The present invention relates to a process for the preparation of lansoprazole with desired particle-size in high yield and purity with appropriate particle-size distribution.
Chemically, lansoprazole is 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl] methyl] sulfinyl] benzimidazole of Formula I and is known from US patent No. 4,628,098.
(Formula Removed)
Formula I
Lansoprazole is one of the well known gastric proton pump inhibitor and has a broader antiulcerative and antigastric properties. Other benzimidazole derivatives having similar properties include omeprazole, pantoprazole and rabeprazole.
Lansoprazole and other 2-(2-pyridylmethyl)sulfinylbenzimadazole derivatives tend to lose stability and undergo decomposition at high temperature and when contaminated with traces of a solvent, particularly water, in their crystal structure.
Several processes have been reported for the preparation and purification of lansoprazole such as those described in WO 99/47514, WO 2001/68594, WO 2001/21617, US 5374730, US 7060837, WO 0121617, ES 2063705, WO 99/47514, US 6998490, US 7022859, WO 2002074766, WO 2004011455, US 6603009, US 6998490, US 7105681, US 7064213 which are herein, incorporated for the reference only.
US patent '098 discloses the purification of crude lansoprazole involving column chromatography (silica gel, eluent; ethyl acetate) and further by crystallization from a mixture of solvents. It provides tedious and time consuming purification process which is not viable for commercial production.
US patent No. 6,180,652 describes a method for the purification of lansoprazole through its acetone complex. This permits the separation of sulfone derivative but brings the drawback of low yield of the desired sulfoxide.
US 6,002,011 describes a process for preparing lansoprazole, which involves subjecting (water and alcohol)-solvate crystals of the compound to being suspended, left standing or stirred in water for a sufficient time, and drying the resultant product.
WO 03/062223 describes purification of sulfone and sulfide contaminated lansoprazole by treating it with potassium carbonate in aqueous alcohol at elevated temperature.
US 6,919,459 describes a process for purification of lansoprazole involving extraction with aqueous alkaline solution at high pH.
US 6,909,004 describes a method of purifying lansoprazole from a solution of crude lansoprazole in organic solvent or a mixture of organic solvent and water in presence of amine compound.
Although attempts have been made and literature reports a number of methods for preparation and purification of lansoprazole but it does not provide any reference related to preparation of lansoprazole with desired particle-size and specified particle-size distribution. Moreover, the methods employed for obtaining pure crystalline lansoprazole in the literature involves tedious chromatographic techniques, extraction procedures or multi solvent crystallization at high temperature.
Lansoprazole is thermally labile by nature, therefore there is a need for simple, cost effective and industrially advantageous process for the preparation and purification of stable lansoprazole at low temperature and free of residual solvents and impurities that overcomes the drawbacks of prior-art processes. . It is always advantageous to develop a simple and economically efficient process for the preparation of pharmaceutically acceptable particles with well defined particle-size distribution for formulation to achieve better dissolution and increased bioavailability and also which does not involve an extra step of milling and avoids contamination and degradation of the product.
Accordingly, the present invention provides a method for producing pure lansoprazole of desired particle-size comprising:
a. Suspending lansoprazole in ketonic solvent
b. Cooling the mixture and
c. Isolating pure lansoprazole of desired particles size.
Lansoprazole used as a starting material may be obtained from any of the synthetic routes described in the prior art, including those described in WO 99/47514, WO 2001/68594, WO 2001/21617, US 5374730,
US 7060837, WO 0121617, ES 2063705, WO 99/47514, US 6998490, US 7022859, WO 2002074766, WO 2004011455, US 6603009, US 6998490, US 7105681, US 7064213 which are herein incorporated for the reference only.
Examples of ketonic solvent may be selected from the group comprising of acyclic ketones, cyclic ketones or a mixture thereof, which are inert under reaction conditions.
Examples of acyclic ketone may be selected from the group comprising of acetone, 2-butanone, 2-pentanone, 3-pentanone, methylisobutyl ketone or a mixture thereof.
Examples of cyclic ketone may be selected from the group comprising of cyclopentanone, cyclohexanone, lactone, phenone, pyrone or a mixture thereof.
The mixture may be stirred for about 2 to about 8 hours.
The mixture may be stirred at a temperature range of from about 10°C to about 45°C.
The mixture may be cooled to about -20 10 about 5°C.
Isolation of lansoprazole may be accomplished by precipitation, cooling, filtration, centrifugation, drying or a combination thereof
The obtained lansoprazole may have particles characterized by dgo of about 22u-m or below.
The obtained lansoprazole may have particles characterized by d50 of about 12µm or below. The obtained lansoprazole may have particles characterized by d10 of about 6µm or below.
The obtained lansoprazole may have less than about 0.1%, wt/wt, water.
The obtained lansoprazole may have less than about 0.1%, wt/wt, sulfide derivative. The obtained lansoprazole may have less than about 0.1%, wt/wt, sulfone derivative.
In the following section embodiments are described by way of examples to illustrate the intendment of invention. However, these are not intended in any to limit the scope of present invention. Several variants of these examples would be evident to persons ordinarily skilled in the art.
Example-l
Preparation of Lansoprazole:
To a mixture of 2-[[3-methyl-4-(2,2,2-trifluoromethoxy)pyrid-2-yl]methylthio]benzimadazole (lOOg) and acetonitrile (1 Lt), aqueous sodium hydroxide solution (23g in 200 ml water) was added at 15-20°C and was stirred to get clear solution. It was then cooled to -5°C to -10°C and sodium hypochlorite solution (~8%(w/w); 400g) was added slowly at -10°C to -5°C over 60 minutes. The reaction mixture was allowed to stir for 120 minutes and sodium thiosulphate (20g in 200ml H2O) was added followed by water (1 Lt) at 0-5°C. The pH was adjusted to 8.8-9.0 with 20% acetic acid. Water was added (1 Lt) and temperature was raised to 10-15°C. The solid was separated, filtered, washed with water and dried under vacuum to result crude lansoprazole (93g).
Crude lansoprazole (90g) was suspended in DNS (900ml) and water (90ml) and cooled to 5-8°C. Sodium hydroxide solution (4g in 30ml water) was added at the same temperature and was stirred for 10-15 minutes. The reaction mixture was heated to 45-50°C to get a clear solution and stirred further for 5-10 minutes. Water (200ml) was then added and cooled to 2-8°C. The pH was adjusted to 8.9-9.2 with 50% acetic acid and stirred for 120 minutes. The product was filtered, washed with a mixture of 1:1 DNS: Water (200ml each) and dried under vacuum to yield lansoprazole (84g). Yield - 80%
Example-2
Preparation of pure lansoprazole with desired particle-size:
Lansoprazole from Example-l was suspended in acetone (750ml) at 20-25°C and stirred for 4 hours. The
suspension was cooled to -10 to -15°C and stirred for 60 minutes. The solid was filtered, washed with
cold acetone (100ml) and dried under vacuum to yield lansoprazole (72g) d9o - 18.95µm
d50- 10.04 µm
d10 - 4.763µm
HPLC Purity- 99.97 %.
Water content- less than 0.1% (by Karl-Fisher)
Suiphone- 0.0%
Sulphide-0.03%

WE CLAIM:
1. A method for producing pure lansoprazole of desired particle-size comprising:
a. Suspending lansoprazole in ketonic solvent
b. Cooling the mixture and
c. Isolating pure lansoprazole of desired particle size.
2. The method according to claim 1 wherein, the ketonic solvent is selected from the group comprising of
acyclic ketones, cyclic ketones or a mixture thereof.
3. The method according to claim 2 wherein, the acyclic ketonic solvent is selected from the group
comprising of acetone, 2-butanone, 2-pentanone, 3-pentanone, methylisobutyl ketone or a mixture
thereof.
4. The method according to claim 1 wherein, the mixture is stirred for about 2 to about 8 hours.
5. The method according to claim 1 wherein, the mixture is stirred at a temperature range of from about
10°C to about 45°C.
6. The method according to claim 1 wherein, the mixture is cooled to about -20 to about 5°C.
7. The method according to claim 1 wherein, obtained lansoprazole has particles characterized by dc;o of
about 22um or below.
8. The method according to claim 1 wherein, obtained lansoprazole has particles characterized by dso of
about 12µm or below.
9. The method according to claim 1 wherein, obtained lansoprazole has particles characterized by dio of
about 6µm or below.

10. The method according to claim 1 wherein, obtained lansoprazole has particles containing less than about 0.1% wt/wt water or less than about 0.1% wt/wt sulfide derivative or less than about 0.1% wt/wt sulfone derivative.