WO2013087237A1 - Purification de sevelamer et de polyallylamines associées - Google Patents

Purification de sevelamer et de polyallylamines associées Download PDF

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Publication number
WO2013087237A1
WO2013087237A1 PCT/EP2012/066472 EP2012066472W WO2013087237A1 WO 2013087237 A1 WO2013087237 A1 WO 2013087237A1 EP 2012066472 W EP2012066472 W EP 2012066472W WO 2013087237 A1 WO2013087237 A1 WO 2013087237A1
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WO
WIPO (PCT)
Prior art keywords
allylamine
sevelamer
content
polyallylamine
process according
Prior art date
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PCT/EP2012/066472
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English (en)
Inventor
Marijn BUURMAN
Dongyuan WANG
Guy J.C. BAUW
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Synthon Bv
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Publication date
Application filed by Synthon Bv filed Critical Synthon Bv
Priority to EP12753466.7A priority Critical patent/EP2791227A1/fr
Publication of WO2013087237A1 publication Critical patent/WO2013087237A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00—Use of organic ingredients
    • C08K5/16—Nitrogen-containing compounds
    • C08K5/17—Amines; Quaternary ammonium compounds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K7/00—Use of ingredients characterised by shape
    • C08K7/02—Fibres or whiskers
    • C08K7/04—Fibres or whiskers inorganic
    • C08K7/14—Glass

Definitions

  • Sevelamer is a non-absorbed phosphate binding polymer used in the treatment for the control of serum phosphorus in patients with Chronic Kidney Disease (CKD). It is a polymer of poly(allylamine) crosslinked with epichlorohydrin. Its chemical structure is as follows:
  • the compound contains multiple amines that become partially protonated in the intestine and interact with phosphate ions through ionic and hydrogen bonding.
  • phosphate ions By binding phosphate in the gastrointestinal tract facilitating phosphorus excretion in feces, sevelamer lowers the plasma phosphorus concentration.
  • Sevelamer may form acid addition salts, in which a part of the amine groups has been neutralized by an acid ion.
  • sevelamer is marketed as sevelamer carbonate (Renvela®) or sevelamer hydrochloride.
  • poly(allylamine hydrochloride) of relatively high molecular weight (around 15 000) is prepared by polymerization of allylamine in concentrated HC1 using a suitable initiator of polymerization such as azobis(amidinopropane) dihydrochloride.
  • the polyallylamine polymer reacts with epichlorohydrin in alkalinized water.
  • the formed gel is solidified in isopropanol, washed and dried to form the final product as a granular solid.
  • a product of low allylamine content may be obtained by lowering the content of allylamine in the starting polyallylamine to the sufficient extent and/or by purification of the crude sevelamer.
  • US 5667775 discloses a process for reducing the allylamine content in poly(allylamine hydrochloride) by precipitation in methanol and repeated washing of the poly(allylamine hydrochloride) with methanol.
  • the purification is not efficient as the polymer is produced in a granulated mass in which the allylamine is easily entrapped. Consequently, the amount of methanol necessary to purify 1 kg of poly(allylamine hydrochloride) in the first step is around 80 kg, which is undesirable in respect of cost of goods, environment, etc.
  • WO 01/18072 discloses a process in which the produced poly(allylamine
  • JP 63-286405 describes a process for purifying poly(allylamine hydrochloride) containing 9.93% unreacted monomers by using electrodialysis using ion-exchanging membranes and 1% sodium chloride aqueous solution at 16- 17V for 1.5h to give a product containing 0.3% monomers.
  • the present invention relates to a process of separation of a crosslinked polyallylamine from allylamine and, consequently, to a process of determination of the content of the allylamine in the crosslinked polyallylamine.
  • the invention provides a process of decreasing the content of allylamine in a crosslinked polyallylamine, preferably in a polyallylamine crosslinked by epichlorohydrin, comprising a step of treating, under agitation, the crosslinked
  • the buffer is a borate buffer, preferably of a concentration of between 1 and 50 mM, most preferably between 5 and 25 mM.
  • the time of treating is from 10 to 40 hours, preferably from 20 to 30 hours.
  • the above step is followed by a step of separation of the solid material from the liquid phase, preferably at ambient temperature.
  • the above process provides a crosslinked polyallylamine with a content of residual allylamine of less than 5 ppm.
  • the liquid phase is subjected to a step of determination of the content of residual allylamine by a suitable analytical method.
  • the invention provides a process of determination of the content of residual allylamine in a crosslinked polyallylamine comprising the steps of
  • the buffer is a borate buffer, preferably of a concentration of between 1 and 50 mM, most preferably 5 and 25 mM.
  • the temperature of treating is higher than 80°C, typically between 90 and 105°C.
  • the time of treating is from 10 to 40 hours, preferably from 20 to 30 hours.
  • the analytical method is a HPLC method.
  • the objective of the invention is to provide a process of separating a crosslinked polyallylamine from the residual unreacted allylamine, which results in decreasing the content of the allylamine in the polyallylamine.
  • the crosslinked polyallylamine is a polyallylamine crosslinked by epichlorohydrin such as sevelamer and/or a salt of sevelamer such as sevelamer hydrochloride or carbonate.
  • the process may serve both for the purification of the crosslinked polyallylamine polymer from the residual allylamine and for the determination of the content of the residual allylamine in the polymer as well.
  • the process of the present invention which will be disclosed in more detail below, is very effective in that it may decrease the content of residual allylamine in the crude water insoluble crosslinked polyallylamine such as sevelamer and/or sevelamer carbonate to a content below 20 ppm, and is relatively simple. In certain aspects, it may provide a crosslinked polyallylamine with a content of residual allylamine of less than 5 ppm.
  • the effectivity of the process is so high that this process may even serve as a part of a process of analyzing the content of residual allylamine in the substrate comprising crosslinked polyallylamine, as the allylamine present in the substrate (in the analytical sample) may be removed essentially quantitatively and reliably and thus the result of measurement of the content of the removed allylamine may be regarded as an accurate reflection of its actual presence in the tested sample of the substrate.
  • the crosslinked polyallylamine may be prepared by a crosslinking of polyallylamine by a suitable crosslinking agent.
  • a suitable crosslinking agent Some useful crosslinking agents have been disclosed, e.g., in US 4,504,640.
  • the crosslinking agent is epichlorohydrin.
  • the starting polyallylamine has molecular weight of between 7000 and 20000.
  • the processes for making it are well known in the art. For instance, the polyallylamine may be prepared by
  • polymerization of allylamine in concentrated HC1 using azobis(amidinopropane) dihydrochloride may be precipitated by adding methanol and isolated by filtration.
  • Poly(allylamine hydrochloride) may be optionally neutralized by a suitable alkali to obtain polyallylamine free base.
  • the content of the residual allylamine in the polyallylamine may be decreased to a certain extent by any of the purification processes disclosed in the prior art and outlined above.
  • Such purification process should preferably provide a purified polyallylamine with a content of residual allylamine lower than 500 ppm, preferably lower than 100 ppm.
  • the polyallylamine, in an aqueous solution may be advantageously subjected to a process of partial distillation at alkaline conditions, preferably under reduced pressure, wherein the volatile allylamine may be removed within the distillate.
  • the distillation residue which is a concentrated alkaline aqueous phase comprising the polyallylamine and corresponding to 40-80% of the original volume, may be then used for the next crosslinking step.
  • the distillation process is performed with aqueous solutions having pH from 8.0 to 13.5, the distillation temperature is between 40 and 90°C and the vacuum degree is lower than 250 mm Hg.
  • the crosslinked polyallylamine is typically a sevelamer polymer, i.e. a polyallylamine crosslinked by epichlorohydrin.
  • the "sevelamer” polymer also comprises salts of sevelamer, such as sevelamer hydrochloride or carbonate. It should be understood that “salts of sevelamer” also comprise sevelamer products, in which only a part of amino-groups has been neutralized by acid anions. Typically, 10-25% of the amino-groups are present in the salt form in currently marketed sevelamer products.
  • Sevelamer is typically manufactured by crosslinking (using epichlorohydrin, advantageously in an amount of 5-12 % by weight) a partially neutralized solution of poly (allylamine hydrochloride) to give an insoluble gel (sevelamer hydrochloride).
  • a partially neutralized solution of poly (allylamine hydrochloride) to give an insoluble gel (sevelamer hydrochloride).
  • the sevelamer hydrochloride is treated with strong base to generate sevelamer free base, which is washed with water.
  • the free base suspension in water is reacted with a carbonate salt or with carbon dioxide to give sevelamer carbonate, the product is then dried to give sevelamer carbonate powder.
  • the process of the present invention is based on a surprising finding that the content of residual allylamine in a crosslinked polyallylamine such as sevelamer or sevelamer salt, preferably hydrochloride or carbonate (the "substrate") may be substantially decreased by treating the substrate with an aqueous buffer of pH higher than 5.0, preferably between 5.0 and 9.0 at a temperature higher than 80°C, preferably between 90 and 105°C, under agitation. Under these conditions the allylamine is essentially quantitatively extracted into the liquid phase and may be simply separated from the solid crosslinked polyallylamine within the liquid phase by a filtration.
  • a crosslinked polyallylamine such as sevelamer or sevelamer salt, preferably hydrochloride or carbonate
  • the selection of pH of the buffer and temperature in the extraction process of the present invention is a result of a study of efficacy of the above extraction process on crosslinked polyallylamine substrates comprising various known amount of allylamine (from about 10 ppm to about 1500 ppm).
  • the substrates comprised sevelamer carbonate. It was found out that the efficacy of extraction by stirring with the extraction liquid depended on the temperature and at a temperature higher than 80°C, typically between 90 and 105°C and particularly at a temperature close to 100°C, the efficacy of extraction raised in some cases to a quantitative yield.
  • the effectivity of the extraction was also found dependent on the pH of the extraction liquid. At pH below 5.0, the efficacy of the extraction was less than 90% even after prolonged treatment at 99 °C, probably due to yet effective ionic binding of allylamine in polymer network. The highest efficacy of the process, which in some aspects exceeds 98%, was observed during treatment with an aqueous buffer of pH higher than 5.0, typically between 5.0 and 9.0.
  • the buffer is a borate buffer, but the invention is not limited thereto.
  • the borate buffer may comprise also a solution of boric acid in water.
  • the concentration (ionic strength) of the buffer is advantageously from 1 to 50 mM, preferably from 5 to 25 mM, most preferably about 10 mM.
  • the inventive process of decreasing the content of allylamine from a substrate comprising crosslinked polyallylamine, in particular the polyallylamine crosslinked by epichlorohydrin accordingly comprises a step of treating, under agitation, the substrate with an aqueous buffer of pH higher than 5.0, preferably between 5.0 and 9.0, at a temperature higher than 80°C, preferably between 90 and 105°C.
  • the above extraction step is followed by a step of separation of the solid from the liquid phase, preferably at ambient temperature.
  • the separation may be typically performed by filtration or centrifugation.
  • the separated polymer may be further treated with a source of the desired salt ion, for instance with a chloride or carbonate salt, to obtain a salt of the crosslinked polymer.
  • a crosslinked polyallylamine product with reduced content of allylamine is thereby obtained in a simple process.
  • a crosslinked polyallylamine such as sevelamer or sevelamer hydrochloride and/or carbonate with the content of residual allylamine of less than 5 ppm and in some aspects even less than 2 ppm may be obtained. If the above extraction and separation steps do not provide the desired level of allylamine content, they may be repeated until the desired level is obtained.
  • the extraction process by a buffer of pH higher than 5.0 may be used in a process of determination of content of residual allylamine in a sample comprising crosslinked polyallylamine.
  • This process is important particularly in making sevelamer or sevelamer hydrochloride and/or carbonate of pharmaceutical quality, where the content of residual allylamine must be very low and controlled by a reliable analytical method.
  • the extraction process of the present invention may serve in a preparation of an allylamine-comprising sample for the process of determination of content of residual allylamine in a crosslinked polyallylamine polymer.
  • the extraction process disclosed above provides, apart from the crosslinked polyallylamine substrate essentially free from allylamine, an aqueous solution comprising essentially the entire original amount of allylamine present in the starting material.
  • This solution may be subjected to a suitable method of determination of the content of allylamine and the amount of allylamine in the original sample may be then easily calculated.
  • the efficacy of the extraction is in some aspects higher than 98% thus the amount of allylamine found in the aqueous solution is essentially identical with the original amount of residual allylamine in the polyallylamine polymer sample.
  • the present invention also provides a process of determination of the content of allylamine in a crosslinked polyallylamine sample comprising the steps of
  • the crosslinked polyallylamine is sevelamer and/or a salt of sevelamer, such as sevelamer hydrochloride or sevelamer carbonate.
  • a sample of the crosslinked polyallylamine product to be analyzed which may advantageously be sevelamer and/or sevelamer hydrochloride and/or sevelamer carbonate, may be stirred in a milligram amount (typically 5 to 100 mg) in a flask comprising several milliliters (typically 1-10 ml) of the buffer at a selected temperature for a suitable time, which advantageously is from 10 to 40 hours, preferably form 20 to 30 hours.
  • the temperature of treating is higher than 80°C, typically between 90 and 105°C. At this temperature, the efficacy of the extraction process may reach more than 95%, at certain aspect more than 98%.
  • the buffer is advantageously a borate buffer, preferably of a concentration of between 1 to 50 mM, most preferably between 5 and 25 mM.
  • the extraction is advantageously performed in a closed vial or under reflux cooler.
  • the separation step provides a liquid sample comprising allylamine, which is not contaminated by the solid.
  • the liquid may be separated by filtration or
  • centrifugation and may be optionally diluted by water to desired volume.
  • the separation may be only partial, i.e. the solid is allowed to sediment either spontaneously or in a centrifuge and a sample of the supernatant is taken for analysis.
  • the sevelamer extract can be analyzed by any appropriate analytical method developed in the art for separation and quantification of allylamine, or of aliphatic amines or amino acids. In principle any chromatographic or electrophoretic separation technique used for the analysis of amino acids, amines or their derivatives can be used.
  • the allylamine in the sample may be subjected to a derivatization to provide a derivative with better detectability, e.g. by increased absorbance, or by fluorescence.
  • the process of the present invention also comprises a step of treating the liquid sample comprising allylamine with a derivatization agent.
  • a suitable derivatization agent may be, e.g., 6-Aminoquinolyl-N- hydroxysuccinimidyl carbonate (AccQ-TagTM, Waters), fluorenylmethylchloroformate (FMOC), dimethylamino-naphthalensulphonyl chloride (Dansyl-Cl), phenylisothiocyanate (PITC), ortho-phthaldialdehyde, etc.
  • AccQ-TagTM 6-Aminoquinolyl-N- hydroxysuccinimidyl carbonate
  • FMOC fluorenylmethylchloroformate
  • Dansyl-Cl dimethylamino-naphthalensulphonyl chloride
  • PITC phenylisothiocyanate
  • ortho-phthaldialdehyde etc.
  • an HPLC method after a derivatization of allylamine in the sample prepared by the above process of the invention is the most useful method for determining the content of the residual allylamine.
  • Proper stationary and mobile phase may be determined by experimentation; in general, chromatographic columns useful for analyses of amino acids and their derivatives may be used.
  • allylamine may be ion chromatography, gas chromatography or capillary electrophoresis, performed eventually in combination with derivatization.
  • the useful analytical method should have a limit of detection of 0.1 ppm or lower.
  • the processes of determination of the content of allylamine according to the present invention may be used for the analysis of a sample of sevelamer hydrochloride or carbonate for use in pharmaceutical applications.
  • the sample of the sevelamer hydrochloride or carbonate may be a sample of the active substance per se or a sample or the final pharmaceutical composition comprising sevelamer hydrochloride or carbonate, for instance a tablet or a powder for oral suspension.
  • the present invention provides a novel use of a buffer, preferably a borate buffer, of pH higher than 5.0, preferably between 5.0 and 9.0, for purification of crosslinked polyallylamine and/or for making samples for the determination of content of residual allylamine in a crosslinked polyallylamine.
  • a buffer preferably a borate buffer, of pH higher than 5.0, preferably between 5.0 and 9.0, for purification of crosslinked polyallylamine and/or for making samples for the determination of content of residual allylamine in a crosslinked polyallylamine.
  • AccQ-Tag reagent 6-aminoquinolyl-N- hydroxysuccinimidyl carbamate
  • acetonitrile aqueous acetonitrile
  • Appropriate amount of the extract from the extraction process step (by preference ⁇ 0 ⁇ L ⁇ o ⁇ 30 ⁇ L ⁇ (the latter when there are low amounts of allylamine present)) is mixed with 70 ⁇ L ⁇ of AccQ-tag Ultra Borate buffer in an appropriate vial.
  • 70 ⁇ L ⁇ of the dissolved AccQ-Tag reagent is added, mixed immediately and then placed for 5 minutes at 55 °C.
  • the derivatized extract is ready for HPLC analysis. Analysis

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Solid-Sorbent Or Filter-Aiding Compositions (AREA)

Abstract

La présente invention concerne un procédé de séparation d'une polyallylamine réticulée d'une allylamine et, par conséquent, un procédé de détermination de la teneur en allylamine dans la polyallylamine réticulée.
PCT/EP2012/066472 2011-12-13 2012-08-24 Purification de sevelamer et de polyallylamines associées WO2013087237A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP12753466.7A EP2791227A1 (fr) 2011-12-13 2012-08-24 Purification de sevelamer et de polyallylamines associées

Applications Claiming Priority (2)

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EPPCT/EP2011/072604 2011-12-13
EP2011072604 2011-12-13

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Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4504640A (en) 1982-05-19 1985-03-12 Nitto Boseki Co., Ltd. Process for producing monoallylamine polymer
JPS63286405A (ja) 1987-05-20 1988-11-24 Nitto Boseki Co Ltd カチオン性水溶性重合体の精製方法
US5496545A (en) 1993-08-11 1996-03-05 Geltex Pharmaceuticals, Inc. Phosphate-binding polymers for oral administration
US5667775A (en) 1993-08-11 1997-09-16 Geltex Pharmaceuticals, Inc. Phosphate-binding polymers for oral administration
WO2001018072A1 (fr) 1999-09-03 2001-03-15 The Dow Chemical Company Procede de preparation de polymere polyallylamine reticule
WO2008005217A2 (fr) * 2006-07-05 2008-01-10 Genzyme Corporation Traitements contenant du fer(ii) pour l'hyperphosphatémie
US20090155368A1 (en) * 2007-12-14 2009-06-18 Genzyme Corporation Pharmaceutical compositions
WO2010041274A2 (fr) * 2008-10-07 2010-04-15 Shasun Chemicals And Drugs Limited Procédé de préparation de sels de carbonate de polymères d’amine réticulés
WO2011099038A2 (fr) * 2010-02-15 2011-08-18 Sun Pharmaceutical Industries Limited Procédé de préparation d'un polymère d'allylamine réticulé
WO2011106542A2 (fr) * 2010-02-24 2011-09-01 Relypsa, Inc. Polyvinylamine, polyallylamine et polyéthylèneimine réticulées pour l'utilisation comme séquestrants de l'acide biliaire

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4504640A (en) 1982-05-19 1985-03-12 Nitto Boseki Co., Ltd. Process for producing monoallylamine polymer
JPS63286405A (ja) 1987-05-20 1988-11-24 Nitto Boseki Co Ltd カチオン性水溶性重合体の精製方法
EP1676581A2 (fr) 1993-08-11 2006-07-05 Genzyme Corporation Polymère à utilisation thérapeutique
US5496545A (en) 1993-08-11 1996-03-05 Geltex Pharmaceuticals, Inc. Phosphate-binding polymers for oral administration
EP0716606A1 (fr) 1993-08-11 1996-06-19 Geltex Pharmaceuticals, Inc. Polymeres fixant les phosphates pour administration orale
US5667775A (en) 1993-08-11 1997-09-16 Geltex Pharmaceuticals, Inc. Phosphate-binding polymers for oral administration
EP1133989A2 (fr) 1993-08-11 2001-09-19 Geltex Pharmaceuticals, Inc. Polymère à utilisation thérapeutique
EP0831857A2 (fr) 1995-06-06 1998-04-01 Geltex Pharmaceuticals, Inc. Polymeres de liaison du phosphate pour administration par voie orale
WO2001018072A1 (fr) 1999-09-03 2001-03-15 The Dow Chemical Company Procede de preparation de polymere polyallylamine reticule
WO2008005217A2 (fr) * 2006-07-05 2008-01-10 Genzyme Corporation Traitements contenant du fer(ii) pour l'hyperphosphatémie
US20090155368A1 (en) * 2007-12-14 2009-06-18 Genzyme Corporation Pharmaceutical compositions
WO2010041274A2 (fr) * 2008-10-07 2010-04-15 Shasun Chemicals And Drugs Limited Procédé de préparation de sels de carbonate de polymères d’amine réticulés
WO2011099038A2 (fr) * 2010-02-15 2011-08-18 Sun Pharmaceutical Industries Limited Procédé de préparation d'un polymère d'allylamine réticulé
WO2011106542A2 (fr) * 2010-02-24 2011-09-01 Relypsa, Inc. Polyvinylamine, polyallylamine et polyéthylèneimine réticulées pour l'utilisation comme séquestrants de l'acide biliaire

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