This application claims priority to Indian patent application number 3491/CHE/2010 filed on Nov 19,2010

FIELD OF THE INVENTION:

The present invention relates to a process for preparing amorphous Dexlansoprazole, which comprises dissolving crystalline Dexlansoprazole in alcohol solvent, isolating wet crystalline Dexlansoprazole alcoholate, followed by milling and drying.

BACKGROUND OF THE INVENTION:

Benzimidazole compounds such as Lansoprazole, Omeprazole, Rabeprazole and the like have a proton pump inhibitor like activity such as gastric acid secretion suppressing effect and gastric mucosa defensive effect. These compounds are used extensively as agents for the treatment of peptic ulcer.

In the above mentioned benzimidazoles, Lansoprazole, chemically known as 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-lH-benzimidazole, is reported in Japanese Patent Application JP-A-61 -50978, U.S. Pat. No. 4,628,098, JP-A-10-195068 and WO 98/21201 and has been recognized as the most potent antiulcer compound having superior activity. It has more demand having world wide market. These benzimidazole compounds mentioned herein have a sulfur atom which is asymmetrically substituted forming a chiral centre giving rise to R and S isomers of Lansoprazole. R-isomer of Lansoprazole is named as Dexlansoprazole and represented by Formula (I), is less toxic and showed excellent antiulcer action, gastric acid secretion-inhibiting action, mucosa-protecting action, anti-Helicobacter pylori action, etc.,

The method for producing Dexlansoprazole [(R)-lansoprazole] or (S)-lansoprazole was disclosed in JP-A-11-508590 (WO 97/02261), US 7169799 and US 7285668.

US 6664276 disclosed a process for the preparation of amorphous Dexlansoprazole by resolving racemic Lansoprazole by HPLC with the aid of a chiralcel column using mobile phase containing hexane/2-propanol/ethanol. The fractions of the optical isomers of shorter retention time were combined and concentrated. The individual lots were combined and dissolved in ethanol and filtered. Hexane is added and the filtrate was evaporated to dryness to yield amorphous Dexlansoprazole.

US 20060057195 disclosed a process for the preparation of amorphous Dexlansoprazole by drying a hydrated crystalline form of Dexlansoprazole at a temperature between about 20 and 100° C, but the experimental part demonstrates that such drying is actually performed at a temperature between 60 and 70° C, for a time between 6 and 8 hours.

WO 2009088857 disclosed crystals of ethanol hydrate, isopropanol hydrate, hydrate, 1.0 hydrate, 1.5 hydrate, methanol solvate and ethanol solvate of Dexlansoprazole and processes for their preparation.

WO2009087672 disclosed stable amorphous Dexlansoprazole and a process for preparing the same by optically resolving racemic Lansoprazole by forming a reversible host-guest inclusion complex that includes a chiral guest molecule in the Lansoprazole lattice.

US20100204479 Al disclosed a process for the preparation of amorphous Dexlansoprazole by drying Dexlansoprazole crystalline form D at a temperature equal to or lower than 50°C.

The above-mentioned method for the production of amorphous Dexlansoprazole does not necessarily satisfy the stringent purity, solubility, preservation stability and industrial viability. Moreover the prior art process involves heating the product upto 100°C wherein the possibility of forming impurities are more. Thus there is a need for a better process for the preparation of Dexlansoprazole having superior properties than the ones disclosed in the prior art and which can result in amorphous dexlansoprazole consistently with no contamination of crystalline product and have a better impurity profile and stability profile. Thus, the present invention relates to an improved process for preparation of amorphous Dexlansoprazole.

SUMMARY AND OBJECT OF THE INVENTION:

The present invention provides an improved process for preparing amorphous Dexlansoprazole.

One aspect of the present invention provides a process for the preparation of amorphous Dexlansoprazole which comprises the steps of a) dissolving crystalline Dexlansoprazole in an alcohol solvent, b) cooling, filtering crystalline Dexlansoprazole alcoholate, c) milling the wet product obtained in step d), and e) drying to give amorphous Dexlansoprazole.

Another aspect of the present invention is to provide a pharmaceutical composition comprising amorphous dexlansoprazole and pharmaceutically acceptable carrier or excipient.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention provides a process for preparing amorphous Dexlansoprazole, which comprises dissolving crystalline Dexlansoprazole in alcohol solvent and water, isolating wet crystalline Dexlansoprazole alcoholate, followed by milling and drying

One embodiment of the present invention provides a process for the preparation of amorphous Dexlansoprazole, which comprises the steps of

a) dissolving crystalline Dexlansoprazole in an alcohol solvent,
b) cooling to crystallise the product,
c) filtering crystalline Dexlansoprazole alcoholate,
d) subjecting the wet product obtained in step c) to milling, and
e) drying to give amorphous Dexlansoprazole.

According to the present invention crystalline Dexlansoprazole is dissolved in an alcohol solvent selected from methanol, ethanol, propanol, isopropanol or butanol, preferably ethanol or n-propanol optionally containing a few drops of ammonia at 30-50°C. Water is added to the solution thus formed and stirred for about 5-20 min at the same temperature. The clear solution is cooled to 0-15°C for about 2-5 hrs. The solid obtained is filtered. The wet product is then subjected to milling, followed by drying the milled product under reduced pressure at 30-60°C for about 7-17hrs to give amorphous Dexlansoprazole.

According to the present invention milling is performed by using Co-Miller with 300-3000 RPM having 2-10 mm hole mesh under nitrogen blanket.

According to the present embodiment the crystalline Dexlansoprazole is in hydrate, preferably crystalline Dexlansoprazole sesquihydrate.

Another embodiment of the present invention is to provide a pharmaceutical composition comprising amorphous dexlansoprazole and pharmaceutically acceptable carrier or excipient.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.

EXPERIMENTAL SECTION:

Example 1:

Dexlansoprazole (lOOg) was dissolved in ethanol (200ml) containing few drops of aqueous ammonia at 40-48°C. DM water (50ml) was slowly added to the solution at the same temperature and stirred for about 10-15 min. The solution was filtered through hyflow bed to get a clear filtrate and the resultant filtrate was cooled to 5-10°C for about 3-4hrs. The solid obtained was filtered in centrifuge and spin dried for about 15-60 min. Wet product (having LOD -30%) was milled using a Co-Miller with 300-3000 RPM using 2-10 mm hole mesh under nitrogen blanket. The milled product was dried under reduced pressure at 40-50°C for 8-14 hrs to give amorphous Dexlansoprazole (70g). The drying and conversion of crystalline solvate to amorphous product is monitored by XRPD analysis.

Example 2:

Dexlansoprazole (100g) was dissolved in n-propanol (250ml) containing few drops of aqueous ammonia at 40-48°C. DM water (50ml) was added to the reaction mass at the
same temperature and stirred for about 10-15 min. The reaction mass was filtered through hyflow bed to get a clear filtrate and the resultant filtrate was cooled to 5-10°C for about 3-4hrs. The solid obtained was filtered in centrifuge and spin dried for about 15-60 min. Wet product (having LOD -25%) was milled using a Co-Miller with 300-3000 RPM using 2-10 mm whole mesh under nitrogen blanket. The milled product was dried under reduced pressure at 40-50°C for 8-14 hrs to give amorphous Dexlansoprazole (60g).

We Claim:

1. A process for the preparation of amorphous Dexiansoprazole comprising steps:

a) dissolving crystalline Dexiansoprazole in an alcohol solvent,
b) cooling to crystallise the product,
c) filtering crystalline Dexiansoprazole alcoholate,
d) subjecting the wet product obtained in step c) to milling, and
e) drying to get amorphous Dexlansoprazole.

2. The process according to claim 1, wherein an alcohol solvent is selected from methanol, ethanol, propanol, isopropanol, butanol or n-propanol.

3. The process according to claim 1, wherein the alcohol solvent is optionally contains ammonia solution.

4. The process according to claim 1, wherein the solution of step a) is diluted with water.

5. The process according to the claim 1, the crystalline dexlansoprazole is in hydrate.

6. The process according to claim 4, the hydrate is dexlansoprazole sesquihydrate.

7. The process according to claim 1, wherein the obtained reaction mass in step b) is cooled 0-15 °C.

8. The process according to claim 1, wherein the milling is performed using CoMiller with 300-3000 RPM having 2-10 mm hole mesh under nitrogen blanket.

9. The process according to claim 1, wherein drying is performed at 40-50 °C for 8- l4hrs.

10. A pharmaceutical composition comprising amorphous dexlansoprazole and pharmaceutically acceptable carrier or excipient.