FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)


"AN IMPROVED METHOD FOR PREPARATION OF CROSS-LINKED POLYALLYLAMINE POLYMERS"
Emcure Pharmaceuticals Limited.,
an Indian company, registered under the Indian Company's Act 1957
and having its registered office at
Emcure House, T-184, M.I.D.C., Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.


FIELD OF INVENTION
The present invention relates to an improved method for preparation of globular cross-linked polymers, having a.definite particle size, shape for use in the preparation of a pharmaceutical composition.
BACKGROUND OF THE INVENTION
Cross-linked polyallylamine polymers having several therapeutic applications, are useful for reducing blood cholesterol levels by reducing reabsorption of bile acid agents. Therapeutic methods for reducing serum phosphate level includes dialysis, reduction in dietary phosphates and oral administration of phosphate binders like cross-linked polymers to reduces gastrointestinestinal absorption. Further cross-linked polymers have many applications like use as food preservatives.
Various methods are known for production of cross~linked polymers. A general method for the preparation of cross-link polymers comprises reaction of the polyallylamine polymer with a suitable cross-linking agent in basic aqueous or aqueous immiscible solvent medium. These prior art methods for preparation of cross-linked polymers are tedious and require stringent conditions for isolation and drying on an industrial scale, since the polymer gel becomes sticky and hard during drying to remove volatile contents and it is difficult to extricate the material after drying,
US 6,362,266 discloses a process for manufacture of cross-linked polyallylamine polymer gel having reduced cohesiveness by utilizing LIST reactors, which are specially designed reactors for high viscosity processing (LIST DISCOTHERM B) and equipped with temperature control, vacuum control for the drying process.
US 6,362,266 discloses a method for manufacture of Sevelamer utilizing a combination of a LIST reactor and a surfactant, which is added just before drying of the wet cake. However, there is no mention that the utilization of surfactants results in the formation of Sevelamer, as globular or spherical balls.

Thus, prior art methods specialized equipment like a LIST reactors, which requires extensive capital investment.
Thus, a method needs to be developed, which could furnish sevelamer of formula (I) in globular form with a definite particle size, shape for easy drying and removal from the drier.
Formula-I

a, b = number of primary amine groups a f b = 9
c-~ number of cross linking groups c~l
n= fraction of prolongated amines n = 0.4
m = large number to indicate extended polymer network
OBJECT OF THE INVENTION
An object of the present invention is to provide a novel method for the production of cross-linked polyallylamine polymer in globular form with desired particle size, shape and suitable for use in pharmaceutical composition.
Another object of the present invention is to provide a simple, economical and industrially viable method for the manufacturing of cross linked polyallylamine polymer.
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A further object of the present invention is for the use of the surfactants without utilizing hazardous solvents or a specialized reactor in the process of manufacturing cross linked Polyallylamine polymer.
SUMMARY OF THE INVENTION
The present invention provides an improved method for manufacture of cross-linked Polyallylamine polymer comprising of dissolving polyallylamine hydrochloride in water, adjusting pH 10 by using an aqueous solution of an alkali, adding a cross-linking agent and an aromatic hydrocarbon, an aqueous solution of a surfactant, refluxing till completion of reaction and isolating globular sevelamer hydrochloride of formula (I) after drying.
One aspect of the invention relates to a process for preparation of cross-linked polyallylamine polymer suitable for pharmaceutical composition comprising reaction of a aqueous solution of polyallylamine polymer with a cross linking agent in presence of a surfactant and isolating globular shaped cross-linked polymer.
Another aspect of the invention comprises the use of cross-linked Polyallylamine polymer in globular form for preparation of pharmaceutical composition.
Yet another aspect of the invention is to provide a simple, economical and industrially viable method for preparation of cross-linked Polyallylamine polymer.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a method for the manufacture of cross-linked polyallylamine polymer having a globular shape and usenil for preparation of pharmaceutical composition.
Polyallylamine hydrochloride was prepared by the conventional method of polymerization of monoallyamine hydrochloride in presence of azo type radical initiator, as per the method disclosed in US 4,528,347.
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The method of the present invention can be utilized for preparing cross-linked polymers like Sevelamer, Colsevelam etc.
Polyallylamine hydrochloride was neutralized prior to the cross-linking. The neutralization was carried by using an aqueous inorganic base like alkali metal hydroxides selected from potassium hydroxide and sodium hydroxide
A cross-linking agent such as epichlorohydrin was added to the alkaline mixture. The cross-linking agent was either added as such or dissolved in a solvent like toluene
A surfactant was added to the aqueous solution. An organic solvent was optionally added to the mixture alongwith epichlorohydrin.
During the method of production of cross-linked Polyallylamine polymer, surfactants was used to reduce reaction time, better yield and for the desired shape of the product. The surfactant was used as aqueous solution in the cross-linking of polymers.
The surface active agents or surfactants that can be used are selected from the group comprising of sodium dodecylbenzenesulfonate, potassium tridecylbenzenesulfonate, sodium octadecylbenzenesulfonate, MICRO-90, stearic acid etc.
Reaction mixture was refluxed till completion of reaction. The mixture was concentrated partially and cooled. Polymer was isolated after cooling. Wet cake was washed with water and dried to get a cross linked polymer having a definite geometrical shape.
The invention is further explained with the help of following illustrative example,
however, in no way these examples should be construed as limiting the scope of the
invention.
Although, the invention herein has been described with reference to particular
embodiments, it is to be understood that these embodiments are merely illustrative of the
principles and applications of the present invention. It is therefore to be understood that
numerous modifications may be made to the illustrative embodiments and that other
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arrangements may be devised without departing from the spirit and scope of the present invention as described above.
EXAMPLE:
Example -1: Preparation of cross-linked Polyallylamine polymer.
Polyallylamine Hydrochloride (200 g) was charged in to DM water (120 ml) and stirred to get clear solution at room temperature. Aqueous solution of sodium hydroxide (50%) was charged in the reaction mixture at 25 to 30°C under stirring till pH 10-10.5. Toluene (900 ml) and Dodecyl Benzene Sodium Sulfonate (0.5 gm in water 5 ml) was charged to the reaction vessel. Reaction mass was refluxed for 1 to 2 hours. Cool the reaction mass to 75 to 80°C. Epichlorohydrin (6 gm) was added in 10 minutes. Reaction mass was refluxed further for 3 hours. Water from the reaction mass was distilled off and fresh toluene was charged to maintain volume of the reaction. The reaction was refluxed for 5 hours, and toluene was distilled off completely under vacuum at 60 to 65°C. The residue was diluted with water to maintain the reaction volume. The reaction mass was cooled between 25 to 30°C. Product was isolated from aqueous after stirring for 30 minutes at 25 to 30°C. The wet cake was dried in tray dryer at 70 to 75°C-Yield: 80 g.
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Claims
1) A process for the preparation of a cross-linked polyallylamine polymer in a globular form, comprising treatment of polyallylamine hydrochloride with an aqueous solution of an alkali metal hydroxide followed by reaction with a cross-linking agent in presence of a surface tension reducing agent and an organic solvent, refluxing and isolating the cross-linked polyallylamine polymer.
2) A process as claimed in claim 1, wherein the alkali metal hydroxide is sodium hydroxide or potassium hydroxide.
3) A process as claimed in claim 1, wherein the cross-linking agent is epichlorohydrin.
4) A process as claimed in claim 1, wherein the surface tension reducing agent is selected from the group comprising of sodium dodecylbenzenesulfonate, potassium tridecylbenzenesulfonate, sodium octadecylbenzenesulfonate, MICRO-90 and stearic acid.
5) A process as claimed in claim 4, wherein the surface tension reducing agent is
preferably sodium dodecylbenzenesulfonate.
6) A process as claimed in claim 1, wherein the organic solvent is selected from the group comprising of aromatic hydrocarbon or aliphatic hydrocarbon but preferably aromatic hydrocarbon.
7) A process as claimed in claim 6, wherein the aromatic hydrocarbon is preferably toluene.
Dated this twenty-fifth (25th) day of May 2009
(Signed) *Syi['\-J —
Mukund K. Gurjar Chief Scientific Officer Em cure Pharmaceuticals Ltd.

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