Title of Invention	HIV 1+2 ELISA KIT FOR DETECTION OF ANTIBODIES TO HUMAN IMMUNODEFICIENCY VIRUS IN HUMAN BLOOD,SERUM AND PLASMA
Abstract	The present invention relates to an improved and industrial feasible process for the manufacture of copolymer, chemically known as poly(allylamine-co-N,N'-diallyl-l,3- diamino -2-hydroxypropane hydrochloride. 10 MAY 2006

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COMPLETE AFTER PROVISIONAL FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13) 1. TITLE OF THE INVENTION "AN IMPROVED PROCESS FOR PREPARATION OF SEVELAMER" 2. APPLICANT (S) (a) NAME (b) NATIONALITY (c) ADDRESS Emcure Pharmaceuticals Ltd. India 12/2 F-ll Block, M.I.D.C, Pimpri, Pune- 411 018. AN IMPROVED PROCESS FOR PREPARATION OF SEVELAMER INTRODUCTION Hyperphosphatemia is a disease associated with acute and chronic renal failure and occurs when the serum phosphorus level is greater than 5 mg/dL (1.6 mmol/L), usually in the form of inorganic phosphorus. Hyperphosphatemia involves decreased Ca++ due to increased sperm phosphorus, increased parathyroid hormone secretion, and associated sequelae (Ref: http://www.phosphoruscontrol.com/HY/Default.aspx). Therapeutic efforts directed toward the control of hyperphosphatemia include dialysis, dietary phosphate reduction, and oral administration of insoluble phosphate-binding agents. As dialysis and dietary phosphate reduction alone is not able to sufficiently maintain normal phosphorus level in hyperphosphatemia! patients, a combination of therapies must be used such as use of one or more phosphate binders, which is routinely used to treat these patients (Ref: US 5 496 545 A). Phosphate binding agents act to reduce serum phosphorus ingested through the diet and include calcium, aluminium and magnesium salts or organic polymers such as poly (allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride. Calcium based phosphate binders have been widely used to bind intestinal phosphate and prevent absorption. Calcium carbonate and calcium acetate are the most commonly used calcium based phosphate binders, although calcium citrate, ketovalin, and alginate are also available. The ingested calcium combines with phosphate to form insoluble calcium phosphate salts. Side effects associated with these agents limit their effectiveness. The major side effect of this therapy is hypercalcemia. Hypercalcemia causes serious side effects such as renal failure, confusion etc. Treatment with calcium base phosphate binders requires frequent monitoring of serum calcium level (Ref: US 5 496 545 A; http://www.phosphoruscontrol.com/PH/CalciumBasedBinders.aspx). Aluminum is also an effective phosphate binder and is administered in the form of aluminum hydroxide, Al (OH) 3 gel and marketed as "Amphojel®". These compounds form complex with intestinal phosphate, to form highly insoluble aluminium phosphate. Prolong use of these gels may lead to aluminum toxicity accompanied by symptoms such as myopathy, severe bone disease and anemia (Ref: US 5 496 545 A and http://www.phosphoruscontrol.com/PH/AluminumBasedBinders.aspx). Magnesium salts are also known to work as phosphate binder however; they are rarely used because of risk of hypomagnesaemia in renal failure. Organic polymers are also used as phosphate binders. The said organic polymers are, for example the ion exchange resins like Dowex®, XF43311 etc. These resins have several drawbacks like need for high dosage, poor binding capacity etc. (Ref: US 5 496 545 A). Poly(allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride is one of the therapeutic drug used for the treatment of hyperphosphatemia. It is a copolymer of allylamine and epichlorohydrin, which is a phosphate binder used to reduce the absorption of dietary phosphate. It is used to reduce the serum phosphorus in patients with severe kidney disease known as End Stage Renal Disease (ESRD). Poly(allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride is marketed by Geltex Pharmaceuticals after USFDA approved the active ingredient in October 1998 for the treatment of high level of serum phosphorus in patients with end-stage renal disease. This active ingredient, which is both calcium-free and aluminum-free, enables the fast treatment of hyperphosphatemia without the risks associated with other treatments. Poly(allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride treatment also results in a lowering of low-density lipoprotein (LDL) and total serum cholesterol levels. (Ref: http://www.centerwatch.com/patient/drugs/dru640.html) and label information of poly(allylamine-co-N, N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride, available on USFDA website). BACKGROUND OF THE INVENTION: Poly(allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane)hydrochloride of formula (I) is a poly(allylamine hydrochloride) cross-linked with epichlorohydrin in which 40% amines are protonated. 3 mixture was quenched with methanol. Poly(allylamine hydrochloride) of formula (III) was isolated by filtration and dried at 50°C under reduced pressure. An aqueous solution of polyallylamine was prepared by neutralizing compound of formula (III) with an aqueous solution of sodium hydroxide. Epichlorohydrin (IV) was added to an aqueous solution of polyallylamine and stirred for two minutes. The resulting mixture was added into a mixture of chlorobenzene, o-dichlorobenzene and Silvan S-83, to obtain a dispersion, which was allowed to cross-link at 25°C for 30 minutes and at 50°C for 2 hours. The desired compound was filtered and washed successively with methanol, IN sodium hydroxide, and D.M water. The compound of formula (I) was then dried under reduced pressure at 50°C. The above embodiment for the preparation of compound of formula (I) has the following disadvantages, which are: a) isolation of intermediates like monoallylamine hydrochloride of formula (IIA) and poly(allylamine hydrochloride) of formula (III) makes the process time consuming, lengthy and tedious, b) the intermediate (III) was dried under vacuum due to its hygroscopic nature, and this step utilizes more utility and time, c) the process for the preparation of compound (I) utilizes Class 2 solvents such as chlorobenzene, o-dichlorobenzene for the reaction, which in turn makes the process hazardous for human health and environment, and d) the above process also requires a dispersion stabilizer like Silvan S-83, which makes the process uneconomical. US 2004/0028803 Al discloses synthesis of compound of formula (I) in the form of gel, comprising reaction of poly(allylamine hydrochloride) (III) with epichlorohydrin of formula (IV) in an aqueous solution, at a pH between 10.0 and 10.4 adjusted by addition of 50% caustic lye, and maintaining the temperature between 5°C to 10°C followed by a process of gelling for 24 hours. 6 "8 1 10000 50800 4000 54800 1 09/05/06 ongwith claims men ted Tota e Pay 44708 Da c o tion a anc cat fica o n r- Q. Description Form 18 (B Cheque No. Filing new ap Complete sp ype of ppln. — $ H ay 09,20 roadcast 3 CO S c o 5/0 .19 Title/ Patent Appln. No. 1335/MUMNP/2005 Scalable Encoding For Multicast E Multimedia Service An improved process for preparat sevelamer Cheque No. 144709 Dated 09/0 lient / cant Thornton comm Inc ure Pharmaceuticals ppl U i Attorney/Secy. 2946 '> oDC 3704 /Babu 2509 /Nakul File IPO V>> IPO 55 IPO £ Scheme-2: Method as disclosed in US 5 496 545 for preparation of compound of formula (I)- The method disclosed in US 5 496 545 for preparation of compound of formula (I) comprises of two steps: i) reacting allylamine (II) with concentrated hydrochloric acid in aqueous medium to form allylamine hydrochloride (IIA), followed by removal of water by vacuum distillation at 60°C-70°C, ii) adding the catalyst azobis(amidinopropane) dihydrochloride in two lots and stirring the reaction for 24 hours and 44 hours respectively, after the addition of each lot, to form poly (allylamine hydrochloride) of formula (III), iii) separating out compound (III) after quenching with methanol, followed by filtering and leaching with methanol repeatedly, and iv) reacting epichlorohydrin (IV) with compound (III) in an aqueous medium, by adjusting pH 10 with solid sodium hydroxide and curing for 18 hours, followed by quenching with isopropanol to give compound of formula (I), which was vacuum dried for 18 hours. The above process also has several drawbacks like: a) water has to be removed under vacuum during the preparation of poly (allylamine hydrochloride) of formula (III). Removal of water by distillation consumes lot of energy, which makes the process cumbersome, time consuming and tedious on commercial scale, b) due to hygroscopic nature of the intermediate of formula (III), the filtration has to be carried out under stringent conditions, c) further, there is a danger of loss in yield during filtration and leaching, which is done repeatedly. Repeated methanol washing and filtration generates large quantity of effluent, that has to be either recycled by distillation or disposed in the effluent treatment plant. US 6,290,947 (assigned to Geltex Pharmaceuticals) discloses the preparation of compound of formula (I) comprising reaction of poly (allylamine hydrochloride) of formula (III) in an aqueous medium, at a pH of 10.5 with solid sodium hydroxide, until homogenous mixture was formed. Reaction with epichlorohydrin of formula (IV) was carried out at a pH of 10.2 (Ref: Example 5 of US 6 290 945) and the reaction mixture cured for 18 hours to provide a gel, which is broken up with Kitchen Aid Mixer. Further, washings are given until the conductivity of the effluent was equal to 16.7 mS/cm. The co-polymer of formula (I) was air-dried at 60°C for 5 days. The above process, although it seems to be commercially viable, has some limitations like: a) during the process, pH was reduced to a specific range between 10.2 and 10.5. Maintaining pH on a commercial scale, at a precise pH is very tedious. Further, monitoring the sharp pH for a long period is cumbersome. b) use of Kitchen Aid Mixer for breaking gel on commercial scale is another limitation. c) monitoring the washing process of final gel till the conductivity of effluent equals 16.7 mS/cm is cumbersome, and puts limitation on online quality control, adds additional manpower, requires more analytical instruments. d) the final product of formula (I) prepared by this method takes 5 days for drying, thereby increasing the time cycle for each run. This increases drier occupancy and utility for a longer time, thereby, making the process uneconomical. US 6 525 113 discloses the preparation of Poly(allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride of formula (I) comprising reaction of an aqueous solution of Poly(allylamine hydrochloride) of formula (III) in presence of sodium hydroxide, with epichlorohydrin of formula (IV) at temperature between 20°C to 30°C. The reaction was carried out in a water-miscible solvent like acetonitrile. It should be noted that this method also utilizes a Class 2 solvent like acetonitrile (methyl cyanide), which has got quite a low exposure limit of 410 ppm. Utilization of such a hazardous cyanide solvent on an industrial scale makes the process environmentally dangerous and less feasible. 9 Considering all the above shortcomings in the prior art, the applicant has developed a simple and industrially viable process for the preparation of compound of formula (I), which is one-pot reaction, avoiding isolation of compound of formula (III). The method embodied in this invention reduces the time cycle for each batch run, reduces cost, efforts and thereby, makes the process commercially viable. OBJECT OF THE INVENTION An object of the invention is to provide simple and cost effective process for the preparation of poly(allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride of formula (I)- Another object of the invention is to provide a single-pot process for the preparation of poly (allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride, wherein the overall period for completion of the reaction is reduced, making the process suitable for commercial applications. Yet, another object is to provide a-process for the preparation of poly(allylamine-co-N, N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride having phosphate binding capacity as per desired specification. SUMMARY OF THE INVENTION: One aspect of the invention is to provide an economical, simple and improved process for the preparation of poly(allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride of formula (I). Another aspect of the invention relates to an industrially feasible, one pot reaction for preparation of poly(allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride of formula (I), which comprises reaction of allylamine of formula (II) with hydrochloric acid in presence of a catalyst i.e. azobis(amidinopropane) dihydrochloride, and optionally a solvent to 10 form a poly (allylamine hydrochloride) of formula (III), which is treated in situ with epichlorohydrin of formula (IV) at a pH between 10 to 10.5 in an aqueous medium. Further aspect of the invention relates to a simple and commercially viable process for the preparation of poly(allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride of formula (I), in a single pot, comprising reaction of allylamine of formula (II) with hydrochloric acid in an organic solvent, in presence of catalyst i.e. azobis (amidinopropane) dihydrochloride, to form poly(allylamine hydrochloride) (III), which on further reaction with epichlorohydrin (IV) at a pH between 10 to 10.5, leads to the formation of poly(allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride of formula (I). DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an improved method for the preparation of poly (allylamine-co-N, N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride of formula (I), without isolation of the intermediate, poly (allylamine hydrochloride) of formula (III). The said process broadly comprises the steps of: a) reacting allylamine of Formula (II) with hydrochloric acid in an organic or inorganic solvent to get allylamine hydrochloride of formula IIA b) reacting allylamine hydrochloride in-situ in presence of catalyst to get polyallylamine hydrochloride of Formula (III), and 11 aqueous solution of catalyst azobis (amidinopropane) dihydrochloride, and stirring the reaction mixture at a temperature between 50°C and 55°C after the addition of catalyst, b) adding water to the reaction mixture and adjusting the pH of the reaction mixture between 10.0 and 11.0 with an inorganic base, c) adding epichlorohydrin of formula (IV) into the reaction mixture at room temperature and keeping for curing for 15 to 20 hours, d) quenching the reaction mass with an organic solvent to separate the compound of formula (I), followed by leaching the filtered solid with an inorganic and organic solvent and filtering the same, and e) air-drying at 70°C -75°C for 25 to 35 hours. In the present invention, all steps are carried out in a single step i.e. the preparation of compound of formula (I) is a one pot reaction, which obviates the need for isolation of compound (III), thereby reducing the time cycle for each batch run and making the process cost-effective. The compound of formula (I) is a very important and a very costly copolymer used for phosphate binding, in the treatment of hyperphosphatemia. It is very important that compound of formula (I), is obtained in high yield with desired specifications, without utilization of additional steps of purification and isolation of intermediate (III). Compound (I) is prepared by adding allylamine (II) to aqueous concentrated hydrochloric acid and adding a catalyst to yield poly(allylamine hydrochloride) (III) in situ; epichlorohydrin (IV) is then added to the reaction mass and stirred, till compound (I) of desired specification is obtained. The reaction of allylamine and concentrated hydrochloric acid is carried out between the temperatures -10°C to +5°C. The preferred temperature is between -5°C and 0°C to form allylamine hydrochloride. The reaction mass pH is adjusted up to 2.0. 13 Excess water was distilled off at the temperature between 45°C and 60°C. The preferred temperature is around 50°C. A catalyst like azobis(amidonopropane) dihydrochloride is added and stirred for around 90 hours. The reaction is carried out at a temperature selected between 45°C and 70°C. The preferred temperature is between 50°C to 55°C for preparation of poly(allylamine hydrochloride) of formula (III). Any other similar catalyst such as 4-4"-azobis (4-cyanovaleric acid), l,r-azobis(cyclohexene carbonitrile), benzoylperoxide, cumene hydroperoxide may also be employed. The addition of epichlorohydrin of formula (IV) is carried out by adjusting the pH of reaction mass with an inorganic base selected from the group comprising of hydroxides, carbonates or alkoxide of alkali or alkaline earth metals, but preferably the hydroxide of an alkali metal. The amount of allyl amine and epichlorohydrine is in the ratio of 1: 0.075 to 1: 0.175. The preferred allyl amine and epichloro hydrine ratio is 1: 0.115. The preferred alkali metal hydroxide is sodium hydroxide. An aqueous solution of sodium hydroxide is added to the mixture. The amount in moles of sodium hydroxide added is between 0.50 moles to 0.65 moles per mole of allylamine (II). The preferred amount of sodium hydroxide is between 0.55 moles to 0.60 moles per mole of compound (I). The compound of formula (I) is obtained by co-polymerization of compound of formula (III) with epichlorohydrin of formula (IV) after adjusting the pH of the reaction mixture with an inorganic base in an aqueous medium. The co-polymerization of compound (III) is carried out at a pH between 10 and 11. The preferred pH range is between 10.4 and 10.6. The addition of epichlorohydrin (IV) to the reaction mixture-containing compound (III) is carried out at a temperature between 25°C and 40°C. The preferred temperature is between 30°C and 35°C. 14 The cross linked polymer of formula (I) is cured for 15 to 20 hours, but preferably 18 hours at a temperature between 25°C and 40°C. The preferred temperature is between 30°C and 35°C. The amount of epichlorohydrin (IV) added may vary from 0.075 to 0.175 mole equivalent with respect to allyl amine. The compound of formula (1) is obtained by quenching the reaction mixture with a water-miscible protic or aprotic organic solvent. The preferred solvent is a water-miscible protic solvent. Water miscible protic solvents are selected from the group like alcohols, thiols, etc. The preferred water-miscible protic solvent is an alcohol. The alcohol employed is selected from the group comprising of methanol, ethanol, isopropanol etc. The preferred alcohol is isopropanol. The reaction mixture is filtered and the wet cake is then leached separately with an inorganic or a organic solvent. The inorganic solvent utilized for leaching is water. Organic solvents utilized for the leaching is selected from the group comprising of alcohol, nitrile, hydrocarbons etc. The preferred organic solvent is an alcohol. The alcohol employed is selected from the group comprising of methanol, ethanol, isopropanol etc. The preferred alcohol is isopropanol. The compound of formula (I) is air-dried at the temperature selected between 65°C and 80°C. The preferred temperature is between 70°C and 75°C. The compound is dried for 25 to 35 hours, but preferably for 30 hours. It should be noted that in the present embodiment, the final product is air-dried for only 30 hours, which is comparatively less time consuming than the prior art, thereby making the process economical. 15 of hydrochloric acid leading to formation of allylamine hydrochloride (N-A). removing the organic solvent under vacuum, adding an aqueous solution of catalyst, azobis (amidinopropane) dihydrochloride, to the reaction mixture at a temperature between 45°C to 55°C and stirring the reaction mixture. b) adding water to the residue and adjusting the pH of the reaction mixture between 10.0 and 11.0 with an inorganic base. c) adding epichlorohydrin of formula (IV) to the reaction mixture at room temperature and curing for 15 to 20 hours. d) quenching the reaction mass with an organic solvent to separate the compound of formula (I), followed by leaching the filtered solid by inorganic and organic solvent and filtering the same. e) air-drying at 70°C -75°C for 25 to 35 hours. In both the methods, compound (I) is prepared one-pot, without isolation of compound (III). An important feature of Method-B is the utilization of an organic solvent in step (a), which is removed very readily and in a short time after preparation of compound (III) as compared to Method-A and is much superior to prior art methods. Method-B reduces time cycle, saves considerable energy and thereby makes the process more economical, cost-effective and commercially viable. Hydrochloric acid either as gas or as an aqueous solution is added to an organic solvent. The organic solvent is selected from the group comprising of an alcohol, ether, hydrocarbons etc. The preferred solvent is an alcohol. The alcohol employed is selected from the group comprising of methanol, ethanol, isopropanol etc. The preferred alcohol is methanol. Allylamine of formula (II) is added to a mixture of methanol and HCl (g) or aqueous HCl at a temperature between -10°C to +5°C. The preferred temperature is in between -5°C and 0°C. The reaction mass pH is adjusted preferably up to 2.0. 17 The reaction mixture was stirred for duration of between 1 hour and 3 hours. The preferred time duration is 2 hours. Methanol is distilled off at a temperature between 45°C and 60°C. The preferred temperature is around 50°C. A catalyst like azobis(amidinopropane) dihydrochloride was added and stirred for around 84 hours. The reaction is carried out at a temperature selected between 45°C and 70°C. The preferred temperature is between 50°C to 55°C for preparation of poly(allylamine hydrochloride) of formula (III). The addition of epichlorohydrin (IV) is carried out by adjusting the pH of reaction mass with an inorganic base selected from the group comprising of hydroxides, carbonates or alkoxide of alkali or alkaline earth metals, but preferably the hydroxide of an alkali metal. The preferred alkali metal hydroxide is sodium hydroxide. An aqueous solution of sodium hydroxide is added to the mixture. The amount in moles of sodium hydroxide required is between 0.50 moles to 0.75 moles per mole of allylamine (II). The preferred amount of sodium hydroxide is between 0.55 moles to 0.65 moles per mole of compound (I). The compound of formula (I) is obtained by co-polymerization of a compound of formula (III) with epichlorohydrin of formula (IV) after adjusting the pH of the reaction with an inorganic base in aqueous medium. The co-polymerization of compound (III) is carried out at a pH between 10.0 and 11.0. The preferred pH range is between 10.4 and 10.6. 18 The addition of epichlorohydrin (IV) to the reaction mixture-containing compound (III) is carried out at a temperature between 25°C and 40°C. The preferred temperature is between 30°C and 35°C. The cross-linked polymer of formula (I) is cured for 15 to 20 hours, but preferably 18 hours at a temperature between 25°C and 40°C. The preferred temperature is between 30°C and 35°C. The compound of formula (I) is obtained by quenching the reaction mixture with a water-miscible protic or aprotic organic solvent. The preferred organic solvent is a water-miscible protic solvent. Water miscible protic solvents are selected from the group like alcohols, thiols, etc. The preferred water miscible protic solvent is an alcohol. The alcohol employed is selected from the group comprising of methanol, ethanol, isopropanol etc. The preferred alcohol is isopropanol. The volume of isopropanol added is between 15 volumes and 30 volumes per gram of compound (II). The reaction mixture is then stirred, filtered and leached separately with inorganic and organic solvent and filtered. The inorganic solvent utilized for the leaching is water. Organic solvents utilized for leaching is selected from the group comprising alcohol, nitrile, hydrocarbons etc. The preferred organic solvent is alcohol. The alcohol employed is selected from the group comprising of methanol, ethanol, isopropanol etc. The preferred alcohol is isopropanol. 19 The compound of formula (I) is air-dried at the temperature selected between 65°C and 80°C. The preferred temperature is between 70°C and 75°C. The compound is dried for 25 to 35 hours, but preferably for 30 hours. It should be noted that in the present embodiment, the final product is air-dried for only 30 hours, which is comparatively less time consuming than the previous embodiments, thereby making the process economical. The compound of formula (I), thus obtained by the process of the present invention exhibits a phosphate-binding activity between 14 meq/g and 17 meq/g, which is desired as per specification. We have calculated the Sevelamer yield, which is obtained by the Emcure's process with respect to the prior art process and the details are as follows: S.No Patent Number Allyl amine weight Sevelamer weight Yield w/w 1 US 4,605,701 570 gm 330 gm 0.57 w/w 2 i US 5,496,545 1798 gm 1668 gm 0.94 w/w 3 Invented Process 380 gm 410 gm 1.0 w/w (Example 3) to 1.08 w/w (Example 1) The invention can be further illustrated by the following examples, which however, should not be construed as limiting the scope of the invention. One pot synthesis of poly(allyIamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride. Example-1 Allylamine (500 ml, 6.66 mol.) was added drop-wise to a cold concentrated hydrochloric acid (35%, 562.5 ml). The reaction mass was stirred for 2 hours at 0°C to 5°C and the excess water (350 ml) was removed by vacuum distillation at 50°C. Azobis(amidonopropane) 20 dihydrochloride (15 gin) suspended in water (30ml) was added and the reaction temperature maintained at 50°C for 24 h. Azobis(amidinopropane) dihydrochloride (15 gm) suspended in water (30ml) was again added and stirred with heating for 64 to 68 hours. Distilled water (2400ml) was added and the pH of the reaction mixture was adjusted at 10.4 to 10.6 by addition of 30% caustic lye (500 ml, 0.5630 mol.). Epichlorohydrin (60 ml) was added in one lot at the temperature between 30-35°C and the reaction mass cured for 18 hours at the same temperature. The gel was then mixed with isopropanol (1725 ml) and stirred for 30 minutes. The solid was collected by filtration. The solid was rinsed once by suspending it into the water (7.5 liters), stirring the mixture for 1 hours and collecting the solid by filtration. The solid was leached with isopropanol (12 litres) for 1 hour and filtered. The solid was air-dried at 70-75°C for 30 hours to obtain compound of formula (I) Yield: 400-410 gms. One pot synthesis of poIy(aIlylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride Example-2 Allylamine (500ml, 6.66 mol) was mixed in water (75ml) then passed hydrochloric acid gas till the reaction mass had pH between 1.0 to 2.0. The reaction mass was stirred for 30 min. at 0°C to 5°C. Azobis(amidonopropane) dihydrochloride (15 gm) in water (30 ml) was added and the reaction temperature increased to 50°C and maintained for 24 h. Azobis(amidinopropane)dihydrochloride (15 gm) suspended in water (30ml) was again added and stirred with heating for 64 to 68 hours. Distilled water (2400ml) was added and the pH of the reaction mixture was adjusted at 10.0 to 10.6 by addition of 50% caustic lye (500 ml, 0.5630 mol.). Epichlorohydrin (60 ml) was added in one lot at the temperature between 30-35°C and the reaction mass cured for 18 hours at the same temperature. The gel was then mixed with isopropanol (1725 ml) and stirred for 30 minutes. The solid was collected by filtration. The wet cake was washed with water (7.5 liters). The solid was further washed with isopropanol (12 litres). The solid was dried at 70-75°C to obtain compound of formula (I) Yield: 395 gms. 21 One pot synthesis of poly(allylamine-co-N,N'-diaIlyI-l,3-diamino-2-hydroxypropane) hydrochloride Example-3 Allylamine (500 ml, 6.66 mol.) was dissolved in a mixture of methanol (500ml) and toluene (500ml) then passed hydrochloric acid gas between 0-5°C, till the reaction mass had pH between 1.0 to 2.0. The reaction mass was stirred for 2 hours at 0°C to 5°C and removed methanol and toluene by vacuum distillation at 50°C. Azobis(amidonopropane) dihydrochloride (15 gm) in water (30ml) was added and the reaction temperature increased to 50°C and maintained for 24 h. Azobis(amidinopropane)dihydrochloride (15 gm) suspended in water (30ml) was again added and stirred with heating for 64 to 68 hours. Distilled water (2400ml) was added and the pH of the reaction mixture was adjusted at 10.0 to 10.6 by addition of 50% caustic lye (500 ml, 0.5630 mol.). Epichlorohydrin (60 ml) was added at the temperature between 30-35°C and the reaction mass cured for 18 hours at the same temperature. The gel was then mixed with isopropanol (1725 ml) and stirred for 30 minutes. The solid was collected by filtration. The wet cake was washed with water (7.5 liters). The solid was further washed with isopropanol (12.5 litres). The solid was dried at 70-75°C to obtain compound of formula (I) Yield: 380 gms. ADVANTAGES: The advantages of the process of the present invention are as follows: i) This process is a single step process for preparing compound of formula (I) without isolation of compound (III), ii) It utilizes comparatively safer solvents having higher exposure limits like alcohols, instead of nitriles such as acetonitrile or chlorinated solvents like chlorobenzene and o- dichlorobenzene. Avoids use of hazardous solvents such as methyl cyamide. iii) It reduces the load on effluent by preparing compound (I) by eliminating the step of repeated leaching or washing of compound (III), 22 iv) The process avoids the operational difficulties, which are due to the hygroscopic nature of the intermediate (III) i.e. like loading of material from centrifuge into the dryer, etc. v) The process dries of the compound of formula (III) is avoided. Thus, the utility, efforts and cost of the process are reduced. vi) Use of caustic lye during the preparation of compound (I) from compound (III), makes the process comparatively more feasible than the use of solid sodium hydroxide as addition of solid sodium hydroxide makes the reaction suddenly exothermic and due to slow dissolution of solid sodium hydroxide, one cannot have an idea about the exact pH of the reaction mass, whereas caustic lye mixes easily due to which the reaction temperature and pH is controlled effectively. vii) The process is simple and economical since it avoids filtration of compound of formula (III) and avoids water distillation. 23 WE CLAIM: 1) A one pot process for the preparation of Sevelamer of formula I comprising the steps of: a) contacting allylamine of Formula (II) with hydrochloric acid in solvent to obtain allylamine hydrochloride of formula IIA b) contacting allylamine hydrochloride in-situ with a catalyst to obtain polyallylamine hydrochloride of Formula (III), and c) reacting pollyallylamine hydrochloride of Formula (III) with epichlorohydrin in the presence of base to get Sevelamer. Epichlorohydrine Poly (allylamine hydrochloride) *■ Sevelamer (III) Base (I) 2) A process according to claim 1, wherein hydrochloric acid is hydrochloric acid in solvent, or hydrochloric acid in gaseous state or liquid state. 3) A process according to claim 2, wherein the solvent is selected from the group comprising of water, an alcohol, ether, hydrocarbons and mixtures thereof. 4) A process according to claim 3, wherein the solvent is water. 5) A process according to claim 3, wherein the alcohol is selected form the group comprising of methanol, ethanol, isopropanol and mixtures thereof. 24 6) A process according to claim 5, wherein the more preferred solvent is methanol. 7) A process according to claim 4, wherein the preferred solvent is water. 8) A process according to claim 1, wherein the pH during the step 1(a) is upto 2.0 9) A process according to claim 1, wherein the catalyst is selected from the group comprising of azobis(amidinopropane)dihydrochloride , 4-4,-azobis (4-cyanovaleric acid), l,1-azobis(cyclohexene carbonitrile), benzoylperoxide, cumene hydroperoxide. 10) A process according to claim 9, wherein the preferred catalyst is azobis(amidinopropane)dihydrochloride. 11) A process according to claim 1, wherein the base is selected from alkali or alkaline earth metal hydroxides. 12) A process according to claim 11, wherein the preferred base is alkali hydroxide, carbonate, alkoxide of a alkali, alkaline earth metal or hydroxide of alkali metal. 13) A process according to claim 12, wherein the base is sodium hydroxide. 14) A process according to claim 1, wherein the pH in step (c) is between 10.0-11.0. 15) A process for the preparation of Sevelamer, substantially as described herein with reference to the examples. Dated this 9th day of May, 2006. [RAJESHWARI H.] OF K& S PARTNERS ATTORNEY FOR THE APPLICANT 25 ABSTRACT The present invention relates to an improved and industrial feasible process for the manufacture of copolymer, chemically known as poly(allylamine-co-N,N'-diallyl-l,3- diamino -2-hydroxypropane hydrochloride. 10 MAY 2006 26 COMPLETE AFTER PROVISIONAL FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13) 1. TITLE OF THE INVENTION "AN IMPROVED PROCESS FOR PREPARATION OF SEVELAMER" 2. APPLICANT (S) (a) NAME (b) NATIONALITY (c) ADDRESS Emcure Pharmaceuticals Ltd. India 12/2 F-ll Block, M.I.D.C, Pimpri, Pune- 411 018. AN IMPROVED PROCESS FOR PREPARATION OF SEVELAMER INTRODUCTION Hyperphosphatemia is a disease associated with acute and chronic renal failure and occurs when the serum phosphorus level is greater than 5 mg/dL (1.6 mmol/L), usually in the form of inorganic phosphorus. Hyperphosphatemia involves decreased Ca++ due to increased sperm phosphorus, increased parathyroid hormone secretion, and associated sequelae (Ref: http://www.phosphoruscontrol.com/HY/Default.aspx). Therapeutic efforts directed toward the control of hyperphosphatemia include dialysis, dietary phosphate reduction, and oral administration of insoluble phosphate-binding agents. As dialysis and dietary phosphate reduction alone is not able to sufficiently maintain normal phosphorus level in hyperphosphatemia! patients, a combination of therapies must be used such as use of one or more phosphate binders, which is routinely used to treat these patients (Ref: US 5 496 545 A). Phosphate binding agents act to reduce serum phosphorus ingested through the diet and include calcium, aluminium and magnesium salts or organic polymers such as poly (allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride. Calcium based phosphate binders have been widely used to bind intestinal phosphate and prevent absorption. Calcium carbonate and calcium acetate are the most commonly used calcium based phosphate binders, although calcium citrate, ketovalin, and alginate are also available. The ingested calcium combines with phosphate to form insoluble calcium phosphate salts. Side effects associated with these agents limit their effectiveness. The major side effect of this therapy is hypercalcemia. Hypercalcemia causes serious side effects such as renal failure, confusion etc. Treatment with calcium base phosphate binders requires frequent monitoring of serum calcium level (Ref: US 5 496 545 A; http://www.phosphoruscontrol.com/PH/CalciumBasedBinders.aspx). Aluminum is also an effective phosphate binder and is administered in the form of aluminum hydroxide, Al (OH) 3 gel and marketed as "Amphojel®". These compounds form complex with intestinal phosphate, to form highly insoluble aluminium phosphate. Prolong use of these gels may lead to aluminum toxicity accompanied by symptoms such as myopathy, severe bone disease and anemia (Ref: US 5 496 545 A and http://www.phosphoruscontrol.com/PH/AluminumBasedBinders.aspx). Magnesium salts are also known to work as phosphate binder however; they are rarely used because of risk of hypomagnesaemia in renal failure. Organic polymers are also used as phosphate binders. The said organic polymers are, for example the ion exchange resins like Dowex®, XF43311 etc. These resins have several drawbacks like need for high dosage, poor binding capacity etc. (Ref: US 5 496 545 A). Poly(allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride is one of the therapeutic drug used for the treatment of hyperphosphatemia. It is a copolymer of allylamine and epichlorohydrin, which is a phosphate binder used to reduce the absorption of dietary phosphate. It is used to reduce the serum phosphorus in patients with severe kidney disease known as End Stage Renal Disease (ESRD). Poly(allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride is marketed by Geltex Pharmaceuticals after USFDA approved the active ingredient in October 1998 for the treatment of high level of serum phosphorus in patients with end-stage renal disease. This active ingredient, which is both calcium-free and aluminum-free, enables the fast treatment of hyperphosphatemia without the risks associated with other treatments. Poly(allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride treatment also results in a lowering of low-density lipoprotein (LDL) and total serum cholesterol levels. (Ref: http://www.centerwatch.com/patient/drugs/dru640.html) and label information of poly(allylamine-co-N, N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride, available on USFDA website). BACKGROUND OF THE INVENTION: Poly(allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane)hydrochloride of formula (I) is a poly(allylamine hydrochloride) cross-linked with epichlorohydrin in which 40% amines are protonated. 3 mixture was quenched with methanol. Poly(allylamine hydrochloride) of formula (III) was isolated by filtration and dried at 50°C under reduced pressure. An aqueous solution of polyallylamine was prepared by neutralizing compound of formula (III) with an aqueous solution of sodium hydroxide. Epichlorohydrin (IV) was added to an aqueous solution of polyallylamine and stirred for two minutes. The resulting mixture was added into a mixture of chlorobenzene, o-dichlorobenzene and Silvan S-83, to obtain a dispersion, which was allowed to cross-link at 25°C for 30 minutes and at 50°C for 2 hours. The desired compound was filtered and washed successively with methanol, IN sodium hydroxide, and D.M water. The compound of formula (I) was then dried under reduced pressure at 50°C. The above embodiment for the preparation of compound of formula (I) has the following disadvantages, which are: a) isolation of intermediates like monoallylamine hydrochloride of formula (IIA) and poly(allylamine hydrochloride) of formula (III) makes the process time consuming, lengthy and tedious, b) the intermediate (III) was dried under vacuum due to its hygroscopic nature, and this step utilizes more utility and time, c) the process for the preparation of compound (I) utilizes Class 2 solvents such as chlorobenzene, o-dichlorobenzene for the reaction, which in turn makes the process hazardous for human health and environment, and d) the above process also requires a dispersion stabilizer like Silvan S-83, which makes the process uneconomical. US 2004/0028803 Al discloses synthesis of compound of formula (I) in the form of gel, comprising reaction of poly(allylamine hydrochloride) (III) with epichlorohydrin of formula (IV) in an aqueous solution, at a pH between 10.0 and 10.4 adjusted by addition of 50% caustic lye, and maintaining the temperature between 5°C to 10°C followed by a process of gelling for 24 hours. 6 "8 1 10000 50800 4000 54800 1 09/05/06 ongwith claims men ted Tota e Pay 44708 Da c o tion a anc cat fica o n r- Q. Description Form 18 (B Cheque No. Filing new ap Complete sp ype of ppln. — $ H ay 09,20 roadcast 3 CO S c o 5/0 .19 Title/ Patent Appln. No. 1335/MUMNP/2005 Scalable Encoding For Multicast E Multimedia Service An improved process for preparat sevelamer Cheque No. 144709 Dated 09/0 lient / cant Thornton comm Inc ure Pharmaceuticals ppl U i Attorney/Secy. 2946 '> oDC 3704 /Babu 2509 /Nakul File IPO V>> IPO 55 IPO £ Scheme-2: Method as disclosed in US 5 496 545 for preparation of compound of formula (I)- The method disclosed in US 5 496 545 for preparation of compound of formula (I) comprises of two steps: i) reacting allylamine (II) with concentrated hydrochloric acid in aqueous medium to form allylamine hydrochloride (IIA), followed by removal of water by vacuum distillation at 60°C-70°C, ii) adding the catalyst azobis(amidinopropane) dihydrochloride in two lots and stirring the reaction for 24 hours and 44 hours respectively, after the addition of each lot, to form poly (allylamine hydrochloride) of formula (III), iii) separating out compound (III) after quenching with methanol, followed by filtering and leaching with methanol repeatedly, and iv) reacting epichlorohydrin (IV) with compound (III) in an aqueous medium, by adjusting pH 10 with solid sodium hydroxide and curing for 18 hours, followed by quenching with isopropanol to give compound of formula (I), which was vacuum dried for 18 hours. The above process also has several drawbacks like: a) water has to be removed under vacuum during the preparation of poly (allylamine hydrochloride) of formula (III). Removal of water by distillation consumes lot of energy, which makes the process cumbersome, time consuming and tedious on commercial scale, b) due to hygroscopic nature of the intermediate of formula (III), the filtration has to be carried out under stringent conditions, c) further, there is a danger of loss in yield during filtration and leaching, which is done repeatedly. Repeated methanol washing and filtration generates large quantity of effluent, that has to be either recycled by distillation or disposed in the effluent treatment plant. US 6,290,947 (assigned to Geltex Pharmaceuticals) discloses the preparation of compound of formula (I) comprising reaction of poly (allylamine hydrochloride) of formula (III) in an aqueous medium, at a pH of 10.5 with solid sodium hydroxide, until homogenous mixture was formed. Reaction with epichlorohydrin of formula (IV) was carried out at a pH of 10.2 (Ref: Example 5 of US 6 290 945) and the reaction mixture cured for 18 hours to provide a gel, which is broken up with Kitchen Aid Mixer. Further, washings are given until the conductivity of the effluent was equal to 16.7 mS/cm. The co-polymer of formula (I) was air-dried at 60°C for 5 days. The above process, although it seems to be commercially viable, has some limitations like: a) during the process, pH was reduced to a specific range between 10.2 and 10.5. Maintaining pH on a commercial scale, at a precise pH is very tedious. Further, monitoring the sharp pH for a long period is cumbersome. b) use of Kitchen Aid Mixer for breaking gel on commercial scale is another limitation. c) monitoring the washing process of final gel till the conductivity of effluent equals 16.7 mS/cm is cumbersome, and puts limitation on online quality control, adds additional manpower, requires more analytical instruments. d) the final product of formula (I) prepared by this method takes 5 days for drying, thereby increasing the time cycle for each run. This increases drier occupancy and utility for a longer time, thereby, making the process uneconomical. US 6 525 113 discloses the preparation of Poly(allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride of formula (I) comprising reaction of an aqueous solution of Poly(allylamine hydrochloride) of formula (III) in presence of sodium hydroxide, with epichlorohydrin of formula (IV) at temperature between 20°C to 30°C. The reaction was carried out in a water-miscible solvent like acetonitrile. It should be noted that this method also utilizes a Class 2 solvent like acetonitrile (methyl cyanide), which has got quite a low exposure limit of 410 ppm. Utilization of such a hazardous cyanide solvent on an industrial scale makes the process environmentally dangerous and less feasible. 9 Considering all the above shortcomings in the prior art, the applicant has developed a simple and industrially viable process for the preparation of compound of formula (I), which is one-pot reaction, avoiding isolation of compound of formula (III). The method embodied in this invention reduces the time cycle for each batch run, reduces cost, efforts and thereby, makes the process commercially viable. OBJECT OF THE INVENTION An object of the invention is to provide simple and cost effective process for the preparation of poly(allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride of formula (I)- Another object of the invention is to provide a single-pot process for the preparation of poly (allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride, wherein the overall period for completion of the reaction is reduced, making the process suitable for commercial applications. Yet, another object is to provide a-process for the preparation of poly(allylamine-co-N, N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride having phosphate binding capacity as per desired specification. SUMMARY OF THE INVENTION: One aspect of the invention is to provide an economical, simple and improved process for the preparation of poly(allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride of formula (I). Another aspect of the invention relates to an industrially feasible, one pot reaction for preparation of poly(allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride of formula (I), which comprises reaction of allylamine of formula (II) with hydrochloric acid in presence of a catalyst i.e. azobis(amidinopropane) dihydrochloride, and optionally a solvent to 10 form a poly (allylamine hydrochloride) of formula (III), which is treated in situ with epichlorohydrin of formula (IV) at a pH between 10 to 10.5 in an aqueous medium. Further aspect of the invention relates to a simple and commercially viable process for the preparation of poly(allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride of formula (I), in a single pot, comprising reaction of allylamine of formula (II) with hydrochloric acid in an organic solvent, in presence of catalyst i.e. azobis (amidinopropane) dihydrochloride, to form poly(allylamine hydrochloride) (III), which on further reaction with epichlorohydrin (IV) at a pH between 10 to 10.5, leads to the formation of poly(allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride of formula (I). DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an improved method for the preparation of poly (allylamine-co-N, N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride of formula (I), without isolation of the intermediate, poly (allylamine hydrochloride) of formula (III). The said process broadly comprises the steps of: a) reacting allylamine of Formula (II) with hydrochloric acid in an organic or inorganic solvent to get allylamine hydrochloride of formula IIA b) reacting allylamine hydrochloride in-situ in presence of catalyst to get polyallylamine hydrochloride of Formula (III), and 11 aqueous solution of catalyst azobis (amidinopropane) dihydrochloride, and stirring the reaction mixture at a temperature between 50°C and 55°C after the addition of catalyst, b) adding water to the reaction mixture and adjusting the pH of the reaction mixture between 10.0 and 11.0 with an inorganic base, c) adding epichlorohydrin of formula (IV) into the reaction mixture at room temperature and keeping for curing for 15 to 20 hours, d) quenching the reaction mass with an organic solvent to separate the compound of formula (I), followed by leaching the filtered solid with an inorganic and organic solvent and filtering the same, and e) air-drying at 70°C -75°C for 25 to 35 hours. In the present invention, all steps are carried out in a single step i.e. the preparation of compound of formula (I) is a one pot reaction, which obviates the need for isolation of compound (III), thereby reducing the time cycle for each batch run and making the process cost-effective. The compound of formula (I) is a very important and a very costly copolymer used for phosphate binding, in the treatment of hyperphosphatemia. It is very important that compound of formula (I), is obtained in high yield with desired specifications, without utilization of additional steps of purification and isolation of intermediate (III). Compound (I) is prepared by adding allylamine (II) to aqueous concentrated hydrochloric acid and adding a catalyst to yield poly(allylamine hydrochloride) (III) in situ; epichlorohydrin (IV) is then added to the reaction mass and stirred, till compound (I) of desired specification is obtained. The reaction of allylamine and concentrated hydrochloric acid is carried out between the temperatures -10°C to +5°C. The preferred temperature is between -5°C and 0°C to form allylamine hydrochloride. The reaction mass pH is adjusted up to 2.0. 13 Excess water was distilled off at the temperature between 45°C and 60°C. The preferred temperature is around 50°C. A catalyst like azobis(amidonopropane) dihydrochloride is added and stirred for around 90 hours. The reaction is carried out at a temperature selected between 45°C and 70°C. The preferred temperature is between 50°C to 55°C for preparation of poly(allylamine hydrochloride) of formula (III). Any other similar catalyst such as 4-4"-azobis (4-cyanovaleric acid), l,r-azobis(cyclohexene carbonitrile), benzoylperoxide, cumene hydroperoxide may also be employed. The addition of epichlorohydrin of formula (IV) is carried out by adjusting the pH of reaction mass with an inorganic base selected from the group comprising of hydroxides, carbonates or alkoxide of alkali or alkaline earth metals, but preferably the hydroxide of an alkali metal. The amount of allyl amine and epichlorohydrine is in the ratio of 1: 0.075 to 1: 0.175. The preferred allyl amine and epichloro hydrine ratio is 1: 0.115. The preferred alkali metal hydroxide is sodium hydroxide. An aqueous solution of sodium hydroxide is added to the mixture. The amount in moles of sodium hydroxide added is between 0.50 moles to 0.65 moles per mole of allylamine (II). The preferred amount of sodium hydroxide is between 0.55 moles to 0.60 moles per mole of compound (I). The compound of formula (I) is obtained by co-polymerization of compound of formula (III) with epichlorohydrin of formula (IV) after adjusting the pH of the reaction mixture with an inorganic base in an aqueous medium. The co-polymerization of compound (III) is carried out at a pH between 10 and 11. The preferred pH range is between 10.4 and 10.6. The addition of epichlorohydrin (IV) to the reaction mixture-containing compound (III) is carried out at a temperature between 25°C and 40°C. The preferred temperature is between 30°C and 35°C. 14 The cross linked polymer of formula (I) is cured for 15 to 20 hours, but preferably 18 hours at a temperature between 25°C and 40°C. The preferred temperature is between 30°C and 35°C. The amount of epichlorohydrin (IV) added may vary from 0.075 to 0.175 mole equivalent with respect to allyl amine. The compound of formula (1) is obtained by quenching the reaction mixture with a water-miscible protic or aprotic organic solvent. The preferred solvent is a water-miscible protic solvent. Water miscible protic solvents are selected from the group like alcohols, thiols, etc. The preferred water-miscible protic solvent is an alcohol. The alcohol employed is selected from the group comprising of methanol, ethanol, isopropanol etc. The preferred alcohol is isopropanol. The reaction mixture is filtered and the wet cake is then leached separately with an inorganic or a organic solvent. The inorganic solvent utilized for leaching is water. Organic solvents utilized for the leaching is selected from the group comprising of alcohol, nitrile, hydrocarbons etc. The preferred organic solvent is an alcohol. The alcohol employed is selected from the group comprising of methanol, ethanol, isopropanol etc. The preferred alcohol is isopropanol. The compound of formula (I) is air-dried at the temperature selected between 65°C and 80°C. The preferred temperature is between 70°C and 75°C. The compound is dried for 25 to 35 hours, but preferably for 30 hours. It should be noted that in the present embodiment, the final product is air-dried for only 30 hours, which is comparatively less time consuming than the prior art, thereby making the process economical. 15 of hydrochloric acid leading to formation of allylamine hydrochloride (N-A). removing the organic solvent under vacuum, adding an aqueous solution of catalyst, azobis (amidinopropane) dihydrochloride, to the reaction mixture at a temperature between 45°C to 55°C and stirring the reaction mixture. b) adding water to the residue and adjusting the pH of the reaction mixture between 10.0 and 11.0 with an inorganic base. c) adding epichlorohydrin of formula (IV) to the reaction mixture at room temperature and curing for 15 to 20 hours. d) quenching the reaction mass with an organic solvent to separate the compound of formula (I), followed by leaching the filtered solid by inorganic and organic solvent and filtering the same. e) air-drying at 70°C -75°C for 25 to 35 hours. In both the methods, compound (I) is prepared one-pot, without isolation of compound (III). An important feature of Method-B is the utilization of an organic solvent in step (a), which is removed very readily and in a short time after preparation of compound (III) as compared to Method-A and is much superior to prior art methods. Method-B reduces time cycle, saves considerable energy and thereby makes the process more economical, cost-effective and commercially viable. Hydrochloric acid either as gas or as an aqueous solution is added to an organic solvent. The organic solvent is selected from the group comprising of an alcohol, ether, hydrocarbons etc. The preferred solvent is an alcohol. The alcohol employed is selected from the group comprising of methanol, ethanol, isopropanol etc. The preferred alcohol is methanol. Allylamine of formula (II) is added to a mixture of methanol and HCl (g) or aqueous HCl at a temperature between -10°C to +5°C. The preferred temperature is in between -5°C and 0°C. The reaction mass pH is adjusted preferably up to 2.0. 17 The reaction mixture was stirred for duration of between 1 hour and 3 hours. The preferred time duration is 2 hours. Methanol is distilled off at a temperature between 45°C and 60°C. The preferred temperature is around 50°C. A catalyst like azobis(amidinopropane) dihydrochloride was added and stirred for around 84 hours. The reaction is carried out at a temperature selected between 45°C and 70°C. The preferred temperature is between 50°C to 55°C for preparation of poly(allylamine hydrochloride) of formula (III). The addition of epichlorohydrin (IV) is carried out by adjusting the pH of reaction mass with an inorganic base selected from the group comprising of hydroxides, carbonates or alkoxide of alkali or alkaline earth metals, but preferably the hydroxide of an alkali metal. The preferred alkali metal hydroxide is sodium hydroxide. An aqueous solution of sodium hydroxide is added to the mixture. The amount in moles of sodium hydroxide required is between 0.50 moles to 0.75 moles per mole of allylamine (II). The preferred amount of sodium hydroxide is between 0.55 moles to 0.65 moles per mole of compound (I). The compound of formula (I) is obtained by co-polymerization of a compound of formula (III) with epichlorohydrin of formula (IV) after adjusting the pH of the reaction with an inorganic base in aqueous medium. The co-polymerization of compound (III) is carried out at a pH between 10.0 and 11.0. The preferred pH range is between 10.4 and 10.6. 18 The addition of epichlorohydrin (IV) to the reaction mixture-containing compound (III) is carried out at a temperature between 25°C and 40°C. The preferred temperature is between 30°C and 35°C. The cross-linked polymer of formula (I) is cured for 15 to 20 hours, but preferably 18 hours at a temperature between 25°C and 40°C. The preferred temperature is between 30°C and 35°C. The compound of formula (I) is obtained by quenching the reaction mixture with a water-miscible protic or aprotic organic solvent. The preferred organic solvent is a water-miscible protic solvent. Water miscible protic solvents are selected from the group like alcohols, thiols, etc. The preferred water miscible protic solvent is an alcohol. The alcohol employed is selected from the group comprising of methanol, ethanol, isopropanol etc. The preferred alcohol is isopropanol. The volume of isopropanol added is between 15 volumes and 30 volumes per gram of compound (II). The reaction mixture is then stirred, filtered and leached separately with inorganic and organic solvent and filtered. The inorganic solvent utilized for the leaching is water. Organic solvents utilized for leaching is selected from the group comprising alcohol, nitrile, hydrocarbons etc. The preferred organic solvent is alcohol. The alcohol employed is selected from the group comprising of methanol, ethanol, isopropanol etc. The preferred alcohol is isopropanol. 19 The compound of formula (I) is air-dried at the temperature selected between 65°C and 80°C. The preferred temperature is between 70°C and 75°C. The compound is dried for 25 to 35 hours, but preferably for 30 hours. It should be noted that in the present embodiment, the final product is air-dried for only 30 hours, which is comparatively less time consuming than the previous embodiments, thereby making the process economical. The compound of formula (I), thus obtained by the process of the present invention exhibits a phosphate-binding activity between 14 meq/g and 17 meq/g, which is desired as per specification. We have calculated the Sevelamer yield, which is obtained by the Emcure's process with respect to the prior art process and the details are as follows: S.No Patent Number Allyl amine weight Sevelamer weight Yield w/w 1 US 4,605,701 570 gm 330 gm 0.57 w/w 2 i US 5,496,545 1798 gm 1668 gm 0.94 w/w 3 Invented Process 380 gm 410 gm 1.0 w/w (Example 3) to 1.08 w/w (Example 1) The invention can be further illustrated by the following examples, which however, should not be construed as limiting the scope of the invention. One pot synthesis of poly(allyIamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride. Example-1 Allylamine (500 ml, 6.66 mol.) was added drop-wise to a cold concentrated hydrochloric acid (35%, 562.5 ml). The reaction mass was stirred for 2 hours at 0°C to 5°C and the excess water (350 ml) was removed by vacuum distillation at 50°C. Azobis(amidonopropane) 20 dihydrochloride (15 gin) suspended in water (30ml) was added and the reaction temperature maintained at 50°C for 24 h. Azobis(amidinopropane) dihydrochloride (15 gm) suspended in water (30ml) was again added and stirred with heating for 64 to 68 hours. Distilled water (2400ml) was added and the pH of the reaction mixture was adjusted at 10.4 to 10.6 by addition of 30% caustic lye (500 ml, 0.5630 mol.). Epichlorohydrin (60 ml) was added in one lot at the temperature between 30-35°C and the reaction mass cured for 18 hours at the same temperature. The gel was then mixed with isopropanol (1725 ml) and stirred for 30 minutes. The solid was collected by filtration. The solid was rinsed once by suspending it into the water (7.5 liters), stirring the mixture for 1 hours and collecting the solid by filtration. The solid was leached with isopropanol (12 litres) for 1 hour and filtered. The solid was air-dried at 70-75°C for 30 hours to obtain compound of formula (I) Yield: 400-410 gms. One pot synthesis of poIy(aIlylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride Example-2 Allylamine (500ml, 6.66 mol) was mixed in water (75ml) then passed hydrochloric acid gas till the reaction mass had pH between 1.0 to 2.0. The reaction mass was stirred for 30 min. at 0°C to 5°C. Azobis(amidonopropane) dihydrochloride (15 gm) in water (30 ml) was added and the reaction temperature increased to 50°C and maintained for 24 h. Azobis(amidinopropane)dihydrochloride (15 gm) suspended in water (30ml) was again added and stirred with heating for 64 to 68 hours. Distilled water (2400ml) was added and the pH of the reaction mixture was adjusted at 10.0 to 10.6 by addition of 50% caustic lye (500 ml, 0.5630 mol.). Epichlorohydrin (60 ml) was added in one lot at the temperature between 30-35°C and the reaction mass cured for 18 hours at the same temperature. The gel was then mixed with isopropanol (1725 ml) and stirred for 30 minutes. The solid was collected by filtration. The wet cake was washed with water (7.5 liters). The solid was further washed with isopropanol (12 litres). The solid was dried at 70-75°C to obtain compound of formula (I) Yield: 395 gms. 21 One pot synthesis of poly(allylamine-co-N,N'-diaIlyI-l,3-diamino-2-hydroxypropane) hydrochloride Example-3 Allylamine (500 ml, 6.66 mol.) was dissolved in a mixture of methanol (500ml) and toluene (500ml) then passed hydrochloric acid gas between 0-5°C, till the reaction mass had pH between 1.0 to 2.0. The reaction mass was stirred for 2 hours at 0°C to 5°C and removed methanol and toluene by vacuum distillation at 50°C. Azobis(amidonopropane) dihydrochloride (15 gm) in water (30ml) was added and the reaction temperature increased to 50°C and maintained for 24 h. Azobis(amidinopropane)dihydrochloride (15 gm) suspended in water (30ml) was again added and stirred with heating for 64 to 68 hours. Distilled water (2400ml) was added and the pH of the reaction mixture was adjusted at 10.0 to 10.6 by addition of 50% caustic lye (500 ml, 0.5630 mol.). Epichlorohydrin (60 ml) was added at the temperature between 30-35°C and the reaction mass cured for 18 hours at the same temperature. The gel was then mixed with isopropanol (1725 ml) and stirred for 30 minutes. The solid was collected by filtration. The wet cake was washed with water (7.5 liters). The solid was further washed with isopropanol (12.5 litres). The solid was dried at 70-75°C to obtain compound of formula (I) Yield: 380 gms. ADVANTAGES: The advantages of the process of the present invention are as follows: i) This process is a single step process for preparing compound of formula (I) without isolation of compound (III), ii) It utilizes comparatively safer solvents having higher exposure limits like alcohols, instead of nitriles such as acetonitrile or chlorinated solvents like chlorobenzene and o- dichlorobenzene. Avoids use of hazardous solvents such as methyl cyamide. iii) It reduces the load on effluent by preparing compound (I) by eliminating the step of repeated leaching or washing of compound (III), 22 iv) The process avoids the operational difficulties, which are due to the hygroscopic nature of the intermediate (III) i.e. like loading of material from centrifuge into the dryer, etc. v) The process dries of the compound of formula (III) is avoided. Thus, the utility, efforts and cost of the process are reduced. vi) Use of caustic lye during the preparation of compound (I) from compound (III), makes the process comparatively more feasible than the use of solid sodium hydroxide as addition of solid sodium hydroxide makes the reaction suddenly exothermic and due to slow dissolution of solid sodium hydroxide, one cannot have an idea about the exact pH of the reaction mass, whereas caustic lye mixes easily due to which the reaction temperature and pH is controlled effectively. vii) The process is simple and economical since it avoids filtration of compound of formula (III) and avoids water distillation. 23 WE CLAIM: 1) A one pot process for the preparation of Sevelamer of formula I comprising the steps of: a) contacting allylamine of Formula (II) with hydrochloric acid in solvent to obtain allylamine hydrochloride of formula IIA b) contacting allylamine hydrochloride in-situ with a catalyst to obtain polyallylamine hydrochloride of Formula (III), and c) reacting pollyallylamine hydrochloride of Formula (III) with epichlorohydrin in the presence of base to get Sevelamer. Epichlorohydrine Poly (allylamine hydrochloride) *■ Sevelamer (III) Base (I) 2) A process according to claim 1, wherein hydrochloric acid is hydrochloric acid in solvent, or hydrochloric acid in gaseous state or liquid state. 3) A process according to claim 2, wherein the solvent is selected from the group comprising of water, an alcohol, ether, hydrocarbons and mixtures thereof. 4) A process according to claim 3, wherein the solvent is water. 5) A process according to claim 3, wherein the alcohol is selected form the group comprising of methanol, ethanol, isopropanol and mixtures thereof. 24 6) A process according to claim 5, wherein the more preferred solvent is methanol. 7) A process according to claim 4, wherein the preferred solvent is water. 8) A process according to claim 1, wherein the pH during the step 1(a) is upto 2.0 9) A process according to claim 1, wherein the catalyst is selected from the group comprising of azobis(amidinopropane)dihydrochloride , 4-4,-azobis (4-cyanovaleric acid), l,1-azobis(cyclohexene carbonitrile), benzoylperoxide, cumene hydroperoxide. 10) A process according to claim 9, wherein the preferred catalyst is azobis(amidinopropane)dihydrochloride. 11) A process according to claim 1, wherein the base is selected from alkali or alkaline earth metal hydroxides. 12) A process according to claim 11, wherein the preferred base is alkali hydroxide, carbonate, alkoxide of a alkali, alkaline earth metal or hydroxide of alkali metal. 13) A process according to claim 12, wherein the base is sodium hydroxide. 14) A process according to claim 1, wherein the pH in step (c) is between 10.0-11.0. 15) A process for the preparation of Sevelamer, substantially as described herein with reference to the examples. Dated this 9th day of May, 2006. [RAJESHWARI H.] OF K& S PARTNERS ATTORNEY FOR THE APPLICANT 25 ABSTRACT The present invention relates to an improved and industrial feasible process for the manufacture of copolymer, chemically known as poly(allylamine-co-N,N'-diallyl-l,3- diamino -2-hydroxypropane hydrochloride. 10 MAY 2006 26

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