DESC:RELATED PATENT APPLICATION:

This application claims the priority to and benefit of Indian Provisional Patent Application No. 202141029188 filed on June 29, 2021 titled “AN IMPROVED PROCESS FOR THE PREPARATION OF COLESEVELAM HYDROCHLORIDE” the disclosure of which are incorporated herein by reference.

FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of Colesevelam hydrochloride. More particularly the present invention relates to an improved, economically significant, and advantageous process for the preparation of Colesevelam hydrochloride of formula (I).

BACKGROUND OF THE INVENTION:

Colesevelam hydrochloride is a non-absorbed, polymeric, lipid-lowering and glucose-lowering polymer. The chemical name of the polymer is allylamine polymer with 1-chloro-2,3-epoxy-propane, [6-(allylamino)-hexyl]trimethyl ammonium chloride and N-allyldcylamine hydrochloride.

The chemical structure of Colesevelam hydrochloride is represented by the following structure of formula (I):

Formula I
[Colesevelam hydrochloride]
wherein in the above formula (I)-

(a) represents allyl amine monomer units that have not been alkylated by either of the 1-bromodecane or (6-bromohexyl)-trimethylammonium bromide alkylating agents or cross-linked by epichlorohydrin;

(b) represents allyl amine units that have undergone crosslinking with epichlorohydrin;

(c) represents allyl amine units that have been alkylated with a decyl group;

(d) represents allyl amine units that have been alkylated with a (6-trimethylammonium) hexyl group, and m represents a number = 100 to indicate an extended polymer network.

A small amount of the amines are dialkylated and are not depicted in the formula above. No regular order of the groups is implied by the structure; cross-linking and alkylation are expected to occur randomly along the polymer chains. A large amount of the amines are protonated. The polymer is depicted in the hydrochloride form.
(Source: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022362s007lbl.pdf)

Colesevelam hydrochloride was approved by USFDA on May 26, 2000, which is marketed in USA by Daiichi Sankyo under the tradename Welchol. Colesevelam is efficient than the Colestipol and Cholestyramine in reducing the low density lipoprotein cholesterol (LDL-C) and improved glycemic control in diabetes. Colesevelam hydrochloride was first disclosed in the US Patent No. 5693675 assigned to GelTex Pharmaceuticals.

The literature publication Polymer Preprints 2000, 41(1), 735 discloses the preparation of Colesevelam hydrochloride involving the steps of: (i) polyallylamine hydrochloride (PAA HCl) is cross linked with epichlorohydrin in the presence of sodium hydroxide to a cross linked polymer intermediate; (ii) the cross linked polymer intermediate was alkylated with (6-bromohexyl)-trimethylammonium bromide and 1-bromodecane in the presence of methanolic sodium hydroxide to produce Colesevelam and (iii) the resulted Colesevelam was treated with hydrochloric acid to form Colesevelam hydrochloride, wherein the cross linked polymer intermediate was washed three times with water and one time with isopropanol. Further the formed Colesevelam hydrochloride was washed with methanol; then sodium chloride solution and water.

The polyallylamine hydrochloride (PAA HCl) was prepared by the polymerization reaction of allylamine in the presence of concentrated hydrochloric acid and 2,2’-azobis-(2-methylpropionamidine)dihydrochloride (AAPH) as a radical initiator.

The US Patent No. 5607669 assigned to GelTex Pharma discloses the purification of Colesevelam hydrochloride involving the four times washings with methanol, six times washings with sodium chloride solution and six times washings with water.

The US Patent Nos. 7105631 and 7148319 assigned to DSM Fine Chemical disclose the purification of Colesevelam hydrochloride involving four times washings with each of methanol and sodium chloride solution, six times washings with sodium chloride solution and six times washings with water.

The US Patent No. 7057010 assigned to DSM Fine Chemical discloses the process drying Colesevelam or Sevelamer in a fluidized bed dryer.

The US Patent No. 6600011 assigned Genzyme Corporation discloses the process for the purification and drying of the polymer hydrogel involving the steps of: washing the polymer hydrogel with a water wash medium until the resulting slurry comprising hydrogel till the substantial absence of monomer, oligomer and other contaminants; and spray drying the resulting slurry.

Besides the availability of process for the preparation of Colesevelam hydrochloride in state of the art, there is a need for an improved process for the preparation of Colesevelam hydrochloride that is economically significant and surpass the manufacturing challenges.

OBJECTIVES OF THE INVENTION

The main objective of the present invention is to provide an improved process for the preparation of Colesevelam hydrochloride (I).

Another objective of the present invention is to provide an efficient, simple, industrially viable and economically significant process for the preparation of Colesevelam hydrochloride (I).
Another objective of the present invention is to provide efficient washing process to purify Colesevelam hydrochloride (I).

SUMMARY OF THE INVENTION:

Accordingly, the present invention describes and provides an improved process for the preparation of Colesevelam hydrochloride.

In one aspect, the invention provides a process for the preparation of Colesevelam hydrochloride (I) comprising the step of:

(i) reacting polyallylamine hydrochloride polymer with epichlorohydrin in the presence of a base to obtain to an epichlorohydrin cross-linked polymer in water;

(ii) reacting the epichlorohydrin cross-linked polymer obtained in step (i) with 6-bromohexyltrimethylammonium bromide and 1-bromodecane in the presence of sodium hydroxide in methanol to obtain Colesevelam;

(iii) protonating the Colesevelam obtained in step (ii) by the addition of Hydrochloride acid solution to form Colesevelam hydrochloride (I);

(iv) wet milling Colesevelam hydrochloride (I) obtained in step (iii);

(v) washing the wet milled Colesevelam hydrochloride (I) obtained in step (iv) with methanol; and

(vi) optionally, drying the washed Colesevelam hydrochloride (I) obtained in step (v) in fluidized bed dryer.

The process as described above, wherein the base used in step (i) is sodium hydroxide.

The process as described above, wherein the resulted epichlorohydrin cross-linked polymer in the step (i) is washed with water and/or with any water miscible solvents, selected from isopropyl alcohol, methanol or ethanol or mixture thereof.

The process as described above, wherein the resulted epichlorohydrin cross-linked polymer in step (i) is size reduced before performing the reaction step (ii).

The process as described above, wherein the step (ii) is carried out at temperatures ranging from 40°C to 66°C.

The process as described above, wherein the step (iii) is carried out at ambient temperature.

The process as described above, wherein the step (iv) of the present invention is carried out in COMITROL-1700 mill.

The process as described above, wherein before proceeding to the next step of wet milling at step (iv), the Colesevelam hydrochloride (I) obtained in step (iii) may be slurry washed using sodium chloride solution and/or water.

In another aspect, the invention provides a process for the preparation of Colesevelam hydrochloride (I) comprising the step of:

(i) reacting polyallylamine hydrochloride polymer with epichlorohydrin in the presence of a base to obtain to an epichlorohydrin cross-linked polymer in water;

(ii) reacting the epichlorohydrin cross-linked polymer obtained in step (i) with 6-bromohexyltrimethylammonium bromide and 1-bromodecane in the presence of sodium hydroxide in methanol to obtain Colesevelam;

(iii) protonating Colesevelam obtained in step (ii) by the addition of Hydrochloride acid solution to form Colesevelam hydrochloride (I);

(iv) washing the Colesevelam hydrochloride (I) obtained in step (iii) with tetrahydrofuran (THF);

(v) washing the washed Colesevelam hydrochloride (I) obtained in step (iv) with aqueous sodium chloride solution;

(vi) washing the washed Colesevelam hydrochloride (I) obtained in step (v) with water; and

(vii) optionally, drying the washed Colesevelam hydrochloride (I) in a rotocone vacuum dryer.

The process as described above, wherein the base used in step (i) is sodium hydroxide.

The process as described above, wherein the resulted epichlorohydrin cross-linked polymer in the step (i) is washed with water and/or with any water miscible solvents, selected from isopropyl alcohol, methanol or ethanol or mixture thereof.

The process as described above, wherein the resulted epichlorohydrin cross-linked polymer in step (i) is size reduced before performing the reaction step (ii).

The process as described above, wherein the step (ii) is carried out at temperatures ranging from 40°C to 66°C.

The process as described above, wherein the step (iii) is carried out at ambient temperature.

The process as described above, wherein

- step (iv) comprises washing of the filtered solid comprising Colesevelam hydrochloride (I) obtained after step (iii) with tetrahydrofuran (THF) with stirring for about 60 minutes at about 25-35°C;

- step (v) comprises slurry washing successively with 2M sodium chloride solution three times with stirring for about 60 minutes at about 25-30°C; and

- Step (vi) comprises slurry washing successively with water three times with stirring for about 60 minutes at about 25-30°C.

DETAILED DESCRIPTION OF THE INVENTION:

Accordingly, the present invention provides an improved process for the preparation of Colesevelam hydrochloride (I). More particularly, the present invention provides an improved, economically significant, and advantageous process for the preparation of Colesevelam hydrochloride of formula (I), wherein the process is efficient, simple, industrially viable and economically significant. The invention discloses and provides efficient washing process to purify and to obtain Colesevelam hydrochloride (I) with improved purity.

In the first embodiment, the present invention discloses and provides a process for the preparation of Colesevelam hydrochloride (I) comprising the step of:
(i) reacting polyallylamine hydrochloride polymer with epichlorohydrin in the presence of a base to obtain to an epichlorohydrin cross-linked polymer in water;
(ii) reacting the epichlorohydrin cross-linked polymer obtained in step (i) with 6-bromohexyltrimethylammonium bromide and 1-bromodecane in the presence of sodium hydroxide in methanol to obtain Colesevelam;
(iii) protonating the Colesevelam obtained in step (ii) by the addition of Hydrochloride acid solution to form Colesevelam hydrochloride (I);
(iv) wet milling Colesevelam hydrochloride (I) obtained in step (iii);
(v) washing the wet milled Colesevelam hydrochloride (I) obtained in step (iv) in methanol; and
(vi) optionally, drying the washed Colesevelam hydrochloride (I) obtained in step (v) in fluidized bed dryer.

The step (i) of reacting polyallylamine hydrochloride polymer (PAA-HCl) with epichlorohydrin (ECH) according to the process of present invention may be performed after partially or completely neutralizing the polyallylamine hydrochloride by the addition of a base.
In one embodiment the base used in step (i) is sodium hydroxide (NaOH). The partially or completely neutralizing the polyallylamine hydrochloride polymer (PAA-HCl) of the present invention may be done at high or ambient temperatures. During the high temperatures the polyallylamine hydrochloride solution with sodium hydroxide may be concentrated.

Thus, in one embodiment, in the step (i), to a mixture of liquid polyallylamine hydrochloride (PAA-HCl) solution and water, a solution of sodium hydroxide flakes in water is added slowly with stirring at ambient temperature to get a clear solution. Further water is added into the reaction mixture and concentrated under vacuum at about 50-55°C. The concentrated reaction mixture is cooled to about 25-35°C. To the cooled reaction mixture, water is added and then further concentrated under vacuum at about 50-55°C. The concentrated reaction mixture is then cooled to about 25-35°C. In one embodiment to the above cooled reaction mass, epichlorohydrin is added and stirred for about 10-15 minutes at about 25-35°C, and the stirred reaction mass is then allowed to stand for about 24 hours at ambient temperature to form and obtain a polymer gel.

The epichlorohydrin cross-linked polymer resulted in the step (i) by reacting polyallylamine hydrochloride with epichlorohydrin according to the present invention may be washed with water and/or with any water miscible solvents such as isopropyl alcohol (IPA), methanol or ethanol or mixture thereof.

The cross-linked polymer resulted in the step (i) by reacting polyallylamine hydrochloride with epichlorohydrin according to the present invention may be size reduced before performing the reaction step (ii) of the present invention.

Thus, in one embodiment, the above formed gel of step (i) is broken into pieces and to that water is added and stirred and the resultant solid is filtered, followed by performing slurry washing. In one embodiment the slurry washing is performed with water three times with stirring for about 60 minutes at about 25-35°C successively. Further performing slurry washing with isopropanol (IPA) two times with stirring for about 60 minutes at about 25-35°C to obtain epichlorohydrin crosslinked polymer i.e. poly(allylamine)hydrochloride cross-linked with epichlorohydrin.

In one embodiment, the obtained cross-linked polymer solid may be dried under vacuum at about 50±5°C for around 36 hours. In one embodiment, the dried cross-linked polymer may be further milled and sieved.

The step (ii) of reacting the obtained epichlorohydrin cross-linked polymer with 6-bromohexyltrimethylammonium bromide and 1-bromodecane according to the present invention may be performed at temperatures ranging from 40°C to 66°C, preferably the reaction is performed in presence of methanol at about 64±2°C with stirring to obtain Colesevelam.

In one embodiment the reaction step (ii) uses size reduced epichlorohydrin cross-linked polymer.

During the step (ii) of reacting the obtained epichlorohydrin cross-linked polymer with 6-bromohexyltrimethylammonium bromide and 1-bromodecane according to the present invention sodium hydroxide solution (NaOH solution) may be added to two, four or six lots.

In one embodiment, sodium hydroxide solution (50% NaOH in water) is cooled to ambient temperature and divided into two equal parts is used in two lots.

In one embodiment, sodium hydroxide solution (50% NaOH in water) is cooled to ambient temperature and divided into four equal parts is used in four lots.

In one embodiment, sodium hydroxide solution (50% NaOH in water) is cooled to ambient temperature and divided into six equal parts is used in six lots.

After treating with NaOH solution, the above reaction mass may be then cooled to about 25-35°C with stirring and further may be cooled to about 10-15°C to obtain Colesevelam.

The step (iii) of protonating Colesevelam obtained in step (ii) by the addition of hydrochloride acid solution according to the present invention may be preferably done at ambient temperatures to form Colesevelam hydrochloride (I).

In one embodiment, to the cooled mass of step (ii), dilute hydrochloric acid solution (concentrated HCl solution in water) is added at about 10-15°C with stirring and then further stirred at about 25-35°C for about 90 – 120 minutes to obtain Colesevelam hydrochloride (I), which may be obtained by filtration.

Before proceeding to the next step of wet milling, the above said filtered Colesevelam hydrochloride (I) may be slurry washed successively using sodium chloride solution and water. In one embodiment, this washing step may be performed with 2M sodium chloride solution four times (4000 ml, 4000 ml, 4000 ml, 4000 ml) with stirring for about 60 minutes at about 25-30°C and further slurry washed successively with water four times (4000 ml, 4000 ml, 4000 ml, 4000 ml) with stirring for about 60 minutes at about 25-30°C.

The step (iv) of wet milling of Colesevelam hydrochloride as obtained in above step (iii) according to the present invention may be preferably done in COMITROL-1700 mill.

The wet milled Colesevelam hydrochloride (I) obtained in step (iv) is washed in methanol at step (v) and optionally, the washed Colesevelam hydrochloride (I) obtained in step (v) may be dried in at further step (vi). In one embodiment this drying step (vi) may be performed using a fluidized bed dryer (FBD).

In another embodiment (second), the invention provides a washing process wherein the Colesevelam hydrochloride (I) obtained after protonation at step (iii) is washed by below three washings steps which comprises:
- washing the formed Colesevelam hydrochloride (I) in tetrahydrofuran (THF);
- washing the above THF washed Colesevelam hydrochloride (I) in aqueous sodium chloride solution (aq. NaCl solution); and
- washing the above aq. NaCl solution washed Colesevelam hydrochloride (I) with water.

Accordingly, in the second embodiment, the present invention discloses and provides a process for the preparation of Colesevelam hydrochloride (I) comprising the step of:

(i) reacting polyallylamine hydrochloride polymer with epichlorohydrin in the presence of a base to obtain to an epichlorohydrin crosslinked polymer in water;
(ii) reacting the epichlorohydrin cross linked polymer obtained in step (i) with 6-bromohexyltrimethylammonium bromide and 1-bromodecane in the presence of sodium hydroxide in methanol to obtain Colesevelam;
(iii) protonating the Colesevelam obtained in step (ii) by the addition of Hydrochloride acid solution to form Colesevelam hydrochloride (I);
(iv) washing the formed Colesevelam hydrochloride (I) of step (iii) in tetrahydrofuran (THF);
(v) washing the washed Colesevelam hydrochloride (I) of step (iv) in aqueous sodium chloride solution (aq. NaCl solution);
(vi) washing the washed Colesevelam hydrochloride (I) of step (v) with water; and
(vii) optionally, drying the washed Colesevelam hydrochloride (I) of step (vi) in a rotocone vacuum dryer.

Steps (i) to (iii):
In the above said process of second embodiment comprising the steps (i) to (vii), the process steps (i) to (iii) upto providing Colesevelam hydrochloride (I) after protonation are same and therefore these process steps (i) to (iii) of second embodiment may be performed by a person skilled in the art following the process description as described above for process steps (i) to (iii) of first embodiment.

Steps (iv) to (vii):

Step (iv) of above said process comprises washing the formed Colesevelam hydrochloride (I) of step (iii) in tetrahydrofuran (THF). In one preferred embodiment, this step (iv) comprises washing of the filtered solid comprising Colesevelam hydrochloride (I) obtained after step (iii) with tetrahydrofuran (1520 ml) with stirring for about 60 minutes at about 25-35°C.

Step (v) of above said process comprises washing the washed Colesevelam hydrochloride (I) of step (iv) in aqueous sodium chloride solution (aq. NaCl solution). In one preferred embodiment, this step (v) comprises slurry washing successively with 2M sodium chloride solution three times (1520 ml, 1520 ml, 1520 ml) with stirring for about 60 minutes at about 25-30°C.

Step (vi) of above said process comprises washing the washed Colesevelam hydrochloride (I) of step (v) with water. In one preferred embodiment, this step (vi) comprises slurry washing successively with water three times (1520 ml, 1520 ml, 1520 ml) with stirring for about 60 minutes at about 25-30°C.

After performing the above three washing steps (iv), (v) and (vi), the resulted washed Colesevelam hydrochloride (I) of step (vi) may be further optionally dried at drying Step (vii) of above said process which comprises optionally drying the washed Colesevelam hydrochloride (I) of step (vi). In one embodiment this drying step (vii) may be performed using a rotocone vacuum dryer.

The present invention is explained in detail with reference to the following examples described below, which are given for the purpose of illustration only and are not intended to limit the scope of invention.

EXAMPLES

Example-1: Preparation of poly(allylamine)hydrochloride cross linked with epichlorohydrin
To a mixture of liquid polyallylamine hydrochloride solution (50% w/w, 750.0 g) and water (750 ml), a solution of sodium hydroxide flakes (106.5 g) in water (375 ml) was added slowly with stirring at ambient temperature to get clear solution. Water (750ml) was added into the reaction mixture and concentrated under vacuum at 50-55°C. The concentrated reaction mixture was cooled to 25-35°C. To the cooled reaction mixture, water (750 ml) was added and then concentrated under vacuum at 50-55°C. The concentrated reaction mixture was cooled to 25-35°C followed by the addition of epichlorohydrin (22.12 g) and stirred for 10-15 minutes at 25-35°C. The stirred reaction mass was then stopped and allowed to stand for 24 hours at ambient temperature without stirring to form a gel. The formed gel was broken into pieces. To the broken pieces, water (3750 ml) was added and stirred for 1 hour. The resultant solid was filtered; slurry washed with water three times (3750 ml, 5625 ml, 7500 ml) with stirring for 60 minutes at 25-35°C successively; and then slurry washed with isopropanol two times (6375 ml, 6375 ml) with stirring for 60 minutes at 25-35°C. The obtained solid was dried under vacuum in vacuum oven at 50±5°C for 36 hours and then milled and sieved. Yield: 280.0 g

Example-2: Preparation of Colesevelam hydrochloride.
A mixture of cross-linked polyallylamine (100.0 g), methanol (2650 ml), 6-bromohexyltrimethylammonium bromide (161.0 g), 1-bromodecane (110.5 g) was slowly heated to 64±2°C with stirring. Freshly prepared 50% sodium hydroxide solution (22.5 g of solid sodium hydroxide in 22.5 g of water) was cooled to ambient temperature and divided into two equal parts. First part of 50% w/w sodium hydroxide solution was added to the reaction mixture at 64±2°C in 20-30 minutes and maintained for 2 hours at the same temperature; the second part of 50% w/w sodium hydroxide solution was added to the reaction mixture at 64±2°C in 20-30 minutes and maintained for 12 hours at the same temperature. The reaction mass was then cooled to 25-35°C with stirring and further cooled the mass to 10-15°C. To the cooled mass, dilute hydrochloric acid solution (80.0 g of concentrated HCl solution in 800 ml of water) was added at 10-15°C with stirring and then stirred at 25-35°C for 90 – 120 minutes. The resultant solid was isolated by filtration; the filtered solid was slurry washed successively with 2M sodium chloride solution four times (4000 ml, 4000 ml, 4000 ml, 4000 ml) with stirring for 60 minutes at 25-30°C; slurry washed successively with water four times (4000 ml, 4000 ml, 4000 ml, 4000 ml) with stirring for 60 minutes at 25-30°C. The portion of the wet cake (375.0g) obtained was slurried in water (500 ml). The water swollen slurry mass was directly charged to COMITROL-1700 mill rotating at appropriate RPM (8500 to 11800 RPM). The wet milled slurry mass collected at the bottom was isolated by filtration followed by slurry washing in methanol (1333 ml). The filtered solid was dried in fluidized bed dryer (FBD) at 60±5°C for 24-36 hours. Dried solid was then passed through 100 mesh sieve. Yield: 67.0g

Example 3: Preparation of Colesevelam Hydrochloride
A mixture of cross-linked polyallylamine (38.0 g), methanol (1007 ml), 6-bromohexyltrimethylammonium bromide (61.18 g), 1-bromodecane (42.0 g) was slowly heated to 64±2°C with stirring. Freshly prepared 50% sodium hydroxide solution (17.1g of solid sodium hydroxide in 17.1g of water) was cooled to ambient temperature and divided into four equal parts. First part of 50% w/w sodium hydroxide solution was added to the reaction mixture at 64±2°C in 20-30 minutes and maintained for 2 hours at the same temperature; second part of 50% w/w sodium hydroxide solution was added to the reaction mixture at 64±2°C in 20-30 minutes and maintained for 2 hours at the same temperature; third part of 50% w/w sodium hydroxide solution was added to the reaction mixture at 64±2°C in 20-30 minutes and maintained for 2 hours at the same temperature; and finally the fourth part of 50% w/w sodium hydroxide solution was added to the reaction mixture at 64±2°C in 20-30 minutes and maintained for 12 hours at the same temperature. The reaction mass was then cooled to 25-35°C with stirring and further cooled the mass to 10-15°C. To the cooled mass, dilute hydrochloric acid solution (30.4 g of concentrated HCl solution in 304 ml of water) was added at 10-15°C with stirring and then stirred at 25-35°C for 90 – 120 minutes. The resultant solid was isolated by filtration; the filtered solid was washed with tetrahydrofuran (1520 ml) with stirring for 60 minutes at 25-35°C; slurry washed successively with 2M sodium chloride solution three times (1520 ml, 1520 ml, 1520 ml) with stirring for 60 minutes at 25-30°C; slurry washed successively with water three times (1520 ml, 1520 ml, 1520 ml) with stirring for 60 minutes at 25-30°C. The wet cake was dried in rotocone vacuum dryer (RCVD) at 60±5°C for 24 hours. Dried solid was then taken for size reduction and sieved through 100 mesh sieve. Yield: 78.5g

Example-4: Preparation of Colesevelam hydrochloride.
A mixture of cross-linked polyallylamine (38.0 g), methanol (1007 ml), 6-bromohexyltrimethylammonium bromide (61.18 g), 1-bromodecane (42.0 g) was slowly heated to 64±2°C with stirring. Freshly prepared 50% sodium hydroxide solution (17.1g of solid sodium hydroxide in 17.1g of water) was cooled to ambient temperature and divided into four equal parts. First part of 50% w/w sodium hydroxide solution was added to the reaction mixture at 64±2°C in 20-30 minutes and maintained for 2 hours at the same temperature; second part of 50% w/w sodium hydroxide solution was added to the reaction mixture at 64±2°C in 20-30 minutes and maintained for 2 hours at the same temperature; third part of 50% w/w sodium hydroxide solution was added to the reaction mixture at 64±2°C in 20-30 minutes and maintained for 2 hours at the same temperature; and finally the fourth part of 50% w/w sodium hydroxide solution was added to the reaction mixture at 64±2°C in 20-30 minutes and maintained for 24±1 hours at the same temperature. The reaction mass was then cooled to 25-35°C with stirring and further cooled the mass to 10-15°C. To the cooled mass, dilute hydrochloric acid solution (30.4 g of concentrated HCl solution in 304 ml of water) was added at 10-15°C with stirring and then stirred at 25-35°C for 90 – 120 minutes. The resultant solid was isolated by filtration; the filtered solid was washed with methanol (25080 ml) with stirring for 60 minutes at 25-35°C; slurry washed successively with 2M sodium chloride solution three times (1520 ml, 1520 ml, 1520 ml) with stirring for 60 minutes at 25-30°C; slurry washed successively with water three times (1520 ml, 1520 ml, 1520 ml) with stirring for 60 minutes at 25-30°C. The wet cake was dried in rotocone vacuum dryer (RCVD) at 60±5°C for 24 hours. Dried solid was then taken for size reduction and sieved through 100 mesh sieve. Yield: 79.5g.
,CLAIMS:1. A process for the preparation of Colesevelam hydrochloride (I) comprising the step of:

(i) reacting polyallylamine hydrochloride polymer with epichlorohydrin in the presence of a base to obtain to an epichlorohydrin crosslinked polymer in water;

(ii) reacting the epichlorohydrin cross-linked polymer obtained in step (i) with 6-bromohexyltrimethylammonium bromide and 1-bromodecane in the presence of sodium hydroxide in methanol to obtain Colesevelam;

(iii) protonating the Colesevelam obtained in step (ii) by the addition of Hydrochloride acid solution to form Colesevelam hydrochloride (I);

(iv) wet milling Colesevelam hydrochloride (I) obtained in step (iii);

(v) washing the wet milled Colesevelam hydrochloride (I) obtained in step (iv) with methanol; and

(vi) optionally, drying the washed Colesevelam hydrochloride (I) obtained in step (v) in fluidized bed dryer.

2. A process for the preparation of Colesevelam hydrochloride (I) comprising the step of:

(i) reacting polyallylamine hydrochloride polymer with epichlorohydrin in the presence of a base to obtain to an epichlorohydrin crosslinked polymer in water;

(ii) reacting the epichlorohydrin cross-linked polymer obtained in step (i) with 6-bromohexyltrimethylammonium bromide and 1-bromodecane in the presence of sodium hydroxide in methanol to obtain Colesevelam;

(iii) protonating Colesevelam obtained in step (ii) by the addition of Hydrochloride acid solution to form Colesevelam hydrochloride (I);

(iv) washing the Colesevelam hydrochloride (I) obtained in step (iii) with tetrahydrofuran (THF);

(v) washing the washed Colesevelam hydrochloride (I) obtained in step (iv) with aqueous sodium chloride solution;

(vi) washing the washed Colesevelam hydrochloride (I) obtained in step (v) with water; and

(vii) optionally, drying the washed Colesevelam hydrochloride in a rotocone vacuum dryer.

3. The process as claimed in claim 1 and claim 2, wherein the base used in step (i) is sodium hydroxide.

4. The process as claimed in claim 1 and claim 2, wherein the resulted epichlorohydrin cross-linked polymer in the step (i) is washed with water and/or with any water miscible solvents, selected from isopropyl alcohol, methanol or ethanol or mixture thereof.

5. The process as claimed in claim 1 and claim 2, wherein the resulted epichlorohydrin cross-linked polymer in step (i) is size reduced before performing the reaction step (ii).

6. The process as claimed in claim 1 and claim 2, wherein the step (ii) is carried out at temperatures ranging from 40°C to 66°C.

7. The process as claimed in claim 1 and claim 2, wherein the step (iii) is carried out at ambient temperature.

8. The process as claimed in claim 1, wherein the step (iv) of the present invention is carried out in COMITROL-1700 mill.

9. The process as claimed in claim 1, wherein before proceeding to the next step of wet milling at step (iv), the Colesevelam hydrochloride (I) obtained in step (iii) of claim 1 may be slurry washed using sodium chloride solution and/or water.

10. The process as claimed in claim 2, wherein

- step (iv) comprises washing of the filtered solid comprising Colesevelam hydrochloride (I) obtained after step (iii) with tetrahydrofuran (THF) with stirring for about 60 minutes at about 25-35°C;

- step (v) comprises slurry washing successively with sodium chloride solution three times with stirring for about 60 minutes at about 25-30°C; and

- Step (vi) comprises slurry washing successively with water three times with stirring for about 60 minutes at about 25-30°C.