FIELD OF THE INVENTION
The present invention relates to a process for the preparation of inorganic acid addition salts of Sevelamer - a crosslinked polyallylamine polymer.
BACKGROUND
Sevelamer is a polymer of allylamine that is crosslinked with epichlorohydrin. It is chemically known as Poly(allylamine-co-N,N'-dialIyl-l,3-diamino-2-hydroxypropane). Sevelamer is approved by the U.S. FDA for use as a phosphate-binding agent and is marketed in the U.S. as Renagel®, which contains Sevelamer hydrochloride. Its polymeric structure can be represented as

The U.S. FDA has also approved Sevelamer carbonate (Renvela®) for the same indication.
Renagel® and Renvela® are indicated for the reduction of serum phosphorus in patients with chronic renat disease / end-stage renal disease (ESRD). Individuals with inadequate renal function or other medical conditions such as hypo-parathyroidism or acute untreated acromegaly often have hyperphosphatemia, that is, their serum phosphate level is over 6mg/dL. Such a condition leads to severe abnormalities in calcium and phosphorus metabolism. Although therapeutic efforts to reduce serum phosphate like dialysis, reduction in dietary phosphate and the oral administration of insoluble phosphate binders are used, these methods were found to be insufficient to control the condition. Furthermore, there are adverse side effects, such as Hypercalcemia, and other toxicities that are associated with the

prolonged use of the oral phosphate binders like the calcium- and aluminium-based phosphate binders.
In comparison, Sevelamer being a crosslinked organic polymer that is not systemically absorbed there are no concomitant side effects. It is administered orally and it prevents the absorption of dietary phosphate in vivo. From the above structure of Sevelamer hydrochloride it can be seen that forty percent of the amines are protonated. It is believed that it is these protonated amino groups that interact with the phosphate ions through ionic and hydrogen bonding, thus leading to their sequestration (J. Macromolecular Science - Pure and Applied Chemistry 1999, A36, p. 1085, Clinical Pharmacokinetics 2002, 41(7), p.517).
Sevelamer is prepared by the polymerization of allylamine and subsequent cross-linking as is described in the patent US 5,496,545. This patent specifically discloses the preparation of Sevelamer hydrochloride whereas the patent application US2006/0251614 discloses the preparation of Sevelamer carbonate.
262/CHE/2006 describes a process for the preparation of novel soft salts of Sevelamer by ion-exchange metathesis. It is presumed that the soft salts refer to organic acid salts.
OBJECT OF THE INVENTION
It is thus an object of the present invention to provide a synthetic process for the preparation of inorganic acid addition salts of Sevelamer.
It is also another object of the invention to provide a process that is commercially viable even on an industrial scale.
SUMMARY OF THE INVENTION
The invention provides a synthetic process for the preparation of inorganic acid addition salts of Sevelamer comprising the steps of dissolving allylamine in an acid and polymerizing to polyallylamine; partially neutralizing this poiyallylamine and crosslinking with epichlorohydrin and then treating it with a solution of an inorganic salt.

DETAILED DESCRIPTION
Allylamine is the monomer of the polymer polyallylamine. The preparation of polyallylamine by the polymerization of allylamine had been known to result in a polymer having a low degree of polymerization. However, the situation changed with the use of initiators bearing the Azo group. Thus, to prepare polyallylamine, allylamine, which is a toxic liquid with a strong smell, is converted into its salt. This can be done by dissolving allylamine directly in an acid. To this solution of an acid containing the allylamine salt, the solution of an Azo-based radical initiator can be added. Usually, the allylamine salt is separated from the acid in which it is dissolved before the radical initiator is added to it. However when the same has to be practised on a large scale the isolation of the salt can be tedious and is inefficient in terms of the time involved and the energy consumed.
Thus, allylamine salt or the acid solution containing the allylamine salt can be treated with the radical initiator and the polyallylamine polymer that is obtained is isolated and purified. The polyallylamine that is isolated is the corresponding acid salt of the allylamine that was used as starting material. This polyallylamine salt is neutralized before being crosslinked.
For the preparation of Sevelamer, the polyallylamine salt is dissolved in an aqueous solution of a base such that it is neutralized partially. Epichlorohydrin, which is the crosslinking agent and being insoluble in water is dissolved in a hydrocarbon solvent. This solution is then added to the aqueous polyallylamine solution for the crosslinking to take place. Preferably the crosslinking is carried out in the presence of a dispersing agent. A surfactant or dispersing agent is added to the solution containing the crosslinking agent and the whole is added to the aqueous solution of polyallylamine. Alternatively, the crosslinking agent may be added to the solution containing the surfactant and polyallylamine. The reaction mixture is stirred, warmed and maintained for about 3 hours for the crosslinking to take place.
The polymer that is formed is insoluble in most solvents and can be separated by filtration. Other methods of product isolation will be known to persons skilled in the art and can also be used. The polymer is purified by washing with isopropanol several times and finally with demineralized water and dried. Isopropanol was the solvent chosen in order to remove the traces of epichlorohydrin. Depending on the addition of a dispersing agent the product is obtained in the end as a gel or a free-flowing powder. When crosslinking is carried out in the

absence of a dispersing agent, the polymer is formed as a gel that requires curing. The dispersing agent however prevents gel formation. (This invention forms the subject of our co-pending application 719/KOL/2008.) The inventors have observed that the order of the addition of the crosslinking agent and the dispersing agents also affects the formation of the gel. By allowing the reaction between polyallylamine and epichlorohydrin to occur strictly in the presence of a dispersing agent the formation of gel can be minimized considerably. Also the polymer that is obtained by this process does not require further milling, grinding or blending. It can be used directly for all further processes and operations.
Sevelamer that is manufactured is isolated as a salt. In order to convert it into another salt, it is then treated with a solution of the inorganic salt for about 1 day. The product is isolated and washed with water thoroughly and dried.
Although, on an industrial scale, any suitable drying equipment can be employed, during the course of the process developed for the manufacture of Sevelamer salts, especially carbonate and bicarbonate salts, the present inventors have observed that a fluidized bed dryer is the most suitable. When drying was carried out on a tray dryer and a rotary vacuum dryer, the drying time and drying temperature that were required were high. The optimum temperature was about 70°C whereas the drying time was between fifteen and thirty hours. In comparison, optimum drying in a fluidized bed dryer was found to be quicker and more effective in a time of about four hours as can be seen from the below table. Also the temperature required for drying was about 55°C, which is considerably lower than about 70°C that is needed with other dryers.
TABLE COMPARING DIFFERENT DRYING METHODS FOR SEVELAMER CARBONATE


Another advantage of using the fluidized bed dryer over the other dryers was that the carbonate content of the dry product remained unchanged. When using a tray dryer or a rotary vacuum dryer, it has been observed that the carbonate content of Sevelamer carbonate reduces to about 18-25 %. However when a fluidized bed dryer is used, the carbonate content is between about 30% and about 44%, which corresponds to the product specifications of Renvela®. The inventors believe that drying methods that need longer drying time and higher drying temperature bring about a loss of carbonate; the carbonate being lost as carbon dioxide. Due to the shorter drying time and lower temperature of a fluidized bed dryer, such a decarboxylation happens to a lower degree. Hence the use of a fluidized bed dryer as a drying method for Sevelamer carbonate is of special merit.
The process of the invention can be illustrated by the use of concentrated hydrochloric acid for polymerization and sodium bicarbonate as the inorganic salt.
EXAMPLES
Polymerization of allylamine:
200mL of Cone. HC1 was taken in a round-bottomed flask of 1L capacity and cooled to less than 5°C. 100g of allylamine was added slowly over a period of 1-1.5 hrs while stirring and maintaining the temperature at less than 10°C. After about 30 minutes the temperature of the reaction mixture was brought to room temperature. After another 30 minutes the temperature of the reaction mixture was raised to about 50°C.
20g of 2,2-azobis-(2-amidinopropane) dihydrochloride was dissolved separately in 9mL of demineralized water and warmed slightly to get a clear solution. This solution was added to the reaction flask containing allylamine. The reaction mixture was stirred for around 24 hours at 5O-55°C and a second aliquot (2g) of 2,2-azobis-(2-amidinopropane) dihydrochloride was added to it. The reaction mixture was maintained for another 40-44 hours and then cooled to room temperature. It was then poured into 1.7L of methanol in a nitrogen atmosphere. This solution was maintained at room temperature for 1 hour and filtered under vacuum in a nitrogen atmosphere. The product was washed with methanol and dried under vacuum. Yield: 140g

Crosslinking of polvallylamine:
27g of NaOH was dissolved in 300mL of demineralized water. Polyallylamine hydrochloride was added to this solution at room temperature and stirred for about 45 minutes.
In another flask 4mL of sorbitan sesquioleate was dissolved in 500mL of toluene. This solution was subjected to charcoal treatment and 9mL of epichlorohydrin was added to it. After 5-10 minutes the aqueous solution of polyallylamine was added to the toluene solution. The reaction mixture was stirred at room temperature for about 45 minutes and then heated to around 50°C. It was maintained at this temperature for about 2.5 hours and then cooled to room temperature.
The solid was collected by filtration and washed thoroughly with Isopropanol to remove traces of epichlorohydrin. After a final spray-wash with demineralized water the polymer was dried under vacuum. Yield: ~750g
Sevelamer Carbonate:
100g of Sevelamer hydrochloride was taken in a round-bottomed flask and 2.5L of 1M sodium bicarbonate was added to it. The mixture was stirred for 20 hours at about 25°C. The solid was then filtered and washed with a little water. The polymer was slurried in about 2.5L of demineralized water, warmed to 55 - 60°C and stirred for about 2 hours. The solid was then filtered and dried under vacuum. Yield: ~55g

We claim:
1. A process for the preparation of an inorganic acid addition salt of Sevelamer
comprising
A] polymerization of allylamine;
B] crosslinking polyallylamine obtained from step [A] using epichlorohydrin;
C] contacting the Sevelamer prepared in step [B] with an inorganic salt to obtain the
corresponding acid addition salt of Sevelamer;
D] drying the salt obtained from step [C] using a fluidized bed drier.

2. A process according to Claim 1, wherein polyallylamine is crosslinked with
epichlorohydrin in the presence of a dispersing agent.
3. A process according to claim 1 or 2, wherein the inorganic salt is chloride salt.
4. A process according to claim 1 or 2, wherein the inorganic salt is carbonate salt.
5. A process according to claim 1 or 2, wherein the inorganic salt is bicarbonate salt.
6. Acid addition salt of Sevelamer obtained according to the process of claim 1 is
Sevelamer carbonate.
7. Acid addition salt of Sevelamer obtained according to the process of claim 1 is
Sevelamer bicarbonate.
8. Sevelamer carbonate according to claim 6, having a carbonate content from about
30% to about 44%.
9. Sevelamer bicarbonate according to claim 7, having a bicarbonate content from about
30% to about 44%.

The invention relates to process for the preparation of an inorganic acid addition salt of Sevelamer.