DESC:RELATED PATENT APPLICATION(S)

This application claims the priority to and benefit of Indian Patent Application No. 201841003732 filed on January 31, 2018; the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to an improved process for the purification of Mesalamine or the preparation of crystalline Mesalamine, particularly purification of Mesalamine or the preparation of crystalline Mesalamine for the pharmaceutical preparations.

BACKGROUND OF THE INVENTION

Mesalamine chemically known as 5-amino-2-hydroxy-benzoic acid, is used for the treatment of weakly to moderately active ulcerative colitis and is available in different dosage forms such as suppositories, enemas, sachets with micropellets and tablets. Mesalamine is administered in dosages of more than 3 grams per day for the treatment of ulcerative colitis.

The US Patent No. 4,670,112 discloses a process for the purification of Mesalamine by recrystallization from water followed by decoloration with active carbon. The Patent also describes the crystallization of Mesalamine by adjusting the pH to about 4 by addition of hydrochloric acid.

The publication Journal of Crystal Growth 1997, 181, pages 403-409 discloses the precipitation of crystals of Mesalamine by the addition of a dilute base to the aqueous acidic solution of Mesalamine, till the equivalence point. The pH of solution influences the solubility of 5-aminosalicylic acid in water.

Mesalamine undergoes oxidative degradation with the formation of 5-amino-salicylic acid polymers and the mechanism of degradation has been reported in the publication International Journal of Pharmaceutics 1992, 88, pages 177 to 187. This publication discloses the oxidative degradation of Mesalamine at neutral pH to highly coloured compounds.
Quantification of the physical properties of the API (Active Pharmaceutical Ingredient) are significant when they are used for high load formulations. Small level of impurities in the API can also alter the surface property of a material. The impurities of Mesalamine API formed during preparation and storage causes discolouration of the API.

The Patent application US 20130225539 discloses the purification process of Mesalamine involving the addition of a strongly basic solution into acidic Mesalamine solution for the precipitation of large Mesalamine crystals at temperatures more than 70°C.

The PCT publication WO 2015036920 discloses the precipitation of crystals of Mesalamine involving the addition of aqueous acidic solution of Mesalamine into the aqueous solution buffered with a buffer system based on acetic acid and sodium acetate at temperatures more than 70°C.

The publication International Journal of Pharmaceutical and Chemical Sciences Apr-Jun 2013, vol-2(2), pages 978 to 981 discloses that the rate of degradation of Mesalamine increases with increase in temperature. Hence, purification or precipitation procedures at the higher temperatures increase the degradation impurities of Mesalamine.

By aforementioned facts, there is a need for a simple and commercially significant process for the purification of Mesalamine at large scale.

OBJECT OF THE INVENTION

The object of the invention is to provide a process for the purification of Mesalamine.

Another object of the invention is to provide a process for the preparation of crystalline Mesalamine.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a process for the purification of Mesalamine and the process for obtaining crystalline Mesalamine.

One aspect of the present invention is to provide a process for the purification of Mesalamine comprising the steps of:
(a) adding activated charcoal to aqueous alkaline solution of Mesalamine;
(b) stirring the mixture obtained in step (a) at temperature ranging from 25°C to 65°C;
(c) filtering the stirred solution obtained in step (b);
(d) adding an inorganic acid or its solution into filtrate obtained in step (c) at temperature ranging from 25°C to 65°C;
(e) optionally stirring the acidic reaction mixture obtained in step (d);
(f) adding activated charcoal to aqueous acidic solution of Mesalamine obtained in step (d) or step (e);
(g) stirring the mixture obtained in step (f) at temperature ranging from 25°C to 65°C;
(h) filtering the stirred solution as obtained in step (g);
(i) adjusting the pH of the filtrate obtained in step (h) between 2.5 to 5.0 by addition of aqueous solution of base;
(j) optionally stirring the reaction mixture obtained in step (i); and
(k) isolating the crystalline Mesalamine from the reaction mixture obtained in step (i) or step (j).

In some embodiment of the invention, alkaline solution of Mesalamine in step (a) of the above described process for the purification of Mesalamine is obtained by adding alkali or alkaline earth metal hydroxides, carbonates, bicarbonates; weak base selected from triethylamine, sodium acetate, triethanolamine, trimethylamine or ammonia or mixture thereof. In some embodiment, the alkaline solution is obtained by addition of ammonia.

In some other embodiment of the invention, the temperature in the step (b) of the above described process for the purification of Mesalamine ranges from 50°C-55°C.

In yet another embodiment of the invention, the inorganic acid added in the step (d) of the above described process for the purification of Mesalamine is hydrochloric acid.

In some embodiment of the invention, the temperature in the step (g) of the above described process for the purification of Mesalamine ranges from 30°C-40°C.

In some embodiment of the invention, in step (i) of the above described process for purification Mesalamine the pH of the filtrate is adjusted between 2.5 to 3.5. In some other embodiment of the invention, the base used for pH adjustment in the above described process for the purification of Mesalamine is sodium acetate.

In some embodiment of the invention, there is provided a process for the purification of Mesalamine, said process comprising the steps of:
(a) adding activated charcoal to aqueous alkaline solution of Mesalamine having pH between 8.0-8.5;
(b) stirring the mixture obtained in step (a) at temperature ranging from 50°C to 55 °C for 90 minutes;
(c) filtering the stirred solution obtained in step (b);
(d) adding an hydrochloric acid or its solution into filtrate obtained in step (c) at temperature ranging from 30°C to 40°C;
(e) stirring the acidic reaction mixture obtained in step (d);
(f) adding activated charcoal to aqueous acidic solution of Mesalamine obtained in step (d) or step (e);
(g) stirring the mixture obtained in step (f) at temperature ranging from 30°C to 40°C for 90 minutes;
(h) filtering the stirred solution as obtained in step (g);
(i) adjusting the pH of the filtrate obtained in step (h) between 2.5 to 3.5 by addition of aqueous solution of sodium acetate;
(j) stirring the reaction mixture obtained in step (i); and
(k) isolating the crystalline Mesalamine from the reaction mixture obtained in step (j).

In some embodiment of the invention, the step (j) of the above described process for the purification of Mesalamine is carried by stirring the reaction mixture at 30°C-35°C for 30 minutes followed by stirring at 15°C-20°C for another 30 minutes.

DETAILED DESCRIPTION OF THE INVENTION

The inventors of the present invention have surprisingly found an improved process for the purification of Mesalamine and the preparation of crystalline form of Mesalamine.

In one aspect of the invention, there is provided a process for the purification of Mesalamine comprising the steps of:
(a) adding activated charcoal to aqueous alkaline solution of Mesalamine;
(b) stirring the mixture obtained in step (a) at temperature ranging from 25°C to 65°C;
(c) filtering the stirred solution as obtained in step (b);
(d) adding an inorganic acid or its solution into filtrate obtained in step (c) at temperature ranging from 25°C to 65°C;
(e) optionally stirring the acidic reaction mixture obtained in step (d);
(f) adding activated charcoal to aqueous acidic solution of Mesalamine obtained in step (d) or step (e);
(g) stirring the mixture obtained in step (f) at temperature ranging from 25°C to 65°C;
(h) filtering the stirred solution as obtained in step (g);
(i) adjusting the pH of the filtrate obtained in step (h) between 2.5 to 5.0 by addition of aqueous solution of base;
(j) optionally stirring the reaction mixture obtained in step (i); and
(k) isolating the crystalline Mesalamine from the reaction mixture obtained in step (i) or step (j).

The preparation of Mesalamine of the invention may be prepared in methods known in the state of art. Some of the references disclosing the processes for the preparation of Mesalamine are the Patents US 6,808,616, US 9,067,867, US 20130225539, US 20120203031, US 4,670,112, US 4,788,331and US 4,764,263. Preferably, the Mesalamine may be prepared from salicylic acid involving the preparation of 5-(phenylazo)salicylic acid from salicylic acid and aniline; and the reduction of 5-(phenylazo)salicylic acid to obtain Mesalamine. The prepared Mesalamine is purified by the process provided by the present invention.

The aqueous alkaline solution of Mesalamine employed in the step (a) of the present invention may be prepared by the steps of (i) suspending or mixing Mesalamine in water or a mixture of water and water miscible solvents and then (ii) adjusting the pH of the suspension or mixture of Mesalamine in water or a mixture of water and water miscible solvents by the addition of alkali or alkaline earth metal hydroxides, carbonates, bicarbonates; weak base selected from triethylamine, sodium acetate, triethanolamine, trimethylamine or ammonia or mixture thereof. In some embodiment of the invention, the alkaline solution is obtained by addition of ammonia.

In some embodiment of the invention, the mixture of activated charcoal and aqueous alkaline solution of Mesalamine as mentioned in the step (b) is carried out in 15 minutes to 120 minutes, preferably 50 minutes to 100 minutes, most preferably 90 minutes at temperature ranging from 25°C to 65°C, preferably 40°C to 60°C. In some embodiment of the invention, the temperature in the step (b) of the above described process for the purification of Mesalamine ranges from 50°C-55°C.

In some embodiment of the invention, the addition of an inorganic acid or its solution into filtrate as mentioned in step (d) of the above described process is carried out in 5 minutes to 1 hour at temperatures ranging from 25°C to 65°C, preferably at 30°C to 60°C, most preferably 30°C-40°C. In yet another embodiment of the invention, the inorganic acid added in the step (d) of the above described process for the purification of Mesalamine is hydrochloric acid.

The stirring the mixture of activated charcoal and aqueous acidic solution of Mesalamine as mentioned in the step (g) may be carried out in 15 minutes to 120 minutes, preferably 50 minutes to 100 minutes, most preferably 90 minutes at temperatures ranging from 25°C to 65°C, preferably 30°C to 50°C. In some embodiment of the invention, the temperature in the step (g) of the above described process for the purification of Mesalamine ranges from 30°C-40°C.

The adjustment of pH of the filtrate as mentioned step (i) may be carried out at temperatures ranging from 15°C to 70°C, preferably 20°C to 60°C, most preferably 30°C-45°C. In some embodiment of the invention, in step (i) of the above described process for purification Mesalamine the pH of the filtrate is adjusted between 2.5 to 3.5.

The base employed in the step (i) may be selected from a group comprising of alkali or alkaline earth metal hydroxides, carbonates, bicarbonates; mild bases such as sodium acetate, triethanolamine or trimethylamine or mixture thereof. In some other embodiment of the invention, the base used for pH adjustment in step (i) of the above described process for the purification of Mesalamine is sodium acetate.

The isolation of crystalline Mesalamine isolating the crystalline mesalamine from the reaction mixture obtained as mentioned in step (k) may be done as known in the state of art such as filtering or decanting.

In some embodiment of the invention there is provided a process for purification of Mesalamine, wherein said process comprises the steps of:
(a) adding activated charcoal to aqueous alkaline solution of Mesalamine having pH between 8.0-8.5;
(b) stirring the mixture obtained in step (a) at temperature ranging from 50°C to 55 °C for 90 minutes;
(c) filtering the stirred solution obtained in step (b);
(d) adding an hydrochloric acid or its solution into filtrate obtained in step (c) at temperature ranging from 30°C to 40°C;
(e) stirring the acidic reaction mixture obtained in step (d);
(f) adding activated charcoal to aqueous acidic solution of Mesalamine obtained in step (d) or step (e);
(g) stirring the mixture obtained in step (f) at temperature ranging from 30°C to 40°C for 90 minutes;
(h) filtering the stirred solution as obtained in step (g);
(i) adjusting the pH of the filtrate obtained in step (h) between 2.5 to 3.5 by addition of aqueous solution of sodium acetate;
(j) stirring the reaction mixture obtained in step (i); and
(k) isolating the crystalline Mesalamine from the reaction mixture obtained in step (j).

In some embodiment of the invention, the step (j) of the process described above is carried by stirring the reaction mixture at 30°C-35°C for 30 minutes followed by stirring at 15°C-20°C for another 30 minutes.

In some embodiment of the invention, purified Mesalamine or crystalline Mesalamine obtained according to present invention is suitable for the pharmaceutical preparations.

Certain specific aspect and embodiment of the present invention will be explained in detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the invention in any manner.
EXAMPLES

Example-1: Purification of Mesalamine

Step A: Charcoalization of aqueous alkaline Mesalamine: Mesalamine (100 g) was suspended in water (2000 ml) and the pH of this suspension was adjusted to 8.0-8.5 using aqueous ammonia. The Mesalamine solution at a pH of 8.0-8.5 was heated to 50°C. Activated carbon (Pencarb-N, 2.0 g) was added to heated solution and stirred at 50°C-55°C for 90 minutes under nitrogen atmosphere. The solution was filtered through hyflo.

Step B: Charcoalization of aqueous acidic Mesalamine: The filtrate obtained in step (A) was acidified by addition of concentrated hydrochloric acid (200 ml) at 30°C-40°C. The resultant solution was stirred for 15 minutes. Activated carbon (Pencarb-N, 2.0 g) was added to the heated solution and stirred for 30°C-40°C for 90 minutes under nitrogen atmosphere. The solution was filtered through hyflo.

Step C: Isolation of crystalline Mesalamine: The filtrate obtained in step (B) was filtered through 0.45-micron filter paper. The pH of the filtrate was adjusted 2.5 to 3.5 using 40% sodium acetate trihydrate solution at 30°C-45°C. The obtained solution at a pH of 2.5 to 3.5 was stirred for 30 minutes at 30°C-35°C and cooled to 15°C. The cooled solution was stirred for 30 minutes at 15°C-20°C. The resultant solid was filtered, washed with water (1000 ml) and isopropyl alcohol (100 ml), then dried to obtained purified and crystalline Mesalamine. Yield: 90%.
,CLAIMS:

1. A process for purification of Mesalamine comprising the steps of:
(a) adding activated charcoal to aqueous alkaline solution of Mesalamine;
(b) stirring the mixture obtained in step (a) at temperature ranging from 25°C to 65 °C;
(c) filtering the stirred solution obtained in step (b);
(d) adding an inorganic acid or its solution into filtrate obtained in step (c) at temperature ranging from 25°C to 65°C;
(e) optionally stirring the acidic reaction mixture obtained in step (d);
(f) adding activated charcoal to aqueous acidic solution of Mesalamine obtained in step (d) or step (e);
(g) stirring the mixture obtained in step (f) at temperature ranging from 25°C to 65°C;
(h) filtering the stirred solution as obtained in step (g);
(i) adjusting the pH of the filtrate obtained in step (h) between 2.5 to 5.0 by addition of aqueous solution of base;
(j) optionally stirring the reaction mixture obtained in step (i); and
(k) isolating the crystalline Mesalamine from the reaction mixture obtained in step (i) or step (j).

2. The process as claimed in claim 1, wherein the alkaline solution of Mesalamine in step (a) is obtained by adding alkali or alkaline earth metal hydroxides, carbonates, bicarbonates; weak base selected from triethylamine, sodium acetate, triethanolamine, trimethylamine or ammonia or mixture thereof.

3. The process as claimed in claim 2, wherein said alkaline solution is obtained by addition of ammonia.

4. The process as claimed in claim 1, wherein the temperature in the step (b) ranges from 50°C-55°C.

5. The process as claimed in claim 1, wherein the inorganic acid added in the step (d) is hydrochloric acid.
6. The process as claimed in claim 1, wherein the temperature in the step (g) ranges from 30°C-40°C.

7. The process as claimed in claim 1, wherein in step (i) the pH of the filtrate is adjusted between 2.5 to 3.5.

8. The process as claimed in claim 1, wherein the base used for pH adjustment is sodium acetate.

9. A process as claimed in claim 1, wherein said process comprises the steps of:
(a) adding activated charcoal to aqueous alkaline solution of Mesalamine having pH between 8.0-8.5;
(b) stirring the mixture obtained in step (a) at temperature ranging from 50°C to 55 °C for 90 minutes;
(c) filtering the stirred solution obtained in step (b);
(d) adding an hydrochloric acid or its solution into filtrate obtained in step (c) at temperature ranging from 30°C to 40°C;
(e) stirring the acidic reaction mixture obtained in step (d);
(f) adding activated charcoal to aqueous acidic solution of Mesalamine obtained in step (d) or step (e);
(g) stirring the mixture obtained in step (f) at temperature ranging from 30°C to 40°C for 90 minutes;
(h) filtering the stirred solution as obtained in step (g);
(i) adjusting the pH of the filtrate obtained in step (h) between 2.5 to 3.5 by addition of aqueous solution of sodium acetate;
(j) stirring the reaction mixture obtained in step (i); and
(k) isolating the crystalline Mesalamine from the reaction mixture obtained in step (j).

10. The process as claimed in claim 9, wherein the step (j) is carried by stirring the reaction mixture at 30°C-35°C for 30 minutes followed by stirring at 15°C-20°C for another 30 minutes.