in a cylindrical jacket.
  • the patient' s blood is pumped through the interior of semi-permeable fibers and a dialysate (an aqueous solution) is pumped in a counter-flow direction exterior to the semi- permeable fibers.
  • the toxins within the blood are removed from the blood via a combination of diffusion, convection, and osmosis processes while the blood is flowing within the fibers and the dialysate is flowing outside the fibers.
  • Sorbent dialysis differs from single pass dialysis in that the dialysate is regenerated using a series of adsorbents, chemical powders, or matrices to remove toxins or other molecules from the dialysate.
  • spent dialysate from the dialyzer is pumped through a layer of urease. Urease catalyzes the breakdown of urea into ammonia and carbon dioxide.
  • the dialysate is then pass through a cation exchange layer (e.g., zirconium phosphate) which adsorbs ammonia and other positively charged ions and then through an anion exchange layer (e.g., hydrous zirconium oxide) where anions such as phosphate and fluoride are adsorbed.
  • a cation exchange layer e.g., zirconium phosphate
  • an anion exchange layer e.g., hydrous zirconium oxide
  • anions such as phosphate and fluoride are adsorbed.
  • ammonia and carbon dioxide products result in a lowering of blood pH.
  • the dialysate is finally pumped through an activated carbon where organic metabolites such as creatinine are adsorbed.
  • the filtered dialysate may be passed through a degasser to remove air, carbon dioxide and other gas bubbles that may form or be found in the dialysate.
  • urea binding materials are known.
  • One such material uses methyl acrylic acid and acrylic acid as monomers to form a urea-molecular imprinted polymer (MTP) as a urea detector for water and serum samples, but not for use in conjunction with a dialyzer ⁇ Analytica Chimica Acta, 2010, 669:94-101).
  • MTP urea-molecular imprinted polymer
  • Another assay uses chitosan, a self-assembled solid phase material for binding urea to assay for urea in blood samples ⁇ Analytical Letters, 2014, 47: 1063- 78). None of the reported urea-MTP use dialysate buffer as an adsorbate medium.
  • the discovery is premised on the creation and use of a selective polymeric urea adsorbent to regenerate a dialysate.
  • the selective polymeric urea adsorbent of the present invention can be used in place of urease beds and the like, avoiding the ammonia and carbon dioxide products and their adverse effects on blood chemistry.
  • the urea adsorbent of the present invention can be a molecularly imprinted polymer (M P) having a plurality of urea recognition sites imprinted in a polymerized matrix.
  • the polymerized matrix can be the reaction product of an alkene monomer crosslinked with a multi-alkene molecule. Without wishing to be bound by theory, it is believed that this combination of monomers can be used to produce a MIP that is both efficient at adsorbing urea from a fluid ⁇ e.g., dialysate buffer) without producing excess ammonia or carbon dioxide in the process.
  • a urea adsorbent comprising a molecularly imprinted polymer (MIP) having a plurality of urea recognition sites imprinted in a polymerized matrix, the polymerized matrix comprising an alkene monomer crosslinked with a multi-alkene molecule.
  • MIP molecularly imprinted polymer
  • An alkene compound is a compound having one or more carbon- carbon double bonds that can undergo a polymerization reaction.
  • a multi-alkenealkene molecule (a molecule having two or more alkene groups) can be used (e.g., CH3-(CH 2 )C-CO-0-CH2-CH2-0-CO-C(CH 2 )-CH3; (CH 2 )C-C 6 H4- C(CH 2 ); CH3-CH2-C-[CH 2 -0-CO-C(CH 2 )-CH3]3)).
  • the alkene monomer is allylamine.
  • the adsorbent can further comprise a support. In certain aspects the adsorbent has a urea binding capacity of 10 to 50 mg/g. In particular aspects the adsorbent is a non-enzymatic urea-binding adsorbent.
  • Certain embodiments of the present invention can include a dialysis cartridge or a dialyzer comprising a urea adsorbent material of the present invention.
  • the adsorbent is configured as a membrane or a solid bed.
  • the solid bed is a fine powder, monolith, or nano-fiber bed.
  • a method of making a urea adsorbent can comprise (a) mixing urea with an alkene monomer at a molar ratio of l :n, wherein n is 1 to 10 forming a first mixture; (b) adding a multi-alkene molecule at a ratio of first mixture to a multi-alkene molecule ratio of 1 :n, where n is 1 to 10, forming a matrix precursor; (c) adding a cross linking reagent to the matrix precursor forming a pre- polymerization mixture; (d) exposing the pre-polymerization mixture to polymerization conditions forming a molecularly imprinted polymer/urea complex; and (e) extracting the urea from the molecularly imprinted polymer/urea complex forming a molecularly imprinted polymerized urea adsorbent (urea-MIP).
  • urea-MIP molecularly imprinted polymerized urea adsorbent
  • urea is extracted using a hot solvent wash and/or reflux.
  • urea is extracted using a Soxhlet extractor.
  • the molecularly imprinted polymer/urea complex can be crushed or ground prior to extraction.
  • the polymerization conditions include exposure to heat and/or UV irradiation.
  • Certain embodiments of the present invention are directed to methods of reducing the amount of urea in a fluid comprising passing a urea-containing fluid through and/or over a urea adsorbent of the present invention. This can result in a processed fluid stream having a reduced amount of urea.
  • the fluid can be a dialysate.
  • the processed dialysate can be recycled to a dialyzer.
  • wt.% refers to a weight, volume, or molar percentage of a component, respectively, based on the total weight, the total volume of material, or total moles, that includes the component.
  • 10 grams of component in 100 grams of the material is 10 wt.% of component.
  • FIG. 1 Illustration of a first scheme (scheme-1) for synthesis of a molecularly imprinted polymer of the present invention using class-I and class-Ill monomers.
  • FIG. 2. Illustration of a second scheme (scheme-2) for synthesis of molecularly imprinted polymer using class-II monomer.
  • FIG. 3. Illustration of an example of an application of urea-MIP of the present invention.
  • FIG. 4 Illustration of class I, class II, and class III alkene monomers that can be used to make the M Ps of the present invention.
  • a typical dialysis patient generates an excess of about 24 to about 60 grams of urea per day that must be removed from the blood to avoid uremia.
  • An adsorbent having the capacity to remove this quantity of urea in a reasonable time frame would be beneficial and improve the dialysis process.
  • the urea adsorbent of the present invention can meet and/or exceed this capacity and can be used in dialysis applications while avoiding the creation of excess ammonia or carbon dioxide seen with existing dialysis materials.
  • inventions are not intended to refer to any particular embodiment or otherwise limit the scope of the disclosure. Although one or more of these embodiments may be preferred, the embodiments disclosed should not be interpreted, or otherwise used, as limiting the scope of the disclosure, including the claims.
  • discussion has broad application, and the discussion of any embodiment is meant only to be an example of that embodiment, and not intended to intimate that the scope of the disclosure, including the claims, is limited to that embodiment.
  • Each embodiment can be used alternatively or optionally will all embodiments disclosed herein.
  • M P molecularly imprinted polymer
  • a molecularly imprinted polymer is a polymer that is formed in the presence of a template or target analyte molecule producing a complementary cavity in the polymer when the template or target analyte is removed. Once the target is removed the MIP demonstrates affinity for the original template target analyte. Most MIP materials are based on non-covalent interactions, most notably hydrogen bonding or electrostatic forces.
  • Embodiments of the current invention are directed to a cross-linked molecularly imprinted polymer (MIP) that binds urea (urea-MIP) present in a source material, e.g., a dialysate, employing cross-linked alkene monomers forming selective binding sites for urea.
  • MIP cross-linked molecularly imprinted polymer
  • urea-MIP urea-MIP
  • the urea-MIP can be used for separating or removing urea from a source material.
  • the urea-MIPs described herein demonstrate a high selectivity/specificity towards urea.
  • This urea-MIP can be fabricated into solid phase adsorbents or membranes for selective removal of urea from various fluids or compositions.
  • Some of the features of the urea-MIP include (a) a urea-MIP based adsorbent can be used to perform artificial dialysis without generation of ammonia and carbon dioxide into a recycled blood, i.e., it can be non-catalytic, (b) a urea-MIP adsorbent can withstand moderately high temperatures and wide Ph range; and
  • a urea-MIP adsorbent can be rejuvenated and re-cycled multiple times.
  • M Ps molecularly imprinted polymers
  • the alkene monomer(s) possesses the ability to be incorporated into a polymer by having a polymerizable group or an appropriate reactive functional group.
  • the alkene monomer has chemical groups that bind to the urea and form a three-dimensional structure. In certain aspect the chemical groups form hydrogen bonds with the urea molecule.
  • a crosslinker can be used to hold the structure in place after the target molecule (also called a "template”, “analyte” or “taggant”) is removed. Once removed, the polymerized/crosslinked alkene monomers remain fixed in place to form cavities which are specifically sized and oriented to receive urea.
  • a goal in making a molecularly imprinted polymer is to use an imprinting complex that will survive the polymerization process and leave behind a selective binding site when the target is removed from the imprinting complex.
  • alkene monomers must be chosen that exhibit sufficiently high affinities to resist dissociation.
  • the polymerization process must provide sufficient rigidity to effect structural "memory" but be sufficiently flexible to allow removal of the target.
  • molecularly imprinted polymer and "MTP” as used herein refer to a polymer structure that includes complexing molecules or ligands that are imprinted to selectively bind to target, e.g., urea (urea-MIP).
  • the polymer structure has organized interactive moieties complementary to the spacing of binding sites on the target.
  • Interactive moieties can include functional groups or ligands.
  • the geometrical organization of the interactive moieties imparts selective binding characteristics for the target within the molecularly imprinted polymer.
  • Molecular imprinting creates specific recognition sites in materials, such as polymeric materials.
  • Molecular imprinting techniques involve crosslinking materials in the presence of a functional monomer or mixture of monomers.
  • the template molecule or target interacts with a complementary portion of a functional monomer, either covalently or by other interactions such as ionic, hydrophobic or hydrogen bonding, so that recognition sites for the template molecule can be provided in the substrate material.
  • the template molecule is then removed from the substrate to leave a "cavity" or recognition site. This process is known as “molecular imprinting” or “templating.”
  • the target or template molecule which is urea in the current invention, directs the positioning of the encapsulating molecule by the interactions that occur between certain sites on the target and complementary sites on the binding molecule.
  • the sites that allow complementary associations are certain arrangements of atoms that exhibit an attraction of a specific kind. These localized atomic arrangements are sometimes referred to as "functional groups.”
  • the functional groups on a molecule help to define the molecule's overall chemical properties. In general, the MIP should exhibit as closely as possible the reverse topology of the template molecule.
  • the cross-linked molecularly imprinted polymers (MIPs) of the present invention are made using alkene monomers. Examples of such monomers are provided in FIG. 4. Referring to FIG.
  • a class- 1 alkene monomer CH 3 -C(CH 2 )-CO-OR
  • a multi-alkene molecule a molecule having two or more allyl groups, can be, for example CH 3 -(CH 2 )C-CO-0-CH2-CH 2 - 0-CO-C(CH 2 )-CH 3 ; (CH 2 )C-C6H4-C(CH 2 ); CH 3 -CH 2 -C-[CH 2 -0-CO-C(CH 2 )-CH 3 ] 3 ).
  • the alkene monomer is allylamine.
  • hydroxyl refers to an -OH substituent.
  • esters refers to a -COOR substituent, where R is any substituted or unsubstituted aliphatic, aromatic, heteroaromatic or aliphatic-aromatic group.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a linear (i.e. unbranched) or branched carbon chain, which may be fully saturated, mono- or polyunsaturated.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • Saturated alkyl groups include those having one or more carbon-carbon double bonds (alkenyl) and those having one or more carbon-carbon triple bonds (alkynyl).
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a linear or branched chain having at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, S, P, and Si.
  • the heteroatoms are selected from the group consisting of O and N.
  • the heteroatom(s) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Up to two heteroatoms may be consecutive.
  • heteroalkyl groups trifluoromethyl, - CH 2 F, -CH 2 C1, -CH 2 Br, -CH 2 OH, -CH 2 OCH 3 , -CH 2 OCH 2 CF 3 , -CH 2 OC(0)CH 3 , -CH 2 H 2 , - CH 2 HCH 3 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 C1, -CH 2 CH 2 OH, CH 2 CH 2 OC(0)CH 3 , -CH 2 CH 2 HC0 2 C(CH 3 ) 3 , and -CH 2 Si(CH 3 ) 3 .
  • alkoxy means a group having the structure -OR', where R' is an optionally substituted alkyl or cycloalkyl group.
  • heteroalkoxy similarly means a group having the structure -OR, where R is a heteroalkyl or heterocyclyl.
  • amino means a group having the structure -NR'R", where R' and R" are independently hydrogen or an optionally substituted alkyl, heteroalkyl, cycloalkyl, or heterocyclyl group.
  • amino includes primary, secondary, and tertiary amines.
  • cycloalkyl and heterocyclyl by themselves or in combination with other terms, means cyclic versions of “alkyl” and “heteroalkyl,” respectively. Additionally, for heterocyclyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • aryl means a polyunsaturated, aromatic, hydrocarbon substituent.
  • Aryl groups can be monocyclic or polycyclic (e.g., 2 to 3 rings that are fused together or linked covalently).
  • heteroaryl refers to an aryl group that contains one to four heteroatoms selected from N, O, and S. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
  • Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2- imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5- benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinoly
  • alicyclic means a moiety comprising a non-aromatic ring structure. Alicyclic moieties may be saturated or partially unsaturated with one, two or more double or triple bonds.
  • alicyclic moiety may also be referred to as "cyclic aliphatic moiety” and includes both monocyclic and spirocyclic structures.
  • the main chain of the cyclic hydrocarbon moiety may, unless otherwise stated, be of any length and contain any number of non-aromatic cyclic and chain elements. Typically, the hydrocarbon (main) chain includes 3, 4, 5, 6, 7 or 8 main chain atoms in one cycle.
  • alicyclic benzimidazole means a moiety comprising at least an "alicyclic moiety” and a “benzimidazole group”.
  • binding refers to the physical phenomenon of chemical species being held together by attraction of atoms to each other through sharing, as well as exchanging, of electrons or protons. This term includes bond types such as: ionic, coordinate, hydrogen bonds, covalent, polar covalent, or coordinate covalent.
  • crosslinking agent will be dictated by the chemical (hydrophilicity, chemical stability, degree of cross-linking, ability to graft to other surfaces, interactions with other molecules, etc.) and physical (porosity, morphology, mechanical stability, etc.) properties desired for the polymer.
  • the crosslinking agent is a multi-alkene molecule.
  • Multi-alkene molecules are molecules having two or more allyl groups, and can be, for example, CH3-(CH 2 )C-CO-0-CH2-CH2-0-CO-C(CH 2 )-CH3; (CH 2 )C-C 6 H 4 -C(CH 2 ); CH 3 -CH 2 -C-[CH 2 - 0-CO-C(CH 2 )-CH 3 ] 3 ).
  • the urea template molecules are incorporated into the cross-linked molecularly imprinted polymer prior to or during the crosslinking reaction.
  • the target molecule is removed from the cross-linked molecularly imprinted polymer. Removal of the urea template molecule leaves a cross-linked molecularly imprinted polymer having complementary molecular cavities that have specific binding affinity for urea.
  • the urea template molecule may be dissociated from the binding site within the polymer in a manner that does not adversely affect the imprinted cavity. For example, where the urea template molecule is associated with the complex in a non-covalent manner, the non-covalently bound molecule can leached or washed out after polymerization.
  • a process for preparing a cross-linked molecularly imprinted polymer of the present invention includes (a) providing a reaction product of alkene monomer(s) and a urea template molecule in an appropriate solvent; (b) crosslinking the reaction product of step (a) with a crosslinking agent; and (c) removing the urea template molecule to provide a cross-linked molecularly imprinted polymer comprising cross-linked alkene monomers having selective binding sites for urea.
  • Step (a) includes providing a reaction product of one or more alkene monomers and a urea template molecule in a solvent.
  • the amount of urea template molecule employed will range from mole ratio 1 to about 10.0 with respect to alkene monomer.
  • the process of the present invention employs one or more solvent which is intended to be non-reactive in order to prevent hydrogen bond formation between template-monomer, chain transfer and side reactions.
  • Desirable solvents of the present methods include polar/non- polar aprotic, or dipolar aprotic solvents.
  • Some desired solvents include acetonitrile, chloroform, dichloroethane, water, alcohol, or dipolar aprotic solvents, ethylene carbonate, propylene carbonate, ionic liquids, or a mixture thereof.
  • solvents may include: ethylene glycol, diethylene glycol, triethylene glycol, 2-(2-ethoxyethoxy)ethanol, tetraethylene glycol, glycerine, dimethylsulfoxide (“DMSO”), dimethylforamide (“DMF”), dimethylacetamide (“DMAc”), N-methyl-2-pyrrolidone (" MP”), ionic liquids, ethylene carbonate, and propylene carbonate.
  • Suitable alcohols include methanol, ethanol, propanol, isopropanol, butanol, and tert-butanol.
  • the solvent or solvent blend chosen does not cause precipitation of the polymer product during the reaction.
  • the solvent is acetonitrile, dimethylformate, ethylene carbonate, methanol, ethanol, propylene carbonate, water, dimethylformamide, propionitrile, ethylene glycol, an ionic liquid, or a combination thereof.
  • the amount of solvent employed in the reaction can range from about 10 mL to about 200 mL per gram of alkene monomer.
  • the pre-polymerization mixture are kept at sub-ambient temperature and purged with nitrogen to remove traces of oxygen. It is then sealed and kept for reaction at 60 °C for 12 hrs. alkene.
  • the polymer can be then cross-linked with a suitable crosslinking agent.
  • the cross-linking agents of this invention are co-monomers having at least two unsaturated bonds (hereinafter referred to as "polyunsaturated" monomers).
  • polyunsaturated monomers can be poly-acrylates ("poly" meaning two or more), -methacrylates, or -itaconates of: ethylene glycol, propylene glycol; di-, tri-, tetra-, or poly-ethylene glycol and propylene glycol; trimethylol propane, glycerine, erythritol, xylitol, pentaerythritol, dipentaerythritol, sorbitol, mannitol, glucose, sucrose, cellulose, hydroxyl cellulose, methyl cellulose, 1,2 or 1,3 propanediol, 1,3 or 1,4 butanediol, 1,6 hexanediol, 1,8 octanediol, cyclohexanediol, or cyclohexanetriol.
  • bis(acrylamido or methacrylamido) compounds can be used. These compounds are, for example, methylene bis(acryl or methacryl)amide, 1,2 dihydroxy ethylene bis(acryl or methacryl)amide, hexamethylene bis(acryl or methacryl)amide.
  • Another group of useful polyunsaturated monomers could be represented by di or poly vinyl esters, such as divinyl propylene urea, divinyl-oxalate, -malonate, -succinate, - glutamate, -adipate, -sebacate, -maleate, -fumerate, -citraconate, and -mesaconate.
  • di or poly vinyl esters such as divinyl propylene urea, divinyl-oxalate, -malonate, -succinate, - glutamate, -adipate, -sebacate, -maleate, -fumerate, -citraconate, and -mesaconate.
  • polyunsaturated monomers include divinyl benzene, divinyl toluene, diallyl tartrate, allyl pyruvate, allyl maleate, divinyl tartrate, triallyl melamine, N,N'-methylene bis acrylamide, glycerine dimethacrylate, glycerine trimethacrylate, diallyl maleate, divinyl ether, diallyl monoethyleneglycol citrate, ethyleneglycol vinyl allyl citrate, allyl vinyl maleate, diallyl itaconate, ethyleneglycol diester of itaconic acid, divinyl sulfone, hexahydro 1,3,5- triacryltriazine, triallyl phosphite, diallyl ether of benzene phosphonic acid, maleic anhydride triethylene glycol polyester, polyallyl sucrose, polyallyl glucose, sucrose diacrylate, glucose dimethacrylate, pentaerhr
  • Suitable polyunsaturated cross-linking monomers include ethylene glycol diacrylate, diallyl phthalate, trimethylolpropanetrimethacrylate, polyvinyl and polyallyl ethers of ethylene glycol, of glycerol, of pentaerythritol, of diethyleneglycol, of monothio- and dithio- derivatives of glycols, and of resorcinol; divinylketone, divinylsulfide, allyl acrylate, diallyl fumarate, diallyl succinate, diallyl carbonate, diallyl malonate, diallyl oxalate, diallyl adipate, diallyl sebacate, diallyl tartrate, diallyl silicate, triallyl tricarballylate, triallyl aconitrate, triallyl citrate, triallyl phosphate, divinyl naphthalene, divinylbenzene, trivinylbenzene; alky
  • acryl or methracryl end-capped siloxanes and polysiloxanes, methacryloyl end- capped urethanes, urethane acrylates of polysiloxane alcohols and bisphenol A bis methacrylate and ethoxylated bisphenol A bis methacrylate also are suitable as polyunsaturated monomers.
  • Still another group of polyunsaturated monomers is represented by di or poly vinyl ethers of ethylene, propylene, butylene, and the like, glycols, glycerine, penta erythritol, sorbitol, di or poly allyl compounds such as those based on glycols, glycerine, and the like, or combinations of vinyl allyl or vinyl acryloyl compounds such as vinyl methacrylate, vinyl acrylate, allyl methacrylate, allyl acrylate, methallyl methacrylate, or methallyl acrylate.
  • aromatic, cycloaliphatic and heterocyclic compounds are suitable for this invention.
  • crosslinking agents include multi-alkene molecules such as CH 3 -(CH 2 )C- CO-0-CH2-CH 2 -0-CO-C(CH2)-CH 3 ; (CH 2 )C-C6H4-C(CH 2 ); CH 3 -CH 2 -C-[CH 2 -0-CO- C(CH 2 )-CH 3 ] 3 ).
  • the weight percentage of cross-linker in the MIP compounds can ranges from about 1, 2, 5, 10, 15, 20, 25% to about 30, 35, 40, 45, 50%. In one embodiment, the weight percentage of cross-linking agent in the MIP compound is about 25% to about 35%.
  • a radical initiator may be employed during the crosslinking step.
  • Useful initiators include radical initiating compounds such as diazo compounds or peroxides. The polymerization of the alkene compounds is accelerated by means of well-known initiators which provide free redicals.
  • initiators include ozone; organic peroxidic agents typified by ozonides, peroxides such as acetyl peroxide, lauroyl peroxide, stearoyl peroxide, tertbutyl hydroperoxide, benzoyl peroxide, tert-butyl perbenzoate, di-tert, butyl diperphthalate, di-tert- butyl peroxide, and the barium salt of tert-butyl hydroperoxide; inorganic agents such as barium peroxide, sodium peroxide, hydrogen peroxide; and the so-called per" salts such as the water-soluble perborates, persulfates, and perchlorates.
  • organic peroxidic agents typified by ozonides, peroxides such as acetyl peroxide, lauroyl peroxide, stearoyl peroxide, tertbutyl hydroperoxide, benzoyl peroxide, tert-butyl
  • Preferred initiators are the azo initiators such as 2,2'-azobisisobutyronitlile and 2,2'-azobis (2,4-dimethylpentanenitrile).
  • the initiators are employed in suitable amounts ranging from 0.1 to about 2 percent based on the weight of the monomeric material to be polymerized.
  • the urea template molecule is removed from the cross-linked polymer to leave a polymer with complementary molecular cavities that have specific binding affinity for the target urea molecule with which the polymer was imprinted.
  • the target urea template molecule is removed from the cross-linked polymer by one or more washing steps with a suitable solvent(s).
  • the target urea template molecule can be removed from the cross-linked polymer by one or more washing steps using polar protic solvents or in presence of acids or overnight in a Soxhlet apparatus.
  • the resulting MIP may then be subjected to a drying step such as vacuum drying.
  • the molecularly imprinted polymer of the present invention can be prepared in a wide variety of forms ranging from powders to beads to macro structures such as plates, rods, membranes or other materials.
  • the molecularly imprinted polymer of the present invention is in the form of a fine powder.
  • the molecularly imprinted polymer of the present invention may have an average particle size less than 100 microns.
  • hemodialysis blood from the patient is circulated in an extracorporeal circuit into contact with one side of a semi-permeable membrane of a dialyzer, the other side being in contact with a dialysis fluid (dialysate). Substances are transferred over the membrane via diffusion and convection.
  • the spent dialysis fluid may be regenerated by adsorption of certain substances by an adsorption cartridge.
  • adsorption cartridges Most previously known adsorption cartridges use activated carbon for removal of many unwanted substances. However, activated carbon may be inefficient in adsorbing urea.
  • Urea-MIPs of the present invention can be used in conjunction with these dialysis methods and/or systems and apparatus for the adsorption of urea from a dialysate.
  • the current invention works on the principle of molecularly imprinted polymers for the binding of and sequestration urea.
  • scheme-1 which is illustrated in FIG. 1, the carbonyl and amino group of urea, which is use as template molecule, forms hydrogen bond with an allyl amino and an acrylate, respectively, of two separate monomers. Later, a two ended alkene compound (multi- alkene molecule) is used for crosslinking the monomers resulting in a rigid structure around the urea molecule.
  • Scheme-2 which is illustrated in FIG. 2, follows the same procedure as described in scheme-1 except that a 1,3-dicarbonyl based monomer is used. This has an advantage of using a 1 : 1 mole ratio of monomer to template molecule.
  • the resultant polymer is a urea-MIP that showed high selectivity/specificity towards urea.
  • This urea-MIP can be fabricated into solid phase adsorbents or membranes for selective removal of urea from diverse matrices (Scheme-3, FIG. 3).
  • Scheme-1 and Scheme-2 A 1 : 1 mole ratio of urea and alkene amine/-OH/-COOH/- COOCH3 were allowed to react under nitrogen atmosphere followed by addition of two moles of acrylate monomer (in scheme-1) and 1,3-dicarbonyl monomer (in scheme-2). The system is placed under ice bath for some time before adding cross linker and a catalytic amount of radical initiator. The resultant solution was sealed and exposed to heat or UV irradiation until a solid bulk polymer is formed. The polymer was crushed and template removed by soxhlet extraction. The characterization and performance characteristic of the polymer was done.
  • the urea-MIPs of the present invention can utilize two types of monomers that create a "lock and key" system within the MTP matrix. This lock and key system for urea is created by linking both amino and carbonyl moieties.

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  • Analytical Chemistry (AREA)
  • Organic Chemistry (AREA)
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  • Thermal Sciences (AREA)
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Abstract

Certains modes de réalisation de l'invention concernent un adsorbant d'urée comprenant un polymère à empreinte moléculaire (MIP) ayant une pluralité de sites de reconnaissance d'urée imprimés dans une matrice polymérisée, la matrice polymérisée comprenant un monomère alcène réticulé avec une molécule multi-alcène.
PCT/IB2018/053308 2017-05-15 2018-05-11 Polymères à empreinte moléculaire pour l'adsorption sélective d'urée pour la dialyse WO2018211389A1 (fr)

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US20200316563A1 (en) * 2019-04-02 2020-10-08 University Of Washington Molecularly imprinted polymers for removal of trimethylamine n-oxide
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US20200316563A1 (en) * 2019-04-02 2020-10-08 University Of Washington Molecularly imprinted polymers for removal of trimethylamine n-oxide
US11524275B2 (en) 2019-04-02 2022-12-13 University Of Washington Molecularly imprinted polymers for removal of trimethylamine N-oxide
US20230173459A1 (en) * 2019-04-02 2023-06-08 University Of Washington Molecularly imprinted polymers for removal of trimethylamine n-oxide
US11918718B2 (en) 2019-04-02 2024-03-05 University Of Washington Molecularly imprinted polymers for removal of trimethylamine N-oxide
US11331597B2 (en) 2019-08-05 2022-05-17 Fresenius Medical Care Holdings, Inc. Cation exchange materials for dialysis systems
CN111659347A (zh) * 2020-04-20 2020-09-15 北京西峰科技有限责任公司 一种用于尿素吸附的微孔活性炭及其制备方法和应用

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