FIELD OF THE INVENTION

The present invention relates to an improved process to prepare (S)-5-methoxy-2-[[(4-methoxy-3,5-diniethyl-2-pyridinyl)methyl]sulfinyl]-lH-benzimtdazole Magnesium Dihydrate Form A of Formula I, Formula I

BACKGROUND OF THE INVENTION

(S)-5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyI)methyl]sulfinyl]-lH-benzimidazole of Formula I, which is generically known as Esomeprazole, is a Proton Pump Inhibitor. Esomeprazole Magnesium is being marketed under the Trade name NEXIUM as Delayed Release Capsules. Esomeprazole Sodium is also being marketed under the Trade name NEXIUM IV as an Intravenous Injection.

Esomeprazole is used for inhibiting gastric acid secretion in mammals and man. In a more general sense, Esomeprazole is used for the treatment of gastric acid-related diseases and gastrointestinal inflammatory diseases in mammals and man, such as gastric ulcer, duodenal ulcer, reflux esophagitis, and gastritis.

US 6,369,085 discloses various forms of Esomeprazole magnesium trihydrate and dihydrate Form A and Form B, The process for preparation of Esomeprazole magnesium dihydrate Form A is not industrially efficient as it offers results in the dihydrate being converted to the trihydrate. This process is disadvantageous as the polymorph A of the dihydrate cannot be obtained consistently as the wet dihydrate gels converted to the trihydrate form.

US 2005/0267159 A] discloses a process to prepare Esomeprazole magnesium dihydrate, which comprises adding Esomeprazole magnesium to dimethylformamide and stirred to get the clear solution. The resulting solution was placed in petrie dish and stored under refrigerated conditions to recrystalllze.

WO 2008/102145 A2 discloses a process to prepare Esomeprazole magnesium dihydrate, which comprises dissolving Esomeprazole potassium salt in methanol and thereafter adding methanolic magnesium chloride hexahydrate solution. The methanol was distilled off under vaccum at 45-50°C till the methanol is approximately 70 ml, and is cooled and added water and acetone mixture to crystallize the Esomeprazole magnesium dihydrate. The crystallized Esomeprazole magnesium dihydrate Form A was washed with ethyl acetate and immediately dried at 60-65°C under vacuum.

WO 2009/047775 A2, discloses a process to prepare Esomeprazole magnesium dihydrate, which comprises dissolving Esomeprazole sodium in methanol and adding a solution of anhydrous magnesium chloride in methanol. After completion of the reaction, the methanol was distilled off completely under vacuum and then co-distilled two times with methylene chloride. To the residue added methylene chloride and anhydrous sodium sulfate and stirred. Thereafter, the resulting solution is distilled under vacuum and to the residue methanol was added. The resulting solution was again distilled to remove methanol till the volume one-fourth (1/4) and adding acetone and cooling to 5°C to precipitate Esomeprazole magnesium dihydrate Form A.

WO 2009/074997 A2, discloses a process to prepare crystalline form of magnesium salt of Esomeprazole dihydrate, which comprises dissolving potassium salt of Esomeprazole in dimethylformamide and adding magnesium chloride hexahydrate to the solution. Thereafter, the salts were removed by filtration and anti-solvent was added to precipitate magnesium salt of Esomeprazole, which was isolated and slurry washed with anti-solvent and then dried.

All the above processes are involving tedious work up to isolate Esomeprazole magnesium dihydrate Form A in pure form. In view of the above, there is a need to develop a process, which gives a stable Esomeprazole magnesium dihydrate Form A.

We have now found a process to prepare Esomeprazole magnesium dihydrate Form A, which is commercially feasible, economically viable and stable.

OBJECTIVE

The objective of the present invention is to provide an improved process to prepare Esomeprazole magnesium dihydrate Form A, which is stable.

The objective of the present invention is to provide an improved process to prepare Esomeprazole magnesium dihydrate Form A, which is simple, industrially applicable and economically viable.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 - Powder X-ray diffraction (PXRD) of Esomeprazole magnesium dihydrate Form A

Figure 2 - Powder X-ray diffraction (PXRD) of Esomeprazole magnesium dihydrate Form A, after storage at 40°C/75% RH, 6 M

SUMMARY OF THE INVENTION

An improved process to prepare Esomeprazole magnesium dihydrate Form A of Formula I, Formula I which is free from other hydrates, which comprises,

a) dissolving Esomeprazole salt in DM water;

b) adding a solution of magnesium chloride hexahydrate in DM water;

c) isolating the precipitated Esomeprazole magnesium;

d) slurrying wet Esomeprazole magnesium in acetone;

e) optionally seeding with Esomeprazole magnesium dihydrate; and

f) isolating the Esomeprazole magnesium dihydrate Form A.

DETAILED DESCRIPTION OF THE INVENTION

Esomeprazole salt is dissolved in DM water. To the resulting solution a solution of magnesium chloride hexahydrate dissolved in DM water is added dropwise and stirred to precipitate Esomeprazole magnesium. The precipitated product is filtered. The wet product is slurried in acetone and optionally seeded with Esomeprazole magnesium dihydrate form A, and stirred to give a stabJe and pure Esomeprazole magnesium dihydrate, which is free from other hydrates.

The other hydrates means monohydrate, sesquihydrfte, trihydrate, tetrahydrate, pentahydrate.

The present invention relates to an improved process to prepare substantially pure stable Esomeprazole magnesium dihydrate Form A, which comprises,

a) dissolving Esomeprazole salt in DM water;

b) adding a solution of magnesium chloride hexahydrate in DM water;

c) isolating the precipitated Esomeprazole magnesium;

d) slurrying wet Esomeprazole magnesium in acetone;

e) optionally seeding with Esomeprazole magnesium dihydrate; and

f) isolating the Esomeprazole magnesium dihydrate Form A.

Esomeprazole salt is dissolved in DM water at 20-30°C. To the resulting solution a solution of magnesium chloride hexahydrate dissolved in DM water is added dropwise at 0-10°C and stirred to precipitate Esomeprazole magnesium. The precipitated product is filtered. The wet product is added to acetone at 20-25°C and optionally seeded with Esomeprazole magnesium dihydrate Form A, and stirred to give a stable and pure Esomeprazole magnesium dihydrate, which is free from other hydrates.

Esomeprazole salt is dissolved in DM water at 20-30°C. To the resulting solution a solution of magnesium chloride hexahydrate dissolved in DM water is added dropwise at 0-10°C and stirred to precipitate Esomeprazole magnesium. The precipitated product is filtered. The wet product is added to cold acetone at 0-10°C and optionally seeded with Esomeprazole magnesium dihydrate Form A, and stirred at 20-25°C to give a stable and pure Esomeprazole magnesium dihydrate, which is free from other hydrates.

Esomeprazole salt is dissolved in DM water at 20-30°C. To the resulting solution a solution of magnesium chloride hexahydrate dissolved in DM water is added dropwise at 0-10°C and stirred to precipitate Esomeprazole magnesium. The precipitated product is filtered. The acetone is added to the wet product at 20-25°C and optionally seeded with Esomeprazole magnesium dihydrate Form A, and stirred to give a stable and pure Esomeprazole magnesium dihydrate, which is free from other hydrates.

Esomeprazoie salt is dissolved in DM water at 20-30°C. To the resulting solution a solution of magnesium chloride hexahydrate dissolved in DM water is added dropwise at 0-10°C and stirred to precipitate Esomeprazoie magnesium. The precipitated product is filtered. The acetone is cooled to 0-10°C and added to the wet product and optionally seeded with Esomeprazoie magnesium dihydrate Form A, and stirred at 20-25°C to give a stable and pure Esomeprazoie magnesium dihydrate, which is free from other hydrates.
Esomeprazoie salt is Esomeprazoie sodium salt or Esomeprazoie potassium salt, preferably Esomeprazoie sodium salt.

X-RAY POWDER DIFFRACTION (PXRP)

X-ray powder diffraction analysis is performed on the samples using Seifert, XRD 3003 TT Diffractometer. Cu Kal radiation (k = 1.540598 A°) is used to obtain all powder patterns. Scans were performed over the range between 2.4° to 40** 26 at a step signal of 0.03° 29 per second.

The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

EXAMPLE 1

PREPARATION OF ESOMEPRAZOLE MAGNESIUM DIHYDRATE FORM A

Esomeprazoie sodium (20 g; 54.43 mmol) was dissolved in DM water (100 ml) and filtered. To the filtrate, magnesium chloride hexahydrate (6.07 g; 29.90 mmol) dissolved in DM water (20 ml) was added dropwise at 0-10°C and stirred for 1 h. The precipitated product was filtered and washed with cold DM water till it was free from chlorides. The wet Esomeprazole magnesium was added to cold acetone (70 ml) at 0-10°C and seeded with Esomeprazole magnesium dihydrate Form A (0.2 g). The reaction mass was allowed to raise the temperature till 20-25°C and stirred for 5 h. The product was filtered, washed with cold acetone and dried at 35-40°C under reduced pressure to yield Esomeprazole magnesium dihydrate Form A. Yield: 14.6 g M.C.: 5.3 %

EXAMPLE 2

PREPARATION OF ESOMEPRAZOLE MAGNESIUM DIHYDRATE FORM A

Esomeprazole sodium (20 g; 54.43 mmol) was dissolved in DM water (100 ml) and filtered. To the filtrate, magnesium chloride hexahydrate (6.07 g; 29.90 mmol) dissolved in DM water (20 ml) was added dropwise at 0-10°C and stirred for 1 h. The precipitated product was filtered and washed with cold DM water till it was free from chlorides. The wet Esomeprazole magnesium was added to cold acetone (140 ml) at 0-10°C and seeded with Esomeprazole magnesium dihydrate Form A (0.2 g). The reaction mass was allowed to raise the temperature till 20-25°C and stirred for 5 h. The product was filtered, washed with cold acetone and dried at 35-40°C under reduced pressure to yield Esomeprazole magnesium dihydrate Form A. Yield: 14.7 g M.C.: 5.3 %

EXAMPLE 3

PREPARATION OF ESOMEPRAZOLE MAGNESIUM DIHYDRATE FORM A

Esomeprazole sodium (20 g; 54.43 mmol) was dissolved in DM water (100 ml) and filtered. To the filtrate, magnesium chloride hexahydrate (6.07 g; 29.90 mmol) dissolved in DM water (20 ml) was added dropwise at 0-10°C and stirred for 1 h. The precipitated product was filtered and washed with cold DM water till it was free from chlorides. The wet Esomeprazole magnesium was added to cold acetone (175 ml) at 0-10°C and was allowed to raise the temperature till 20-25°C and stirred for 18 h. The product was filtered, washed with cold acetone and dried at 35-40°C under reduced pressure to yield Esomeprazole magnesium dihydrate Form A. Yield: 13.8 g M.C.:5.7%

EXAMPLE 4

PREPARATION OF ESOMEPRAZOLE MAGNESIUM DIHYDRATE FORM A

Esomeprazole sodium (20 g; 54.43 mmol) was dissolved in DM water (100 ml) and filtered. To the filtrate, magnesium chloride hexahydrate (6.07 g; 29.90 mmol) dissolved in DM water (20 ml) was added dropwise at 5-10°C and stirred for 1 h. The precipitated product was filtered and washed with cold DM water till it was free from chlorides. The wet Esomeprazole magnesium was added to cold acetone (245 ml) at 0-10°C and was allowed to raise the temperature till 20-25°C and stirred for 10 h. The product was filtered, washed with cold acetone and dried at 35-40°C under reduced pressure to yield Esomeprazole magnesium dihydrate Form A. Yield: 13.7 g M.C.:5.7%

EXAMPLE 5

PREPARATION OF ESOMEPRAZOLE MAGNESIUM DIHYDRATE FORM A

Esomeprazole sodium (150 g; 408.27 mmol) was dissolved in DM water (750 ml) and filtered. To the filtrate, magnesium chloride hexahydrate (45.6 g; 224.63 mmol) dissolved in DM water (150 ml) was added dropwise at 5-10°C and stirred for 1 h. The precipitated product was filtered and washed with cold DM water till it was free from chlorides. The wet Esomeprazole magnesium was added to cold acetone (1250 ml) at 0-10°C and seeded with Esomeprazole magnesium dihydrate Form A (1.5 g). The reaction mass was allowed to raise the temperature till 20-25°C and stirred for 13 h. The product was filtered washed with cold acetone and dried at 35-40°C under reduced pressure to yield Esomeprazole magnesium dihydrate Form A. Yield: 108 g M.C.:5.8%

EXAMPLE 6

PREPARATION OF ESOMEPRAZOLE MAGNESIUM DIHYDRATE FORM A

Esomeprazole sodium (20 g; 54.43 mmol) was dissolved in DM water (100 ml) and filtered. To the filtrate, magnesium chloride hexahydrate (6.07 g; 29.90 mmol) dissolved in DM water (20 ml) was added dropwise at 0-10°C and stirred for 1 h. The precipitated product was filtered and washed with cold DM water till it was free from chlorides. The wet Esomeprazole magnesium was added to acetone (140 ml) at 20-25°C and stirred for 5 h. The product was filtered, washed with acetone and dried at 35-40°C under reduced pressure to yield Esomeprazole magnesium dihydrate Form A. Yield: 13.8 g M.C.:5.7%

Claim

1. An improved process to prepare Esomeprazole magnesium dihydrate Form A of
Formula (,which is free from other hydrates, which comprises,

a) dissolving Esomeprazole salt in DM water;

b) adding a solution of magnesium chloride hexahydrate in DM water;

c) isolating the precipitated Esomeprazole magnesium;

d) slurrying wet Esomeprazole magnesium in acetone;

e) optionally seeding with Esomeprazole magnesium dihydrate; and

f) isolating the Esomeprazole magnesium dihydrate Form A.

2. The process according to claim 1, wherein Esomeprazole salt is selected from esomeprazole sodium, esomeprazole potassium.

3. The process according to claim I, wherein Esomeprazole in DM water is dissolved at 20-3O°C.

4. The process according to claim 1, wherein solution of magnesium chloride hexahydrate is added drop-wise at 0-10°C.

5. The process according to claim I, wherein the wet Esomeprazole magnesium is slurried in acetone at 20-25°C,

6. The process according to claim 1, wherein the wet Esomeprazole magnesium is slurried in acetone at 0-10°C.

7. An improved process for the preparation of Esomeprazole magnesium dihydrate of Formula I, as defined in claim 1, substantially as herein described with reference to the examples.