Process for the preparation of colesevelam hydrochloride

1. A process for the preparation of colesevelam and/or pharmaceutically acceptable salts thereof comprising:

(a) reacting a polyallylamine solution with two alkylating agents to form an alkylated polyallylamine; and

(b) crosslinking the alkylated polyallylamine from step (a) with epichlorohydrin to form colesevelam,

wherein one of the two alkylating agents is selected from a group consisting of n-decyl bromide, n-decyl chloride, n-decyl tosylate, n-decyl mesylate, n-decyl triflate, n-decyl iodide, n-decyl fluoride, and a combination thereof; and

wherein the other of the two alkylating agents is selected from a group consisting of 6-bromohexyl trimethyl ammonium bromide, 6-chlorohexyl trimethyl ammonium chloride, and a combination thereof;

wherein the alkylation step (a) and the crosslinking step (b) are conducted in water or an aqueous solvent mixture.

2. A process for the preparation of colesevelam and/or pharmaceutically acceptable salts thereof comprising:

(a) reacting a polyallylamine solution with two alkylating agents to form an alkylated polyallylamine; and

(b) crosslinking the alkylated polyallylamine from step (a) with epichlorohydrin to form colesevelam,

wherein one of the two alkylating agents is selected from a group consisting of n-decyl bromide, n-decyl chloride, n-decyl tosylate, n-decyl mesylate, n-decyl triflate, n-decyl iodide, n-decyl fluoride, and a combination thereof; and

wherein the other of the two alkylating agents is selected from a group consisting of 6-bromohexyl trimethyl ammonium bromide, 6-chlorohexyl trimethyl ammonium chloride, and a combination thereof,

wherein the alkylation step (a) and the crosslinking step (b) are conducted in the same reactor without isolation of the alkylated polyallylamine prior to step (b).

3. The process according to claim 2 , further comprising a step of adding a base to the polyallyamine solution prior to step (a) such that the pH of the polyallylamine solution is in the range of 7-12.

4. The process according to claim 2 , wherein one of the two alkylating agents is n-decyl bromide and the other of the two alkylating agents is 6-bromohexyl trimethyl ammonium bromide, and wherein the ratio polyallylamine to n-decyl bromide is about 1:0.1 to about 1:3 by weight, and the ratio of polyallylamine to 6-bromohexyl trimethyl ammonium bromide is about 1:0.2 to about 1:5 by weight.

5. The process according to claim 2 , wherein the ratio of polyallylamine to epichlorohydrin is about 1:0.01 to about 1:0.25 by weight.

6. The process according to claim 2 , further comprising a step of adding an ion source to form a pharmaceutically acceptable salt of colesevelam.

7. The process according to claim 6 , wherein the ion source is a chloride ion source.

8. The process according to claim 7 , wherein the ion source is concentrated hydrochloric acid.

9. The process according to claim 2 , further comprising a step of washing the colesevelam and/or the pharmaceutically acceptable salts thereof with an organic solvent, a sodium chloride, and water, in any order.

10. The process according to claim 9 , wherein the organic solvent is methanol.

11. The process according to claim 10 , further comprising a step of measuring conductivity of a mother liquid from the water wash, wherein the water wash is repeated until the conductivity of the mother liquor from the wash is no more than 1 mS/cm.

12. The process according to claim 2 , further comprising a step of drying the colesevelam and/or the pharmaceutically acceptable salts thereof.

13. The process according to claim 2 , further comprising a step of reducing particle sizes of the colesevelam and/or the pharmaceutically acceptable salts thereof.

14. A process for the preparation of colesevelam and pharmaceutically acceptable salts thereof comprising:

(a) reacting a polyallylamine solution with one of two alkylating agents to form a first alkylated polyallylamine;

(b) crosslinking the alkylated polyallylamine from step (a) by using epichlorohydrin to form a cross-linked alkylated polyallylamine; and

(c) reacting the cross-linked alkylated polyallylamine with the other of the two alkylating agents to form colesevelam;

wherein the two alkylating agents are selected from a group consisting of n-decyl bromide, n-decyl chloride, n-decyl tosylate, n-decyl mesylate, n-decyl triflate, n-decyl iodide, n-decyl fluoride, and a combination thereof, and selected from a group consisting of 6-bromohexyl trimethyl ammonium bromide, 6-chlorohexyl trimethyl ammonium chloride, and a combination thereof.

15. The process according to claim 14 , wherein the alkylation steps (a) and (c) and the crosslinking step (b) are conducted in water or an aqueous solvent mixture.

16. The process according to claim 14 , wherein the steps (a) to (c) are conducted in the same reactor without isolation of the alkylated polyallylamine or the cross-linked alkylated polyallylamine prior to the next step.

17. The process according to claim 14 , further comprising the step of adjusting a chloride ion of the colesevelam with a suitable chloride ion source.

18. The process according to claim 14 , further comprising a step of adding an ion source to form a pharmaceutically acceptable salt of colesevelam.

19. The process according to claim 18 , wherein the ion source is a chloride ion source.