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WO2012042542A1 - Procédé de préparation de polymère réticulé - Google Patents

Procédé de préparation de polymère réticulé Download PDF

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Publication number
WO2012042542A1
WO2012042542A1 PCT/IN2011/000683 IN2011000683W WO2012042542A1 WO 2012042542 A1 WO2012042542 A1 WO 2012042542A1 IN 2011000683 W IN2011000683 W IN 2011000683W WO 2012042542 A1 WO2012042542 A1 WO 2012042542A1
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Prior art keywords
polyallylamine
sevelamer
partially neutralized
salt
solution
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Inventor
Dhananjay Govind Sathe
Harish Kashinath Mondkar
Samadhan Daulat Patil
Tanaji Shamrao Jadhav
Atul Suresh Patil
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USV Pvt Ltd
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USV Pvt Ltd
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment

Definitions

  • the present invention relates to desalination/desalting of polymer, in particular polyallylamine/crosslinked polymers by membrane separation techniques. More particularly, the present invention relates to a process for removal of salt and low molecular weight compounds from polyallylamine or salts thereof, used for preparation of Poly(allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) or salt thereof, in particular Sevelamer hydrochloride or Sevelamer carbonate.
  • Sevelamer is a non-absorbable polymer marketed as Renagel ® /Renvela ® by Genzyme Corporation. It is known chemically as poly(allylamine-co-N,N'-diallyl- l,3-diamino-2-hydroxypropane). Sevelamer is a non-absorbed phosphate binding crosslinked polymer, free of metal and calcium. It contains multiple amines separated by one carbon from the polymer backbone. These amines exist in a protonated form in the intestine and interact with phosphate molecules through ionic and hydrogen bonding. By binding phosphate in the dietary tract and decreasing absorption, Sevelamer lowers the phosphate concentration in the serum.
  • US4605701 discloses process for preparing a cross-linked monoallylamine polymer. The method involves partially neutralizing polyallylamine hydrochloride followed by addition of epichlorohydrin and homogenization. The product obtained is subjected to multiple washings.
  • WO2006097942 discloses biphasic process for crosslinking partly neutralized aqueous polyallylamine hydrochloride using a crosslinking agent in a hydrocarbon solvent in presence of a dispersing agent to get a crosslinked polymer having a desired particle size range (60-100 mesh).
  • the process is carried out in such a manner that aqueous solution is partly neutralized with alkali, mixed with crosslinking agent and charged to an organic phase containing dispersing agent.
  • Crosslinking is carried out at a high temperature and at a high speed of 800 to 1200 rpm.
  • the crosslinked polymer is then isolated by filtration, followed by water washing to remove salts, followed by isopropyl alcohol (IPA) washing to remove water from the crosslinked polymer and finally drying under vacuum to obtain the desired crosslinked polyallylamine polymer.
  • IPA isopropyl alcohol
  • WO2008062437 discloses a process for preparation of Sevelamer hydrochloride having phosphate binding capacity in the range of about 4.7 mmol/gm to about 6.4 mmol/gm and chloride content in the range of about 4.5 to about 5.5 meq/gm which comprises the steps of; partially neutralizing polyallylamine hydrochloride using aqueous sodium hydroxide solution; the obtained partially neutralized polyallylamine hydrochloride is crosslinked with epichlorohydrin to provide Sevelamer hydrochloride. The obtained Sevelamer hydrochloride is subjected to multiple washings.
  • US6525113 describes a process for preparing crosslinked polyallylamine by mixing polyallylamine, water, a hydroxide or alkoxide and a water miscible organic solvent or co-solvent such as acetonitrile followed by the addition of crosslinking agent.
  • the product obtained is washed with distilled water and 70% aqueous isopropanol to obtain a final conductivity of 0.09 m Siemen/cm.
  • the prior art processes provide polyallylamine/crosslinked polymer with Residue on Ignition (ROI) content in the range of about 40 to 50%, which is not pharmaceutically acceptable.
  • Residue on Ignition (ROI) content preferably less than about 0.1%
  • Sevelamer has to washed several times with huge amounts of water, which is time consuming, tedious and not suitable on a commercial scale.
  • Sevelamer has a capacity to retain about 10 to 12 times of water and swells to at least 5 times the volume of the dried material.
  • Several washings of large quantity of cross-linked polyallylamine (Sevelamer) thus becomes tedious, costly and thus not commercially viable because handling large volume/quantity of polymer requires unusually large capacities of manufacturing equipments. This ultimately affects cost and resources such as usage of man hours and overheads on plant scale.
  • Washings have to be continued till the Residue on Ignition (ROI) content is less than about 0.1%.
  • Number of washings are increased on a commercial scale to achieve the desired product which requires more than 20 days [approximately about 100 kg batch] thereby making the process time consuming and not feasible commercially.
  • For output of 100 kg of material about 1000 to 1200 kg wet cake has to be handled each time which is very difficult commercially as after every washing, the swelled gel has to be transferred to reactor containing pure water for further washings. This process is continued till the Residue on Ignition becomes less than about 0.1 % .
  • US6787587 discloses a process for the production of low-molecular-weight allylamine polymer having a weight average molecular weight of 250 to 4,000 or an addition salt thereof, which comprises neutralizing with an alkali a polymerization solution containing said low molecular weight allylamine polymer to bring said allylamine polymer into a free state; then distilling said low-molecular-weight allylamine polymer solution containing an unreacted monoallylamine and a salt; thereby distilling off the unreacted monoallylamine; then subjecting the residue to electrodialysis; and optionally carrying out acid treatment to get low molecular weight allyl amine polymer having an ignition residue content of 5% by weight or less, which is not pharmaceutically acceptable. If such a polyallylamine is used for the preparation of crosslinked polymer, the final product has to be washed several times to achieve pharmaceutically acceptable product, which is tedious on a commercial scale.
  • US6180754 describes a process for partial neutralization of polyallylamine hydrochloride using ion exchange or electrodialysis to get polyallylamine hydrochloride with reduced salt content which is further subjected to ultrafiltration or nanofiltration to get low molecular weight impurity free aqueous solution of polyallylamine hydrochloride.
  • the solution with reduced salt content is flash evaporated, reconstituted and crosslinked in LIST reactor.
  • This patent further discloses a process for producing a crosslinked polyallylamine polymer comprising partially neutralizing an aqueous solution of polyallylamine hydrochloride polymer with sodium hydroxide; ultrafiltering the partially neutralized aqueous solution of polyallylamine polymer to give a reduced salt, aqueous solution of polyallylamine polymer; concentrating the reduced salt aqueous solution of polyallylamine polymer followed by reacting the reduced salt aqueous solution of polyallylamine polymer with a crosslinking agent to give a crosslinked polyallylamine polymer.
  • Ultrafiltration membranes used have a pore size ranging from 8 KD to 30 KD and the transmembrane pressure is about 3 to 5 bars.
  • HPLC Ion Chromatography PA method is used for the determination of Phosphate Binding Capacity of Sevelamer HC1. (J. R. Mazzeo et al, J. Pharm. Biomed. Anal. 19 (1999) 911-915)
  • the present invention provides a simple, efficient, quicker and cost effective commercial process for desalination/desalting of polymer to get the desired product substantially free from salts, in particular inorganic salt such as sodium chloride, which complies with the ICH requirements.
  • the main object of the present invention is to provide a desalination/desalting process for removing salts from partially neutralized polyallylamine or salts thereof using membrane separation technique, in particular a semi-permeable membrane having MWCO of 0.1 to 3 KD.
  • Another object of present invention is to provide an industrially viable process to provide polyallylamine/crosslinked polymer or salts thereof having Residue on Ignition (ROI) not more than about 0.1%.
  • ROI Residue on Ignition
  • Another object of the present invention is to provide a simple process for preparation of Sevelamer hydrochloride having phosphate binding capacity in the range of about 4.7 mmol/g to about 6.4 mmol/g, chloride content in the range of about 3.74 to about 5.60 meq/g, consistent degree of crosslinking from about 12% to about 18% and Residue on Ignition not more than about 0.1%.
  • step d) converting said partially neutralized polyallylamine salt solution obtained in step b) or step c) to crosslinked polyallylamine polymer.
  • the solution of polyallylamine salt is an aqueous solution.
  • the polyallylamine salt is polyallylamine hydrochloride or polyallylamine carbonate and partial neutralization is preferably carried out using an alkali.
  • the crosslinked polyallylamine polymer is selected from Sevelamer, Colesevelam or salts thereof.
  • the desalination/desalting is carried out by Tangential Flow Filtration or Dialysis.
  • the Tangential Flow Filtration is carried out using spiral wound membrane or filtration cassettes at room temperature and pressure of about 2 to 20 bars.
  • the Dialysis is carried out using a dialysis bag, against water at room temperature.
  • step c) reduction in step c) is carried out by either by increasing transmembrane pressure (TMP) in Tangential Flow Filtration or by distillation under vacuum.
  • TMP transmembrane pressure
  • Another aspect of the present invention provides conversion of partially neutralized aqueous polyallylamine salt to Sevelamer comprising the steps of,
  • isolated Sevelamer is Sevelamer hydrochloride which is further converted to Sevelamer carbonate or Colesevelam.
  • the alkali is sodium hydroxide or potassium hydroxide; dispersing agent is sorbitane trioleate; hydrocarbon is selected from toluene, xylene, ethyl benzene, chlorobenzene, nitrobenzene or mixture thereof; isolation in step d) is carried out by nutsching under suction or centrifuging to obtain a wet cake; and drying is carried out at temperature of 25 to 90°C using Fluidized Bed Dryer or Rotary evaporator or Vacuum Tray Dryer or Rotacone Vacuum Dryer.
  • Another aspect of the present invention provides polyallylamine polymer or crosslinked polymers having residue on ignition not more than about 0.1%.
  • Fig 1 Schematic Representation of Dialysis System.
  • Fig 2 Representation of a Tangential Flow Filtration (TFF) Unit.
  • Fig.3 Schematic Representation showing desalting/desalination of partially neutralized polyallylamine hydrochloride by Tangential Flow Filtration (TFF) process.
  • Fig.4 Graphical representation of Conductivity measurement of permeate collected at various intervals during Tangential Flow Filtration (TFF) process.
  • the present invention describes an industrial process for desalination/desalting of partially neutralized polyallylamine salt, in particular partially neutralized polyallylamine hydrochloride or polyallylamine carbonate comprising subjecting a solution containing partially neutralized polyallylamine salt, in particular partially neutralized polyallylamine hydrochloride or polyallylamine carbonate to membrane separation techniques to get partially neutralized polyallylamine salt having Residue on Ignition content not more than about 0.1%.
  • Polyallylamine is a homopolymer of allylamine monomer obtained by polymerization of allylamine or salt thereof using a radical initiator.
  • Polyallylamine and polyallylamine salts are highly soluble in water, which upon crosslinking with suitable crosslinking agents become water insoluble and forms a water swellable crosslinked polymer.
  • the crosslinked polymer, Sevelamer, being water swellable occupies large volume of at least about 5 times the volume of the dry material upon isolation from water and hence is difficult to operate at a commercial scale.
  • the crosslinked polymer (Sevelamer HC1) has to be repeatedly washed so as to obtain the desired Residue on Ignition, which is time consuming and tedious on a commercial scale.
  • salt in particular sodium chloride formed during partial neutralization of the polyallylamine salt, in particular polyallylamine hydrochloride
  • the final product in particular Sevelamer hydrochloride (Residue on Ignition in the range of about 40 to 50%).
  • Sevelamer hydrochloride Residue on Ignition in the range of about 40 to 50%.
  • Extensive experimentation has been carried out by the inventors of the present invention to find an efficient way to eliminate salts, in particular sodium chloride from polyallylamine/crosslinked polymer.
  • the inventors of the present invention have subjected the partially neutralized polyallylamine hydrochloride to membrane separation techniques to separate salts, in particular sodium chloride from partially neutralized polyallylamine hydrochloride to achieve Residue on Ignition not more than about 0.1%.
  • Sevelamer hydrochloride which does not require several washings of the final product.
  • the process for preparing Sevelamer hydrochloride according to the present invention involves desalination/desalting of partially neutralized polyallylamine or salt thereof at the intermediate stage thereby making the process efficient, quicker, economical and ecofriendly.
  • the process of the present invention brings down the need for washing of the final product which reduces the manufacturing time, minimizes the need for specialized equipments and minimizes the loss of the final product.
  • the process, according to the present invention is thus industrially and economically viable.
  • partially neutralized polyallylamine or salts thereof, obtained by neutralization is subjected to membrane separation technique, in particular using a semi-permeable membrane having MWCO of 0.1 to 3 KD for desalination/desalting.
  • membrane separation technique in particular using a semi-permeable membrane having MWCO of 0.1 to 3 KD for desalination/desalting.
  • the pore size of semipermeable membrane plays an important role in the separation process.
  • Desalination/Desalting of polymer refers to any of several processes that remove excess salt as well as other low molecular weights from the polymer. Desalination/Desalting can be done by known techniques such as ion exchange, membrane separation techniques, electrostatic separation and the like. Membrane separation techniques involve dialysis, microfiltration (MF), ultrafiltration (UF), nanofiltration (NF) and reverse osmosis (RO). Membrane filtration system can be either Direct filtration system or Tangential Flow Filtration system (also known as Crossflow filtration).
  • Dialysis is a separation technique that facilitates the removal of small, unwanted compounds from macromolecules in solution by selective and passive diffusion through a semi-permeable membrane.
  • small undesired molecules pass through a semi-permeable membrane, whilst molecule of interest remains inside the dialysis cell/bag.
  • Tangential Flow Filtration also referred to as Cross Flow Filtration (CFF)
  • CFF Cross Flow Filtration
  • TFF TFF
  • the solution that passes through the membrane is referred to as filtrate or permeate.
  • Molecules or particles larger than the membrane pores are retained in the feed solution and effectively concentrated.
  • TFF can be used to concentrate and desalt sample solutions ranging in volume from a few milliliters to thousands of liters.
  • the important components of TFF process are the membrane material, module format and the pore size of the membrane.
  • step b) subjecting said partially neutralized polyallylamine salt solution to desalination/desalting using semipermeable membrane having MWCO of 0.1 to 3KD to obtain partially neutralized polyallylamine salt solution substantially free of inorganic salt and/or low molecular weight compounds; c) optionally reducing the volume of partially neutralized polyallylamine salt solution obtained in step b); and
  • step d) converting said partially neutralized polyallylamine salt solution obtained in step b) or step c) to crosslinked polyallylamine polymer.
  • the solution of polyallylamine salt is an aqueous solution.
  • the polyallylamine salt is polyallylamine hydrochloride or polyallylamine carbonate and partial neutralization is preferably carried out using an alkali.
  • the crosslinked polyallylamine polymer is selected from Sevelamer, Colesevelam or salts thereof.
  • the process for preparation of partially neutralized polyallylamine salt comprises, loading an aqueous solution of partially neutralized polyallylamine salt, preferably polyallylamine hydrochloride in a 0.1 to 3 KD dialysis bag and dialyzing against water to remove inorganic salts/low molecular weight compounds, preferably sodium chloride from partially neutralized polyallylamine hydrochloride.
  • a bag (A) made up of semipermeable membrane is filled with a solution of partially neutralized polyallylamine salt (B), preferably polyallylamine hydrochloride and then placed in water (C).
  • the soluble particles such as inorganic salts/low molecular weight compounds (E) pass through the membrane (dialysis bag) and go into the water leaving behind partially neutralized polyallylamine salt, preferably polyallylamine hydrochloride substantially free of inorganic salts/low molecular weight compounds (D).
  • (F) in Fig. 1 represents stir bar and
  • (G) represents magnetic stirrer.
  • Dialysis bag most commonly used for laboratory dialysis are made of regenerated cellulose. Dialysis is carried out against water till dialyzed water shows negative for chloride test (Silver nitrate test/measuring conductivity of dialyzed water). In practice, water is changed 3 to 4 times and the process requires 3 to 5 hours for completion. Feed solution concentration of partially neutralized polyallylamine hydrochloride is about 30 to 35%.
  • excess water absorbed during dialysis is distilled out at 50-60° C under vacuum to maintain the original volume.
  • the process for preparation of partially neutralized polyallylamine salt comprises, subjecting an aqueous solution of partially neutralized polyallylamine salt, preferably polyallylamine hydrochloride to Tangential flow filtration by passing through 0.1 to 3 KD spiral wound membrane or filtration cassettes to remove inorganic salts/low molecular weight compounds, preferably sodium chloride from partially neutralized polyallylamine hydrochloride. This process is carried out till the permeate shows negative for chloride test (Silver nitrate test/measuring conductivity of permeate).
  • the process is repeated till the conductivity of the permeate is less than about 100 mSiemen/cm, preferably less than about 25 mSiemen/cm, more preferably less than about 10 mSiemen/cm, most preferably less than about 5 mSiemen/cm.
  • Spiral wound membrane or Filtration cassettes employed in Tangential flow filtration advantageously permits inorganic salts/low molecular weight compounds, preferably sodium chloride to pass on to the permeate side of the membrane.
  • the retentate is substantially free of inorganic salts/low molecular weight compounds.
  • membrane selected has a MWCO of 0.15 to 0.35 KD.
  • Spiral wound membrane is a thin film composite membrane made of polyether sulfone.
  • the membranes may be used either single or in series depending upon batch size. By using membranes in series, collective area increases which helps to achieve desalination within a short time. This is an effective technique to remove inorganic salts/low molecular weight compounds from the polymer.
  • the TFF process for removal of inorganic salts/low molecular weight compounds from the polymer is a continuous process and is as represented in Fig. 2. Three stages involved in the process are,
  • (B) in Fig. 2 represents pump.
  • the parameters for carrying out membrane filtration, according to the invention, are essentially a function of the system or membrane. Depending on the membrane type, the process is carried out at room temperature at a pressure of about 2 to 20 bars, preferably 2 to 17 bars. In practice, the process requires 3 to 10 hours for completion, preferably 3 to 7 hours, more preferably 3 to 5 hours. During the process, regular feeding of water is maintained depending upon rate of permeate coming out.
  • the present invention provides an extremely effective way to achieve the most efficient and cost effective means of removing inorganic salts/low molecular weight compounds from the polymer at intermediate stage thereby avoiding the time consuming water washings of the final product.
  • the volume of the aqueous solution of partially neutralized polyallylamine salt, obtained after desalination/desalting, is reduced using the membrane filtration technique itself, preferably by increasing transmembrane pressure (TMP) thereby avoiding the need for a separate concentration technique such as evaporation under vacuum.
  • TMP transmembrane pressure
  • Concentrated aqueous solution of partially neutralized polyallylamine hydrochloride is collected directly from the feed tank.
  • the excess water is removed from the partially neutralized aqueous polyallylamine salt, preferably polyallylamine hydrochloride solution obtained from desalination/desalting process by increasing the trans membrane pressure (TMP) in the TFF process or by distillation under vacuum.
  • TMP trans membrane pressure
  • Partially neutralized polyallylamine salt preferably polyallylamine hydrochloride having residue on ignition not more than about 0.1%
  • obtained according to the present invention can be converted to Sevelamer or salts thereof by the processes known in the art.
  • Another embodiment of the present invention provides conversion of partially neutralized polyallylamine salt to sevelamer comprising the steps of,
  • Sevelamer is in the form of Sevelamer hydrochloride or Sevelamer carbonate.
  • Alkali is selected from sodium hydroxide or potassium hydroxide.
  • Dispersing agent is selected from trioleate surfactants such as sorbitan trioleate.
  • Hydrocarbon is selected from toluene, xylene, ethyl benzene, chlorobenzene, nitrobenzene or mixture thereof.
  • Isolation in step d) is carried out by nutsching under suction or centrifuging to obtain a wet cake. Drying is carried out at a temperature of 25 to 90°C using Fluidized Bed Dryer (FBD), Air Tray Dryer, Rotacone Vacuum Dryer (RCVD), Vacuum Tray Dryer or rotary evaporator.
  • BFD Fluidized Bed Dryer
  • RCVD Rotacone Vacuum Dryer
  • Vacuum Tray Dryer or rotary evaporator Vacuum Tray Dryer or rotary evaporator.
  • step b) subjecting the obtained solution of step a) to Tangential flow filtration or Dialysis to get partially neutralized aqueous polyallylamine hydrochloride solution substantially free of inorganic salt/low molecular weight compounds, in particular sodium chloride;
  • step b) optionally, reducing the volume of partially neutralized aqueous polyallylamine hydrochloride solution obtained in step b);
  • step b) charging dispersing agent and hydrocarbon solvent to said partially neutralized aqueous polyallylamine hydrochloride solution of step b) or step c) to obtain a mixture;
  • Sevelamer obtained according to the process of the present invention has residue on ignition not more than about 0.1%.
  • Sevelamer hydrochloride obtained according to the present invention has chloride content from about 3.74 to about 5.60 meq/g, Phosphate Binding Capacity of about 4.7 to about 6.4 mmol/g, preferably 5.3 to 6.0 mmol/gm, consistent degree of crosslinking from about 12% to about 18% and residue on ignition of not more than about 0.1%.
  • Sevelamer hydrochloride obtained according to the present invention can be converted to Sevelamer carbonate or Colesevelam.
  • the desalting/desalination technique employed in the present invention can be used to remove the inorganic salt, in particular sodium chloride as well as other low molecular weight compounds from Polyallylamine, in particular polyallylamine hydrochloride/polyallylamine carbonate and crosslinked polymers.
  • the process of the present invention avoids large number of water washings required for removal of salt/low molecular weights.
  • Partially neutralized aqueous polyallylamine hydrochloride solution obtained after Tangential flow filtration does not require further volume reduction/concentration and can be used directly for crosslinking.
  • Membrane filtration cartridges having MWCO of 0.1 to 3 KD are used in the process of the present invention which minimizes the possibility of the material of interest passing on to the permeate side ultimately resulting in better yields at low cost.
  • Process of the present invention is ecofriendly, economical, plant compatible and requires less washings or no washing for removal of inorganic salt, in particular sodium chloride, which saves both time and cost.
  • Sevelamer includes Sevelamer base as well as pharmaceutically acceptable salts of Sevelamer such as hydrochloride, carbonate and the like.
  • Crosslinked polymer includes Sevelamer, Colesevelam and the like.
  • Polyallylamine includes Polyallylamine and salts thereof such as hydrochloride, carbonate and the like.
  • Membrane Filtration means pressure- or vacuum-driven separation process in which undesired molecules can be separated out using semipermeable membrane having a determined MWCO.
  • MWCO Molecular Weight Cutoff
  • TMP Transmembrane pressure
  • substantially free means Polyallylamine/Crosslinked polymer having less than about 0.5%, preferably less than about 0.3%, more preferably less than about 0.1%, most preferably less than about 0.05% of inorganic salt/low molecular weight compounds.
  • Allylamine (75 g) was added to hydrochloric acid (134.2 g) by maintaining the temperature 5 to 15°C.
  • the pH was adjusted to 1 to 2 and the solution was stirred for 30 min.
  • the recovery of acidic water at temp below 90°C was carried out under vacuum to get allylamine hydrochloride and the recovery till approx. about 1 volume of water based on input allylamine was distilled out to get thick mass.
  • the reaction mass was cooled to 25 to 35°C and water was added to get uniform slurry and the reaction mass was heated to 80 to 85°C.
  • VA-086 (9.82 g) an initiator was added in lotwise manner. First lot of VA-086 was added in about 4 hrs at 80 to 85°C.
  • Polyallylamine hydrochloride 25 gm was added to purified water (37.5 ml) under stirring. The mixture was stirred for 15 minutes to get uniform solution. 50 % aqueous sodium hydroxide solution (13.5 gm) [6.75 gm sodium hydroxide pellets in 6.75ml purified water] was added dropwise to the obtained solution maintaining temperature between 0 to 5°C and the mixture was stirred for 30 minutes. The solution (76 gm) was loaded into dialysis bag (MWCO: 1KD) and dialyzed against water for 1 to 2 hour. Water for dialysis was changed three times. Dialyzed water was checked for chloride content. Dialysis was stopped when the dialyzed water shows negative for chloride test. The obtained solution (130 gm) was distilled at 50- 60°C under vacuum till weight is reduced to 76 gm.
  • Sevelamer hydrochloride has residue on ignition of about 40 %. This indicates that dialysis reduces the sodium chloride content in Sevelamer hydrochloride. Residue on Ignition can be further reduced by repeated dialysis. Chloride content: 4.45 meq/g;
  • Dilution also affects degree of cross linking.
  • Chloride content 4.8 meq/g
  • Polyallylamine hydrochloride (700g) and water (1050ml) were mixed at 25 to 35°C to get a clear solution.
  • the solution was further cooled to 0 to 15°C and 189g sodium hydroxide dissolved in 189 ml water was added to the reaction mass at 0 to 5°C and stirred for 30 min.
  • This solution (2128gm) was diluted with 2 lit. purified water.
  • This diluted solution was subjected to tangential flow filtration (TFF) against water through polyether sulfone cartridge of 0.3 KD for 3 to 5 hours by applying control pressure of 2 to 17 bar. Regular feeding of water was maintained depending upon rate of permeate coming out .i.e., volume inside the feed tank was maintained throughout the process.
  • Permeate coming out was checked for chloride content test by silver nitrate/decrease in conductivity of permeate. Then 2 lit water used for dilution is removed from permeate side .i.e., concentration is done by increasing trans membrane pressure (TMP). Concentrated aqueous solution of partially neutralized polyallylamine hydrochloride was collected directly from feed tank and checked for solid content. Crosslinking was done by a process as mentioned in Example 3 and product was isolated by centrifugation. Residue on Ignition of the product obtained was tested and it was found to have Residue on Ignition not more than 0.1%. The wet cake obtained was stirred in purified water for 45 minutes, filtered and dried in rotary evaporator or Fluidised Bed dryer or RCVD or Vacuum Tray Dryer at 25 to 90°C.
  • Chloride content 4.68 meq/g
  • Sevelamer hydrochloride obtained by TFF operation (10 gm) was added into 130 ml solution of Sodium bicarbonate (10 gm NaHC03 in 130 ml water) and the mixture was stirred at 60-65°C for 4 hrs. The material was filtered using Buchner funnel assembly. The obtained wet cake was added into 130 ml solution of sodium bicarbonate (10 gm NaHC03 in 130 ml water) and stirred at 60-65°C for 4 hrs. The material was filtered using Buchner funnel assembly and the wet cake was washed by stirring it in 100 ml water for 1 hr at 60-65°C. The material was filtered using Buchner funnel assembly. The wet cake was washed twice at 60-65°C and dried on rotavapor at 90-95°C to get Sevelamer carbonate (8.5 gm).

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Abstract

La présente invention concerne le dessalement/dessalage de polymère, dans des polymères polyallylamines/réticulés par des techniques de séparation de membrane.
PCT/IN2011/000683 2010-10-01 2011-09-30 Procédé de préparation de polymère réticulé Ceased WO2012042542A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11147833B2 (en) 2017-10-16 2021-10-19 Fujifilm Corporation Therapeutic agent for hyperphosphatemia
US11186685B2 (en) 2016-12-28 2021-11-30 Fujifilm Corporation Emulsion of nitrogen atom-containing polymer or salt thereof, production method therefor, and production method for particles

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4605701A (en) 1983-10-25 1986-08-12 Nitto Boseki Co., Ltd. Small-globular crosslinked monoallylamine polymer and process for producing the same
US6180754B1 (en) 1999-09-03 2001-01-30 The Dow Chemical Company Process for producing cross-linked polyallylamine polymer
WO2001018073A1 (fr) * 1999-09-03 2001-03-15 The Dow Chemical Company Procede de reduction de la cohesivite de gels polymeres de polyallylamine durant le sechage
US6525113B2 (en) 1999-04-16 2003-02-25 Abbott Laboratories Process for producing cross-linked polyallylamine hydrochloride
US6787587B1 (en) 1997-10-13 2004-09-07 Nitto Boseki Co., Ltd. Process for the production of low-molecular-weight allylamine polymer or addition salt thereof
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US11147833B2 (en) 2017-10-16 2021-10-19 Fujifilm Corporation Therapeutic agent for hyperphosphatemia

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