WO2017222402A1 - Polymère de polybenzimidazole à chaîne d'espacement fonctionnalisée et son procédé de préparation pour l'élimination d'impuretés génotoxiques - Google Patents

Polymère de polybenzimidazole à chaîne d'espacement fonctionnalisée et son procédé de préparation pour l'élimination d'impuretés génotoxiques Download PDF

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WO2017222402A1
WO2017222402A1 PCT/PT2017/000008 PT2017000008W WO2017222402A1 WO 2017222402 A1 WO2017222402 A1 WO 2017222402A1 PT 2017000008 W PT2017000008 W PT 2017000008W WO 2017222402 A1 WO2017222402 A1 WO 2017222402A1
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polymer
adenine
solution
gti
reaction
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Frederico CASTELO ALVES FERREIRA
Teresa Sofia ARAÚJO ESTEVES
Ana Isabel FERREIRA FRANCO VICENTE
Carlos Alberto Mateus Afonso
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FACULDADE DE FARMACIA DA UNIVERSIDADE DE LISBOA
Universidade de Lisboa
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FACULDADE DE FARMACIA DA UNIVERSIDADE DE LISBOA
Universidade de Lisboa
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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
    • B01J20/264—Synthetic macromolecular compounds derived from different types of monomers, e.g. linear or branched copolymers, block copolymers, graft copolymers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
    • C08G73/06—Polycondensates having nitrogen-containing heterocyclic rings in the main chain of the macromolecule
    • C08G73/18—Polybenzimidazoles
    • 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
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3202—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the carrier, support or substrate used for impregnation or coating
    • B01J20/3206—Organic carriers, supports or substrates
    • B01J20/3208—Polymeric carriers, supports or substrates
    • 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
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3214—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the method for obtaining this coating or impregnating
    • B01J20/3217—Resulting in a chemical bond between the coating or impregnating layer and the carrier, support or substrate, e.g. a covalent bond
    • B01J20/3219—Resulting in a chemical bond between the coating or impregnating layer and the carrier, support or substrate, e.g. a covalent bond involving a particular spacer or linking group, e.g. for attaching an active group
    • 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
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
    • B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
    • B01J20/3244—Non-macromolecular compounds
    • B01J20/3246—Non-macromolecular compounds having a well defined chemical structure
    • 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
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
    • B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
    • B01J20/3268—Macromolecular compounds
    • B01J20/3272—Polymers obtained by reactions otherwise than involving only carbon to carbon unsaturated bonds
    • B01J20/3274—Proteins, nucleic acids, polysaccharides, antibodies or antigens

Definitions

  • the present invention relates to a polybenziinidazoie (FBI) polymer with a functionalized spacer chain and its structural functional ization method with deoxyribonucleic acid (DNA) bases, namely adenine, thymine, cytosine or guanine, or carboxyiic acid groups (-COOK; ,
  • FBI polybenziinidazoie
  • GTI genotoxic impurities
  • GTIs typically are elect rophi lie species that either- formed during the manufacturing process of the API or generated in vivo may chemically attack the nucleophilic centers present in the DNA molecule and may induce single- or double-strand breaks and damages whose repair mechanisms may not be able to reverse. Ail these anomalies compromise the DNA replication process, which may lead to genetic mutations, implying an increased risk to the health of the patients to whom the API is administered [A. Teasdale et al. Org. Process Res. Dev. 17 (2013) 221-230].
  • the aromatic amine- type compounds constitute another group of GTIs, which although not Inherently genotoxic, during their metabolization in vivo, give rise to electrophilic species. Generally, when they undergo oxidation, N-hydroxy1 compounds are formed which are conjugated as acetates, sulfates or glucuronides . Further deconj ugation of these compounds results in nitrenium ions (ArN*H) , which are considered active genotox.i.ns that bind to DMA [D. J. Snodin, Org. Process Res. Dev. 14 (2010) 960- 976] .
  • the polymeric material used in this invention is a linear polybenzimidazole (PBI) polymer belonging to a class of heterocyclic polymers, the structure of which is shown in Figure 1.
  • the FBI is a polymer compatible with most organic solvents, with accessible functional! zable groups.
  • Modification of PBI with a ONA base is intended to mimic the interaction occurring in vivo between a GTI, for example of the sulfonate type (electrophilic species), and DNA (nucleophiiic centers) .
  • the final material obtained due to its robustness and versatility, allows it to be exploited as a highly specific adsorbent material for the GTI class, in particular the suiphonate fami ly .
  • the polymer modified with -COOH groups allows the selective elimination of GTI from the aromatic amine family.
  • the removal of electrophilic species is ensured, which would result from the in vivo raetabolization of these aromatic compounds , if they were present in the API when administered to the patient.
  • the functionalization chemistry of the PBI polymer has been exploited to obtain highly cross-linked PBI membranes by reaction of the polymer -with dihaiogenated compounds at reflux (80°C) in acetonitriie (MeCN) to give them greater physical robustness in the formulation of membranes for nanof.titration resistant to organic solvents, for example [I. B . Vaitcheva et al . , J. Membrane Sci. 457 (2014) 62-72; I. B. Vaitcheva et al. , J . Membrane Sci. 493 (2015) 568- 579] .
  • US 2012035333&1 document discloses a method for obtaining PBI with carboxyl groups by reaction of the polyraer with cyclic acid anhydrides. In this way a polymer with amide groups directly attached to the PBI rings and to the free carboxylic acid groups is obtained.
  • a halogenated carboxylic acid with a spacer chain there is no amide bond formation and the carboxylic acid function is separated from the structural backbone of the PBI by two carbon atoms or more. This aspect is important to avoid stereochemical impediments that could hinder the binding to the GTIs that are intended to be removed.
  • the relevance of the present invention is that it is possible to modify the structure of the relatively inert PBI polymer to contain a DNA base or a carboxylic acid type functionality by means of a spacer chain between the nitrogen from the imidazole rings of PBI and the new chemical functionality inserted.
  • this spacer chain presents a great advantage, since it facilitates the interaction between the functional groups present in the adsorbent material and the GTI, in which the latter can present several spatial geometries, more or less bulky. In this way, the adsorbent presents a great versatility against several geometries of the different GTI molecules.
  • the present invention relates to a poiybenzimidazole polymer with a functionalized spacer chain and its structural functionalization method with DNA bases or carboxylic acids, chemically compatible with organic solvents, to be applied in the removal of genotoxic impurities.
  • the invention focuses on obtaining a material, which establishes specific interactions with genotoxic impurities of various chemical families, to be exploited as a selective adsorbent thereof.
  • the present invention relates to a poiybenzimidazole polymer with a functionalized spacer chain and its structural functional ization method with deoxyribonucleic acid.
  • (DNA) bases namely adenine, thymine, cytosine or guanine, or carboxylic acid groups.
  • Poiybenzimidazole polymer with functionalized spacer chain general formula of poiybenzimidazole polymer functionalized with a spacer chain R and functional group 2 , R represents a spacer chain composed of aromatic or aliphatic hydrocarbons containing from 2 to 11 carbon atoms and 2 represents a DNA base, or a carboxylic acid group.
  • the present invention relates to a polybenz imidazole polymer with a functionalized spacer chain and its structural functionaiization method with DMA bases or carboxylic acids, chemically compatible with organic solvents, to be applied in the removal of genotoxic impurities.
  • the invention focuses on obtaining a material, which establishes specific interactions with genotoxic impurities of various chemical families, to be exploited as a selective adsorbent, thereof.
  • the present invention relates to a polybenzimidazole polymer with a functionalized. spacer chain and a structural functionaiization method with deoxyribonucleic acid (DNA) bases, namely adenine, thymine, cytosine or guanine, or carboxylic acid groups.
  • DNA deoxyribonucleic acid
  • the spacer chain is composed of aromatic or aliphatic hydrocarbons containing from 2 to 11 carbon atoms.
  • the most nucleophilic positions of the DNA bases are known to be the endocyclic nitrogens of the N3 and N7 positions of guanine and adenine. These sites are preferably reactive to the presence of eiectrophilic species, such as su1 fonate type GT I .
  • the functional ization of the P3I polymer of the present invention results in obtaining a specific material for binding to certain genotoxic impurities, allowing the elimination thereof and consequently the production of active pharmaceutical, ingredients with high purity.
  • genotoxic impurities refer to families of compounds of the sulfonate or aromatic amine type .
  • the method of obtaining the polybenz imidazole polymer with the functional! zed spacer chain is a versatile method, in that it can be included in an industrial process, in particular the pharmaceutical industry, for elimination or reduction of levels of genotoxic impurities. It may also be included in any synthesis based industry, which exploits compounds structurally similar to GTIs, for their disposal of the respective final products.
  • step b) Addition to the solution obtained in step b) of a base at atmospheric pressure;
  • step d) Addition of the haiogenated compound obtained in step a) to the solution, obtained in step cj at atmospheric pressure ;
  • X will have to be a good leaving group, selected from: F, CI, Br, 1; and R may be a chain with aromatic groups of the type ⁇ R-Ph-R 5 or a linear chain containing from 2 to 11 carbon atoms.
  • the DNA molecule with a spacer chain which in the present invention by way of example, relates to the 9- (3- bromopropy1 ⁇ adenine compound, is described in the literature being obtained in yields between 8% and 38% (N . J . Leonard et al., J. Org, Chem. 34 (1969) 3240-3243; WO 2013151663] .
  • yields between 8% and 38% (N . J . Leonard et al., J. Org, Chem. 34 (1969) 3240-3243; WO 2013151663] .
  • For these low yield values contribute the formation of by-products, such as the adenine-R-adenine dimer and a tricyclic derivative.
  • the present invention further describes the synthesis of this compound, the optimization of which allowed it to be obtained in a yield higher than 60%.
  • the development of this synthesis has been achieved iteratively by introducing a set of innovations described below and allowing improved performance of a synthesis which is not. trivial.
  • the step of obtaining an aromatic or aliphatic hydrocarbon compound containing at its ends a halogen atom and a DNA base, or a carboxylic acid group comprises the following steps:
  • step b) Reaction of the solution obtained in step b) at room temperature, up to a period of 16 hours, obtaining the final solution;
  • step f) Purification by column chromatography of the solid obtained in step f) with a DCM/MeOH mixture.
  • the modified adenine base with a bromine atom at its end was incorporated into the PBI polymer. Briefly, the polymer is dissolved in dimethylsulfoxide (DMSO) at 100 °C to 180°C, and thereafter a basic compound is added, in this case the base (KsCCb) , to deprotonate the nitrogen atoms of the imidazole rings of the polymer, and finally the DNA base is added (e.g. modified adenine, In this nuclecphilic
  • substitution compounds of the type HX e.g. HBr
  • substitution compounds of the type HX e.g. HBr
  • the bond between the DNA base (i.e. adenine) and the PBI takes place by the spacer chain present in the first, as shown schematically in Figure 4,
  • the PBI initial solution concentration was increased to 15% and left stirring for 3 hours at 170 °C to achieve complete solubilization of the polymer. After this time, the mixture was allowed to cool to room temperature and 2. eq. of K 2 CG 3 and 1 eq. of S- ( 3 -bromopropyl ) adenine were added. At this stage, the mixture presented itself as a viscous gel that hindered the efficient homogeni zation of the reactionai mixture. For this reason, it was necessary to increase the temperature to 50°C and left stirring for 24 hours at this temperature. At the end of the reaction water (40 mL) was added giving a solid in the form of small particles which was washed multiple times with water and then dried under vacuum .
  • This polymer ⁇ 50 ing was placed in contact with 1 ruL of GTI solution at a concentration of 100 ppro in DCM at room temperature for 24 hours and the percentage of GTI bound to the polymer was quantified at the end. of this time. With this polymer, a preliminary GTI binding value of 14% was obtained. Based on this result, we tried to optimize the reaction using 3 eq. of sodium hydroxide (NaOH) to replace K 2 CO 3 . In this case a final product of high hardness was obtained, impossible to be processed for use in the GTI removal trials. In a further approach, to the 15% PBI solution was added
  • the PBI polymer can be solubilized in a suitable solvent including DMSO, dymethylacetami.de ( DMAc ) , dimethyl formamide (DMF) or N ⁇ methyI-2 ⁇ pyrrolidone (NMP) .
  • a suitable solvent including DMSO, dymethylacetami.de ( DMAc ) , dimethyl formamide (DMF) or N ⁇ methyI-2 ⁇ pyrrolidone (NMP) .
  • DMAc dymethylacetami.de
  • DMF dimethyl formamide
  • NMP N ⁇ methyI-2 ⁇ pyrrolidone
  • K2CO3 can be used for this purpose.
  • the DNA base may contain a spacer chain composed of an aromatic and/or aliphatic hydrocarbon containing from 2 to 11 carbon atoms, with a terminal halogenated function.
  • the DNA molecule with a spacer chain [adenine- (R) -X] , wherein R is independently selected from aromatic and/or aliphatic hydrocarbon chains containing up to 11 carbon atoms, and X is selected from the following: F, Ci, Br or I.
  • the residue obtained was purified by CC using DCM/MeOH 10:1 (v/v) as eluent and 0.55 g of a white solid were obtained in 61% yield.
  • the product was characterized by i H and 13 C nuclear magnetic resonance (NMR) using a Bruker 300 MHz spectrometer for the *H.
  • a PBI solution was prepared in a 25 mL round-bottom flask by solubilizing 2 g of p.oly-2, 2' - (m-phenylene) -5, 5' - bibenzimidazole ⁇ commercially available) in 1.3 ml, of DMSO.
  • a magnetic stirrer was introduced and a reflux condenser was coupled.
  • the system was heated and stirred at atmospheric pressure up to 3 hours in a temperature range of 10Q ⁇ 18G°C. After, the mixture was cooled to about 5Q°C ana 1 eq. of was added.
  • a PBI solution is prepared in a 25 rnL round-bottom flask by solubilizing 2 g of
  • bibenzimidazole (commercially available) in 13 mL of DMSO.
  • a magnetic stirrer is introduced and a reflux condenser is coupled.
  • the system is heated and stirred at atmospheric pressure up to 3 hours in a temperature range of 1G0-180°C.
  • the mixture is cooled to about 50°C and 1 eq. of K 2 C0 3 (1.7 g, 12.5 mmoi; is added followed by the addition of 0,25 eq. of 1- (3- broraopropyl ) thymine (3.2 mmoi, 0.79 g) and the mixture is left stirring for 24 hours at a temperature between 100°C to 150°C.
  • the polymer is separated from the mother liquor by filtration with a 3G porous plate funnel.
  • the solid obtained is allowed to air dry or under reduced pressure .
  • the final product is characterized by MMR in DM30 -de and can be compared with the one obtained for the initial PBI in the same deuterated solvent, represented in Figure 6.
  • ft P31 solution is prepared in a 25 mL round-bottom flask by solubilizing 2 g of poiy-2, 2' - (.m-phenyiene) -5, 5' - bifoenziraidazole (commercially available) in. 13 mL of DMSO.
  • a magnetic stirrer is introduced and a reflux condenser is coupled.
  • the system is heated and stirred at. atmospheric pressure up to 3 hours in a temperature range of 100-180oC.
  • the mixture is cooled to about 50°C and 1 eq. of K2CO3 (1.7 g, 12.5 mmoi) is added followed by the addition of Q.25 eq.
  • the solution is filtered and applied the same procedure using SO mL of OC ' M.
  • the solid is filtered and dried to obtain the final polymer. Between each wash lug the polymer is separated from trie mother liquor t>y filtration with a 3G porous plate funnel. The solid, obtained is allowed to air dry or under reduced pressure.
  • the final product is characterized by d; N.MR in DdiC-o. and can be compared with the one obtained for the initial PBI, in the same deaterated solvent represented in Figure 6.
  • a oh I solution was prepared in a 25 ml, round-bot t om flask by solufoilising 2 g. of poIy-2, 2' - (m-pheny iene ) -5, 5 ' - bifoenzimidazole (commercially available) in 13 mX of DlxiSO, To the rouna-bo r. torn flask a magnetic stirrer was introduced and a reflux condenser was coupled. The system was beared and stirred at atmospheric pressure up to 3 hours in a temperature range of 100-180 °C . After, the mixture was cooled to about 50°C and .1. eq. of R:iCCb ( 1.
  • a PBI solution was prepared in a 25 mL round-bottom flask by solubilizing 2 g of
  • a PBI solution was prepared in a 25 mL round-bottom flask by solubilizing 2 g of
  • the solution was filtered aod applied the same procedure using 80 mX of OCH.
  • the solid. Vae filtered, and dried to obtain the final polymer. Between each washing the polymer was separated from the mother liquor, by filtration with a 3G porous plate funnel.. The collected solid was dried under vacuum.
  • the final product was characterized by 1 H NflR in XgfSO-de and the spectrum is represented in Figure 10.
  • example Z 4- (dimethylanino)pyridine a representative compound of the aromatic amine type GTIs, was used,
  • the GTI binding percentage was deterinined by difference between the initial concentration and the equilibrium, concentration present in. the resulting test solution according to the equation: wherein Co (mg/L) is the initial concentration of GTI and C e (mg/L) is the equilibrium concentration, of GTI in solution.
  • the adsorption capacity of each polymer was determined according to the following equation: wherein. is the amount of GTI bound to the polymer,
  • V (L) is the volume of solution used
  • M (g) is the mass of polymer used in the test.
  • binding to GTI ranged from 591-87%.
  • the polymer obtained .in example 1.2 was used.
  • the GTI used was methyl metnanesulfonate (MMS) , a compound belonging to the sulfonate type GTIs.

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  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)

Abstract

L'invention concerne un polymère de polybenzimidazole à chaîne d'espacement fonctionnalisée, selon la formule générale (I) et son procédé de préparation, avec des bases d'acide désoxyribonucléique ou des acides carboxyliques, chimiquement compatibles avec des solvants organiques, à appliquer dans l'elimination d'impuretés génotoxiques. En particulier, l'invention se concentre sur l'obtention d'un matériau, qui établit des interactions spécifiques avec des impuretés génotoxiques de diverses familles chimiques, à exploiter en tant qu'adsorbant sélectif.
PCT/PT2017/000008 2016-06-22 2017-05-11 Polymère de polybenzimidazole à chaîne d'espacement fonctionnalisée et son procédé de préparation pour l'élimination d'impuretés génotoxiques Ceased WO2017222402A1 (fr)

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PT109480 2016-06-22
PT109480A PT109480B (pt) 2016-06-22 2016-06-22 Polímero de polibenzimidazolo com cadeia espaçadora funcionalizada e seu método de obtenção para remoção de impurezas genotóxicas

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115326937A (zh) * 2021-05-11 2022-11-11 山东省食品药品检验研究院 一种基因毒杂质捕捉用固相探针及其使用方法与应用

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US20120035333A1 (en) 2010-08-04 2012-02-09 Chang Gung University Carboxylic polybenzimidazole
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US4814400A (en) 1987-04-13 1989-03-21 Hoechst Celanese Corporation Polybenzimidazole ester and carboxylic acid
US7259230B2 (en) 2004-06-07 2007-08-21 Battelle Energy Alliance, Llc Polybenzimidazole compounds, polymeric media, and methods of post-polymerization modifications
US8129498B2 (en) 2004-06-07 2012-03-06 Battelle Energy Alliance, Llc Polymeric medium
US20120035333A1 (en) 2010-08-04 2012-02-09 Chang Gung University Carboxylic polybenzimidazole
WO2012035556A1 (fr) * 2010-09-14 2012-03-22 Council Of Scientific & Industrial Research Polybenzimidazole quaternisé
US20130344567A1 (en) * 2010-12-30 2013-12-26 Lfb Biotechnologies Method for immobilising nucleic ligands
WO2013151663A1 (fr) 2012-04-02 2013-10-10 modeRNA Therapeutics Polynucléotides modifiés pour la production de protéines membranaires

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"Food and Drug Administration, Center for Drug Evaluation and Research (CDER", December 2008, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, article "Guidance for Industry Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches"
A. TEASDALE ET AL., ORG. PROCESS RES. DEV, vol. 17, 2013, pages 221 - 230
A. TEASDALE ET AL., ORG. PROCESS RES. DEV., vol. 14, 2010, pages 999 - 1007
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