FIELD OF THE INVENTION
The present invention relates to a process for the preparation of a crosslinked
polyallylamine polymer.
BACKGROUND OF THE INVENTION
Polyallylamine is a polymer of allylamine and comprises a long carbon chain with
every alternate carbon bearing a pendant amino group. Each amino group is
suspended from the chain by a methylene group and the polymeric structure can be
represented as below.

Polyallylamine can be crosslinked with itself (to form loops) or to other polyallylamine
chains (to form ladder-like structures) or with other compounds through the amino
groups. There are innumerable crosslinking agents known in the art ranging from the
simple to the bulky, exemplary of which are 1,2 dichloroethane and sorbitol poly-
glycidal ether. Depending on the requirements of the crosslinked polyallylamine the
distance between the crosslinked chains can be manipulated effectively by judicious
choice of the crosslinking agent.
The amino groups of polyallylamine also allow for further modification and
functionalization. The combination of these functionalized amino groups and suitable
crosslinking agents leads to endless possibilities and varieties of polyallylamine
polymers. It is possibly this permutation that lends itself to the versatility of
polyallylamine polymers for they are useful in fields as wide-ranging as waste-water
treatment (Journal of Applied Polymer Science, 2001, 80, 2073) and
pharmaceuticals. Polyallylamine linked with glucosyl or galactosyl moieties has been
disclosed for the treatment of Diabetes, Metabolic syndrome and obesity in
WO2007/070135. It has been linked to cyclodextrins for use as drug delivery vectors
(Nature Reviews: Drug Discovery 2004, 3, 1023) and for the preparation of polymeric

colloid nanoparticles - WO2005/015160. Polyallylamine crosslinked using
epichlorohydrin has been approved by the U.S. FDA for therapeutic use in the
treatment of chronic renal failure - Sevelamer, and for the reduction of elevated LDL
cholesterol - Colesevelam. It also finds its uses in other fields like electrochemistry
and as resins.
In 1985, the Japanese company, Nitto Boseki patented an industrial process to
polymerize allylamine using Azo-compounds - US 4,504,640 and the crosslinking of
polyallylamine - US 4,605,701. Allylamine can also be polymerized using
tetraflurorohydrazine - N2F4 (US 3,062,798) and with hydrogen peroxide in the
presence of a multivalent metal ion (US 4,927,896).
According to the crosslinking process of US 5,496,545, an aqueous solution of
polyallylamine hydrochloride is neutralized using sodium hydroxide and then the
crosslinking agent, for example epichlorohydrin, is added to it. Within 15 minutes of
the addition of epichlorohydrin the reaction mixture gels. The gel is cured for about
eighteen hours at room temperature and then put in a blender to get coarse
particles. The formation of a gel leads to handling difficulties and always
necessitates blending to get the desired product.
When polyallylamine is crosslinked as described in US 4,605,701, the polymer is
obtained not as a gel, but as small globules. According to this process the
crosslinking agent is added directly to the partially neutralized aqueous solution of
polyallylamine hydrochloride. This process precludes gel formation by using a
dispersing agent in the crosslinking step and stirring which results in the formation of
small-globular polymer. However when this process is carried out on an industrial
scale, the formation of a gel cannot be avoided entirely.
US 6525113 describes a process for the preparation of crosslinked polyallylamine
hydrochloride in which the swelling of the polymer is controlled. According to this
process an aqueous solution of polyallylamine is first neutralized by using an
alkoxide or a hydroxide. To this reaction mixture a water-miscible organic solvent is
added. This solvent is said to displace the water out of the polyallylamine particles.
3

The crosslinking agent is then added to the reaction mixture and the suspension that
is formed after crosslinking is filtered to recover the product.
US 2006/258812 discloses a process for the preparation of a crosslinked
polyallylamine polymer that has a particle size between 60 and 100 mesh. The
process consists of adding the cross-linking agent to the aqueous solution of partially
neutralized polyallylamine hydrochloride and dispersing the whole in an organic
solvent that contains a surfactant. After a period of heating with concurrent stirring,
the gel particles are isolated by filtration.
OBJECT OF THE INVENTION
It is thus an object of the present invention to provide a process for the preparation of
a polymer that avoids the formation of a gel.
Another object is to provide a process that does not require the curing of the
resultant product.
Yet another object of the invention is to provide a process that is practicable even on
an industrial scale.
SUMMARY OF THE INVENTION
According to one aspect of the present invention there is provided a process for the
polymerization of allylamine by treating an acid addition salt of allylamine in its
solution of an acid with a radical initiator.According to another aspect of the present
invention there is provided a process for preparation of a crosslinked polymer, said
process comprising treating the polymer with a solution comprising crosslinking
agent and dispersing agent.
According to a further aspect of the present invention there is provided a process for
preparation of a crosslinked polymer, said process comprising treating a solution
comprising the polymer and dispersing agent with cross linking agent..

DETAILED DESCRIPTION
The inventors have observed that the order of addition of the crosslinking agent and
the dispersing agents affects formation of the gel with crosslinked polymers. The
present inventors have minimized considerably the formation of a gel by allowing the
reaction between polyallylamine (a polymer) and the crosslinking agent to occur
strictly in the presence of a dispersing agent. The function of the dispersing agent is
to promote the reaction between the polymer and the cross linking agent and to
prevent gel formation. The technical advancement in the use of the dispersing agent
resides in the simultaneous addition of the crosslinking agent and the dispersing
agent to the polymer that is to be crosslinked. The simultaneous addition of the
crosslinking agent and the dispersing agent to the reaction mixture can be
elaborated to the manufacture of any polymer that is prepared in the form of a gel.
Allylamine is the monomer of the polymer polyallylamine. The preparation of
polyallylamine by the polymerization of allylamine had been known to result in a
polymer having a low degree of polymerization. However, the situation changed with
the use of initiators bearing the azo group. Thus, to prepare polyallylamine,
allylamine, which is a toxic liquid with a strong smell, is first converted into its salt.
This can be done by dissolving allylamine directly in an acid. To this solution of an
acid containing the allylamine salt, the solution of an Azo-based radical initiator can
be added. Usually, the allylamine salt is separated from the acid in which it is
dissolved before the radical initiator is added to it. However when the same has to be
practiced on a large scale the isolation of the salt can be tedious and is inefficient in
terms of the time involved and the energy consumed. (On a batch size of 40kg, the
time saved by not separating the allylamine salt or distilling off the excess solvent is
between 24 and 28 hours.)
Consequently, the acid solution containing the allylamine salt is treated with the
radical initiator and the polyallylamine polymer that is obtained is isolated and
purified. The polyallylamine that is isolated is the corresponding acid salt of the
allylamine that was used as starting material.

Before crosslinking, the polyallylamine salt is neutralized in order to free the amino
groups. The polyallylamine salt is dissolved in an aqueous solution of a base such
that it is neutralized partially. The crosslinking agent, for example epichlorohydrin,
being insoluble in water, is dissolved in a hydrocarbon solvent. To this solution is
added the surfactant or dispersing agent and the whole is added to the aqueous
solution of polyallylamine. Alternatively, the crosslinking agent may be added to the
solution containing the surfactant and polyallylamine . The reaction mixture is stirred,
warmed and maintained for about 3 hours for the crosslinking to take place. The
polymer that is formed is insoluble in most solvents and can be separated by
filtration. Other methods of product isolation will be known to persons skilled in the
art and can also be used. It is purified by washing with isopropanol several times and
finally with demineralized water and dried. Isopropanol was the solvent chosen in
order to remove the traces of epichlorohydrin. The product that is obtained in the end
is a free-flowing powder.
Thus, according to the process of the current invention the polymer that is obtained
need not be subjected to curing operations that consume time. The current process
is quicker and more efficient. Also the polymer that is obtained by this process does
not require further milling, grinding or blending. It can be used directly for all further
processes and operations.
The process of the invention can be illustrated by the use of concentrated
hydrochloric acid for polymerization and epichlorohydrin as the crosslinking agent in
the preparation of Sevelamer.
EXAMPLES
Polymerization of allvlamine:
200mL of Cone. HCI was taken in a round-bottomed flask of 1L capacity and cooled
to less than 5°C. 100g of allylamine was added slowly over a period of 1-1.5 hrs
while stirring and maintaining the temperature at less than 10°C. After about 30
minutes the temperature of the reaction mixture was brought to room temperature.
After another 30 minutes the temperature of the reaction mixture was raised to about
50°C.

20g of 2,2-azobis-(2-amidinopropane) dihydrochloride was dissolved separately in
9mL of demineralized water and warmed slightly to get a clear solution. This solution
was added to the reaction flask containing allylamine. The reaction mixture was
stirred for around 24 hours at 50-55°C and a second aliquot (2g) of 2,2-azobis-(2-
amidinopropane) dihydrochloride was added to it. The reaction mixture was
maintained for another 40-44 hours and then cooled to room temperature. It was
then poured into 1.7L of methanol in a nitrogen atmosphere. This solution was
maintained at room temperature for 1 hour and filtered under vacuum in a nitrogen
atmosphere. The product was washed with methanol and dried under vacuum.
Yield: 140g
Crosslinking of polyallylamine:
[a] With Sorbitan sesquioleate.
27g of NaOH was dissolved in 300mL of demineralized water. 100g of
Polyallylamine hydrochloride was added to this solution at room temperature and
stirred for about 45 minutes.
In another flask 4mL of sorbitan sesquioleate was dissolved in 500mL of toluene.
This solution was subjected to charcoal treatment and 9mL of epichlorohydrin was
added to it. After 5-10 minutes the aqueous solution of polyallylamine was added to
the toluene solution. The reaction mixture was stirred at room temperature for about
45 minutes and then heated to around 50°C. It was maintained at this temperature
for about 2.5 hours and then cooled to room temperature.
The solid was collected by filtration and washed thoroughly with Isopropanol to
remove traces of epichlorohydrin. After a final spray-wash with demineralized water
the polymer was dried under vacuum.
Yield: ~750g
[b] With Sorbitan trioleate.
2.7g of NaOH was dissolved in 30mL of demineralized water. 10g of Polyallylamine
hydrochloride was added to this solution at room temperature and stirred for about
45 minutes.

In another flask 0.4mL of sorbitan sesquioleate was dissolved in 50mL of toluene.
This solution was subjected to charcoal treatment and 0.9mL of epichlorohydrin was
added to it. After 5-10 minutes the aqueous solution of polyallylamine was added to
the toluene solution. The reaction mixture was stirred at room temperature for about
45 minutes and then heated to around 50°C. It was maintained at this temperature
for about 2.5 hours and then cooled to room temperature.
The solid was collected by filtration and washed thoroughly with Isopropanol to
remove traces of epichlorohydrin. After a final spray-wash with demineralized water
the polymer was dried under vacuum.
Yield: ~75g

WE CLAIM
1. A process for preparation of crosslinked polymer, said process comprising treating
the polymer with a solution comprising crosslinking agent and dispersing agent.
2. A process for preparation of crosslinked polymer, said process comprising treating a
solution comprising the polymer and dispersing agent with cross linking agent.
3. The process as claimed in claims 1 or 2 wherein the polymer to be crosslinked is
polyallylamine.
4. The process as claimed in claims 1 or 2 wherein the crosslinking agent is
epichlorohydrin.
5. The process as claimed in claims 1 or 2 wherein the dispersing agent is sorbitan
sesquioleate.
6. The process as claimed in claims 1 or 2 wherein the dispersing agent is sorbitan
trioleate.
7. The process as claimed in claims 1 or 2 adapted for manufacture of Sevelamer.

8. The process as claimed in claim 3 wherein said polyallylamine is prepared by
polymerizing allylamine by treating an acid addition salt of allylamine in its solution of an
acid with a radical initiator.
9. The process as claimed in claim 8 wherein the acid is hydrochloric acid.
10.The process as claimed in claim 8 wherein the radical initiator contains an Azo group.

11.The process as claimed in claim 10, wherein the radical initiator is 2,2-azobiz-(2-
amidinopropane).
12. A process for the preparation of Sevelamer by polymerizing allylamine hydrochloride
salt, partially neutralizing the resulting polyallylamine salt and cross polymerize the
polyallylamine by the process as claimed in claim 3.

A process for preparation of cross linked polymer comprising cross linking the polymers
in presence of cross linking agent and dispersing agent. The present invention also
provides a process for the polymerization of allylamine by treating an acid addition salt
of allylamine in its solution of an acid with a radical initiato.