Manufacturing process of making polymeric amine salts
A novel process of manufacturing sevelamer carbonate from a polyallylamine carbonate or bicarbonate chloride salt. Process for manufacture of carbonate and/or bicarbonate salts of water insoluble polymers containing amino groups that are useful as anion binders in the gastrointestinal (GI) system. The process arranges the polyallylamine chain in a solution in such a way that the cross-linking reaction with epichlorohydrin can be controlled at a desired reaction rate.
1. A process of making cross-linked polyallylamine carbonate salt comprising:
(a) reacting homopolymer of polyallylamine hydrochloride with carbonate and/or bicarbonate ions to form polyallylamine carbonate and/or bicarbonate salt, wherein the ratio of amine group of the polyallylamine hydrochloride to the carbonate and/or bicarbonate ions is about 1:0.2 to about 1:0.6;
(b) cross-linking the polyallylamine carbonate and/or bicarbonate salt obtained in step (a) with a cross-linking agent, in the presence of sodium hydroxide to form a wet gel;
(c) reducing the particle size of the wet gel obtained in step (b);
(d) purifying the wet gel particles obtained in the step (c) with water or an aqueous solvent mixture to significantly remove the ionic impurities; and
(e) drying the purified gel particles obtained in step (d).
2. The process of claim 1 , wherein the wet gel obtained is sevelamer carbonate.
3. The process of claim 1 , wherein the purified gel obtained in step (e) predominantly has the carbonate as (CO 3 ) 2− .
4. The process of claim 1 , wherein the purified gel has a chloride ion level below about 0.2% by weight.
5. The process of claim 1 , wherein the purified gel has a chloride ion level below about 0.1% by weight.
6. The process of claim 1 , wherein the purified gel has a chloride ion level below about 0.05% by weight.
7. The process of claim 1 , wherein step (d) of purifying involves treating the gel particles with an aqueous solvent mixture.
8. The process of claim 7 , wherein the aqueous solvent mixture contains water, a base and at least one water miscible solvent.
9. The process of claim 7 , wherein the aqueous solvent mixture comprises water and at least one base.
10. The process of claim 9 , wherein the base is a mixture of one or more bases selected from the group of alkali metal hydroxide, alkali metal carbonates and/or alkali metal bicarbonates.
11. The process of claim 9 , wherein the base is sodium hydroxide.
12. The process of claim 9 , wherein the base is sodium bicarbonate.
13. The process of claim 9 , wherein the base is sodium carbonate.
14. The process of claim 9 , wherein the base is ammonium carbonate.
15. The process of claim 9 , wherein the base is ammonium bicarbonate.
16. The process of claim 1 , wherein the cross-linking agent is epichlorohydrin.
17. The process of claim 1 , wherein during step (e) the drying is performed at 80 to 120° C.
18. The process of claim 1 , wherein during step (e) the drying is performed at 80 to 120° C. under vacuum of about 500 to 755 mm Hg.
19. The process of claim 1 , wherein during step (e) the drying is performed at 80 to 120° C. using the flow of hot air.
20. The process of claim 1 , wherein step (b) completes within about 2 hours at room temperature.
21. A process of making alkylated cross-linked polyallylamine carbonate salt comprising:
(a) reacting homopolymer of polyallylamine hydrochloride with carbonate and/or bicarbonate ions to form polyallylamine carbonate and/or bicarbonate salt; wherein the ratio of amine group of the polyallvlamine hydrochloride to the carbonate and/or bicarbonate ions is about 1:0.1 to about 1:0.6.
(b) simultaneously cross-linking and reacting the polyallylamine carbonate and/or bicarbonate salt obtained in step (a) with a cross-linking agent and alkylating agents in the presence of sodium hydroxide to form a wet gel in a single step operation;
(c) reducing the particle size of the wet gel obtained in step (b);
(d) purifying the wet gel particles obtained in step (c) with water or an aqueous solvent mixture to significantly remove the chloride and/or bromide ions; and
(e) drying the purified gel particles obtained in step (d).
22. The process of claim 21 , wherein the purified gel obtained in step (d) is colsevelam carbonate.
23. The process of claim 21 , wherein the alkylating agent is 6-chlorohexyl trimethyl ammonium chloride.
24. The process of claim 21 , wherein the alkylating agent is n-decylchloride.
25. The process of claim 21 , wherein the alkylating agent is mixture of 6-chlorohexyl trimethyl ammonium chloride and n-decylchloride.
26. The process of claim 21 , wherein the alkylating agent is 6-chlorohexyl trimethyl ammonium chloride and/or 6-bromohexyl trimethyl ammonium bromide.
27. The process of claim 21 , wherein the alkylating agent is n-decylchloride and/or n-decyl bromide.
28. The process of claim 21 , wherein the alkylating agent is mixture of 6-bromohexyl trimethyl ammonium bromide and n-decylbromide.
29. The process of claim 21 , wherein the purified gel in step (e) is colesevelam carbonate.
30. The process of claim 21 , wherein step (d) of purifying involves treating the gel particles with an aqueous solvent mixture.
31. The process of claim 21 , wherein the cross-linking agent is epichlorohydrin.
32. The process of claim 21 , wherein step (b) proceeds at a temperature of about 20° C. to about 35° C.
33. The process of claim 21 , wherein step (b) completes within about 2 hours at room temperature.
34. The process of claim 21 , wherein step (b) proceeds in the absence of an organic solvent.