Title of Invention	PROCESS FOR THE PREPARATION OF SEVELAMER CARBONATE
Abstract	The present invention relates to process for the preparation of copolymer, chemically known as poly(allylamine-co-N,N"-diallyl-1,3-diamino-2-hydroxypropane) carbonate (Sevelamer carbonate), wherein sevelamer base is suspended in solvent then treated with carbon dioxide followed by filtration to get sevelamer carbonate.

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FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION (See section 10, rule 13) “PROCESS FOR THE PREPARATION OF PHOSPHATE BINDING POLYMER EMCURE PHARMACEUTICALS LTD., R&D Centre, T-184, MIDC, Bhosari, Pune 411026, Maharashtra, 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 process for the preparation of copolymer, chemically known as poly(allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) carbonate i.e., Sevelamer carbonate. BACKGROUND OF THE INVENTION: 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 serum 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 hyperphosphatemial 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 (sevelamer hydrochloride) and sevelamer carbonate. 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 2 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). Sevelamer 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). Selvelamer hydrochloride liberates hydrochloride in the gastrointestinal area, hydrochloric acid does not provide any known therapeutic benefit for patient. In hemodialysis patients there is small increase in serum chloride and reduction in serum bicarbonate. Selvelamer hydrochloride treatment demanding the monitoring of chloride and bicarbonate levels, may be eliminated with the replacement of chloride ion by carbonate. Therefore, selvelamer carbonate has been developed as a pharmaceutical alternative to selvelamer hydrochloride ( Ref: Journal of Renal Nutrition, Vol 16, No 3; 248-252). 3 Sevelamer carbonate is having the same polymeric structure as selvelamer hydrochloride, in which carbonate is an alternative counter ion in place of chloride. Though, the counter ion differs from hydrochloride to carbonate, the active moiety "selvelamer" is responsible for binding of phosphate. Sevelamer carbonate is a different formulation i.e., a non chloride formulation and it can be addressed as the treatment to the chronic kidney disease (CKD) patient population and effectively treat dialysis patients. Sevelamer carbonate powder form is expected to be more convenient and lead to better patient compliance. In addition to this, Sevelamer corbonate powder formulation can help to address a wider patient population including pediatric use. The relevant patents US 5,496,545, US 5,667,775, US 6,083,495, US 6,509,013, US 6,858,203, and US 7,014,846, do not disclose the manufacturing process for the preparation of selvelamer carbonate. Thus, the prior art references neither disclose the synthetic process, nor commercial manufacturing process for the preparation of selvelamer carbonate. Therefore, this is a need to develop the industrially feasible process for the preparation of sevelamer carbonate. Herein is developed an industrially feasible process for the preparation of sevelamer carbonate. OBJECT OF THE INVENTION: The object of the invention is to develop commercially feasible process for the preparation of sevelamer carbonate. SUMMARY OF THE INVENTION: The present invention provides a commercially feasible process for the preparation of selvelamer carbonate. 4 DETAILED DESCRIPTION OF THE INVENTION: The present invention provides a commercially feasible process for the preparation of sevelamer carbonate, which comprises the steps of: a) reacting sevelamer hydrochloride in the presence of base in a first solvent medium to get sevelamer base, b) reacting sevelamer base with carbon dioxide in a second solvent medium to obtain sevelamer carbonate which is optionally filtered, washed with a third solvent, and dried. Sevelamer hydrochloride is suspended in first solvent and then the aqueous base is added to the reaction mass. The first solvent may be either water or water in combination with alcohol or ketone. The base is selected form the group comprising of alkali or alkaline earth metal hydroxides. The preferable alkali or alkaline earth metals are sodium, potassium, calcium and magnesium. More preferred alkali metal hydroxide is sodium hydroxide. The preparation of sevelamer base from sevelamer hydrochloride is carried out at about temperature 10-50° C. The preferred temperature is 20-40° C. Sevelamer hydrochloride is suspended in water medium at 20-40° C then the suspension pH is adjusted with aqueous sodium hydroxide solution. The suspension pH is adjusted to 10 to 13. The preferred pH is 12.0 to 13.0. The resulting slurry is filter to get the sevelamer base. Sevelamer base is suspended in a second solvent medium at ambient temperature. The said solvent medium is selected from the group comprising of water or a mixture of water and water miscible organic solvent such as alcohol, ketone etc. The water miscible organic solvent is selected from the group comprising of methanol, ethanol, isopropyl alcohol, acetone, methyl ethyl ketone. The preferred water miscible organic solvent is acetone; more preferred water miscible solvent is methanol. 5 Sevelamer base is suspended in water at temperature about 10-50° C. The preferred temperature is 20-40° C. Sevelamer base is suspended in water or a mixture of water and water miscible organic solvent then the resulting suspension pH is adjusted to 5.0 to 8.0 with carbon dioxide. The preferred pH is 6.0 to 7.0. The resulted slurry is filtered, washed with water or a mixture of water and water miscible organic solvent followed by drying to get sevelamer carbonate. Carbon dioxide can be used in the form of gaseous or solid state. The preferred form of carbon dioxide is in the form of gaseous state. Normally carbonate salts are prepared by using inorganic salts such as sodium carbonate, potassium carbonate, calcium carbonate or magnesium carbonate etc. Thus, the corresponding inorganic salts are present in the final product. The final product needs repeated washings with a third solvent such as water or water miscible organic solvent or combinations thereof to get the desired quality of the final product. The traces of such ions are the obstacles in bulk drugs in view of residue on ignition. The major advantage of the above invention is simple and industrially feasible process for the preparation of sevelamer carbonate, without subjecting repeated water washings to remove the inorganic salts. The gaseous can be simply bubbled into the reaction mass to obtain the carbonate. The present invention is more particularly illustrated in the following example(s), but does not to limit the scope of the present invention. Examples: Example-1 Process for the preparation of Sevelamer carbonate: 6 Sevelamer hydrochloride 250 gm was suspended in water 3.0 L at 25-30° C. Sodium hydroxide 35.55 gm (0.88 mole) in 35.50 ml was added into the above suspension to adjust the pH between 12.0 to 13.0. Stirred the resulting slurry was filtered and washed with water 1250 ml to get sevelamer base. Sevelamer was suspended in water 1.25 L at room temperature. Carbon dioxide gas was purged in to the slurry to adjust pH 6.0 to 7.0. The slurry was filtered and washed with water to get sevelamer carbonate. Dry weight = 220 gm Example-2 Process for the preparation of Sevelamer carbonate: Sevelamer hydrochloride 100 gm was suspended in a mixture of water 600 ml and methanol 600 ml 25-30° C. Sodium hydroxide 14.00 gm (0.35 mole) in 14.00 ml was added into the above suspension to adjust the pH between 12.0 to 13.0. Stirred the resulting slurry was filtered and washed with water to get sevelamer base. Sevelamer base was suspended in a mixture of waiter 250 ml and methanol 250 ml at room temperature. Carbon dioxide gas was purged in to the slurry to adjust pH 6.0 to 7.0. The slurry was filtered and washed with water to get sevelamer carbonate. Dry weight = 84 gm Example-3 Process for the preparation of Sevelamer carbonate: Sevelamer hydrochloride 100 gm was suspended in a mixture of water 600 ml and acetone 600 ml 25-30° C. Sodium hydroxide 12.50 gm (0.31 mole) in 12.50 ml was added into the above suspension to adjust the pH between 12.0 to 13.0. Stirred the resulting slurry was filtered and washed with water to get sevelamer base. 7 Sevelamer base was suspended in a mixture of water 250 ml and acetone 250 ml at room temperature. Carbon dioxide gas was purged in to the slurry to adjust pH 6.0 to 7.0. The slurry was filtered and washed with water to get sevelamer carbonate. Dry weight = 85 gm Example-4 Process for the preparation of Sevelamer carbonate: Sevelamer hydrochloride 60 gm was suspended in water 720 ml at 25-30° C. Sodium hydroxide 6.50 gm (0.16 mole) in 6.50 ml was added into the above suspension to adjust the pH between 12.0 to 13.0. Stirred the resulting slurry was filtered and washed with water to get sevelamer base. Sevelamer base was suspended in water 300 ml at room temperature. Carbon dioxide solid was added in to the slurry to adjust pH 6.0 to 7.0. The slurry was filtered and washed with water to get sevelamer carbonate. Dry weight = 49.5 gm 8 We claim: 1. A process for the preparation of sevelamer carbonate, comprising the steps of: a) reacting sevelamer hydrochloride in the presence of base in a first solvent medium to get sevelamer base, b) reacting sevelamer base with carbon dioxide in a second solvent medium to obtain sevelamer carbonate which is optionally filtered, washed with a third solvent, and dried. 2. A process according to claim la, wherein base is selected form the group comprising of alkali or alkaline earth metal hydroxides. 3. A process according to claim 2, wherein the preferable alkali or alkaline earth metals are sodium, potassium, calcium and magnesium. 4. A process according to claim 3, wherein the said more preferred alkali metal hydroxide is sodium hydroxide. 5. A process according to claim la, wherein the said first solvent is selected from water or combination of water with alcohol or ketone. 6. A process according to claim la and lb, wherein the reaction temperature is about 10-50° C. 7. A process according to claim 6, wherein the said preferred temperature is 20-40° C. 8. A process according to claim lb, wherein the second solvent is selected from the group comprising of water or a mixture of water and water miscible organic solvent. 9. A process according to claim 8, wherein said water miscible organic solvent is selected from the group comprising of alcohol and ketone. 10. A process according to claim 9, wherein the said alcohol is selected from the group comprising of methanol, ethanol and isopropyl alcohol. 9 11. A process according to claim 9, wherein said ketone is selected from the group comprising of acetone and methyl ethyl ketone. 12. A process according to claim 11, wherein the said preferred ketone is acetone. 13. A process according to claim 10, where in said more preferred alcohol is methanol. 14. A process according to claim lb, wherein carbon dioxide is in gaseous or solid state. 15. A process according to claim 14, wherein the carbon dioxide is in gaseous state. 16. A process according to claim lb, wherein the pH is between 5.0 - 8.0. 17. A process according to claim 16, wherein the preferred pH is 6.0 - 7.0. 18. A process according to claim lb, wherein third solvent is selected from the group comprising of water or a mixture of water and water miscible organic solvent. 19. A process for the preparation of sevelamer carbonate, substantially as described herein with reference to the foregoing examples Dated this 14th day of November 2006 , RAJESHWAR] H. OF K & S PARTNERS ATTORNEY FOR THE APPLICANTS 10 ABSTRACT PROCESS FOR THE PREPARATION OF PHOSPHATE BINDING POLYMER The present invention relates to process for the preparation of copolymer, chemically known as poly(allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) carbonate (Sevelamer carbonate), wherein sevelamer base is suspended in solvent then treated with carbon dioxide followed by filtration to get sevelamer carbonate. 11

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1893-mum-2006-abstract(complete)-(15-11-2006).pdf

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1893-mum-2006-description(complete)-(15-11-2006).pdf

1893-mum-2006-description(granted)-(26-7-2010).pdf

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