FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)


TITLE OF THE INVENTION
"IMPROVED PROCESS FOR THE PREPARATION OF OMEPRAZOLE MAGNESIUM"

CADILA HEALTHCARE LIMITED, of Cadila Healthcare Limited, Zydus Research Centre, "Zydus Tower", Satellite Cross Roads, Gandhinagar-Sarkhej Highway, Ahmedabad-380 015, Gujarat, India;
The following specification particularly describes the nature of the invention.


FIELD OF INVENTION
The present invention discloses improved process for preparing magnesium salt of Omeprazole.
BACKGROUND OF THE INVENTION
Proton pump inhibitors are useful for gastrointestinal protection inhibiting gastric acid secretion
and have gastric mucosa protective activity in mammals including man They may be used for
prevention and treatment of gastric acid related disorders and gastrointestinal inflammatory
diseases including gastritis, gastric ulcer and duodenal ulcer. Substituted benzimidazole such as
the compound with the generic name Omeprazole was known as proton pump inhibitor.
Chemically, Omeprazole is 5-methoxy_2.[[(4.methoxy-3,5,-dimethyi-2-
pyridinyl)methyl)sulfiny'.]-lH-benzimidazole and the magnesium salt of Omeprazole has the structural formula as shown in formula (I)

Formula (I)
Omeprazole Magnesium is available commercially in the US as as PRILOSEC as capsules or delayed release pellets and also is available over the counter in the form of delayed release tablets under the brand name PRILOSEC OTC™. It is also sold as a powder combination of Omeprazole, Magnesium hydroxide and sodium bicarbonate under the brand name ZEGER1D. The compound known under the generic name Omeprazole is described in European patent specification 0005129. A problem with Omeprazole is its stability characteristics. During storage under accelerated stability condition, that is at +37 °C and at a relative humidity of 80% for a period of month, about 6 % of the substance is converted to degradation products. So, it is desirable to obtain Omeprazole derivatives which exhibit improved stability. EP0124495 (US 4738974) described the lithium, sodium, potassium, magnesium, calcium, titanium, quaternary alkyl ammonium and guanidinium salts of Omeprazole. The methods described to obtain the Magnesium salts are indirect methods through the first formation of me sodium salt. In one indirect method, Omeprazole sodium is first formed by reacting Omeprazole and 50% Sodium hydroxide in tetrahydrofuran, and the salt is then recrystallize.d by mixing in trichloroethylene.

Magnesium Omeprazole is then prepared by mixing this Omeprazole sodium dissolved in
deionized water with magnesium chloride dissolved in deionized water. This method has the
disadvantages of (i) that the method is indirect; (ii) that the organic solvents used in the formation
of Omeprazole sodium such as trichloroethyiene and THF are environmentally troublesome. A
second procedure is given in example 6 of the same patent. According to this process,
Magnesium is reacted with methanol to give magnesium methoxide, which is added to
Omeprazole dissolved in methanol. The Omeprazole magnesium is recovered by evaporation of
the solvent.
In a subsequently filed application, CA2254572, following comments are made in relation to the
process of EP0124495. This procedure can not be practiced on large scale because of the need to
evaporate to dryness. It has been found that unacceptable and potentially dangerous amounts of
methanol become trapped in this solid, making it pharmaceutically unacceptable.
According to US 5900424, the form of Omeprazole Magnesium disclosed in US 4738974 are
difficult to handle in full manufacturing scale because of the fragility of the Omeprazole
Magnesium crystals prepared according to process described therein. US 5900424 therefore
discloses Omeprazole magnesium having a degree of crystallinity higher than 70 %, a particle
size less than 30um and a bulk density between 1.33 and 1.35 g /cm .
US 6713495 discloses a process for producing substantially amorphous magnesium Omeprazole
by reacting magnesium alkoxide with Omeprazole dissolved in a lower alcohol to produce after
drying a final product with a low level of alcohol.
In US 6048981 disclosed a process, wherein Omeprazole is dissolved in aqueous ammonia to
which various inorganic magnesium salts are added to precipitate magnesium Omeprazole. A
disadvantage of this process is the removal of excess ammonia.
W09741114 (US6124464) discloses a novel process for the preparation of a magnesium salt of a
substituted sulfinyl heterocyclic compound containing an imidazole moiety. The process is
carried out by mixing the substituted heterocycle with a weak base and a magnesium source.
Thus, Omeprazole magnesium salt was obtained by the reaction of the Omeprazole free base with
aq. NH3 and MgSO4-7H2O in MeOH solution.
WO2005082888 discloses a novel process for the preparation of magnesium Omeprazole which
comprises the reaction of Omeprazole with magnesium hydroxide which is a weak inorganic base
as magnesium source.
A problem with Omeprazole Magnesium is that it has a tendency to pickup colour and also the
present inventors found that there was a change in crystallinity when stored for an extended
period of time, more particularly if there is presence of any residual solvents.

Thus, there remains a need for developing a process which overcomes one or more of the deficiencies of the prior art and thereby develop a modified process for preparing magnesium Omeprazole. There also is a need for a process using suitable solvents wherein the crystallinity of Omeprazole is retained even in the presence of residual solvents.
OBJECTIVES OF THE INVENTION
The objective of the present invention is to provide improved processes for preparing Magnesium
Omeprazole In an embodiment is provided a process for preparing Magnesium Omeprazole using polyethylene
glycol, polyvinylpyrrolidone, liquid starch, polyvinyl alcohols and the like as solvents. The above and other embodiments are further described in the following paragraphs.
DETAILED DESCRIPTION
The improved process for preparing magnesium Omeprazole is described in the following scheme: Scheme 1:

Omeprazole was first converted to its sodium salt by reacting Omeprazole with NaOH in a mixture of water and or suitable organic solvent, to obtain sodium salt of Omeprazole. To the reaction mixtures which contains sodium salt of Omeprazole, solution of MgCI2 / Mg (OMe)2 in a mixture of water and or suitable organic solvent was added. The reaction mixture was stirred continuously and after suitable workup was filtered, washed and dried, to get Omeprazole Magnesium. The Omeprazole Mg obtained contains from around 7-12% residual organic solvent. The suitable organic solvent may be selected from suitable alcohols, polyethylene glycol, polyvinylpyrrolidone, liquid starch, polyvinyl alcohols and the like or their suitable mixture. Suitable alcohols may be selected from suitable linear or branched (C1-C12)alcohols such as methanol, ethanol, propanol, butanol, pentanol, decanol and the like; Suitable polyethylene glycols may be selected from Peg-100 to Peg-10,000. Preferably the polyethylene glycols may be selected from Peg-100 to Peg-2000.

The invention is further exemplified by the following non-limiting examples which ilustrate the modes of carrying out the invention.
Example 1 Preparation of Magnesium Omeprazole
In a 1 lit round flask equipped with efficient stirrer is charged Magnesium metal (195 mg) and a 100 ml of methanol. The mixture is stirred-refluxed for 80 minutes. The reaction mixture was cooled to room temperature (20-25°C) and Omeprazole powder 5 gms and methanol (60ml) and ammonia solution (1 ml) is added to the solution. The reaction mixture is stirred for 3 hrs at 20-25°C & filtered through hyflow bed, washed with 20 ml of methanol. Solvent distilled off at 35-37 °C to get oily solid, to it was added water (50 ml) and stirred, solid filtered and washed with water and dried at 50-55° C in vacuum oven, till constant weight, to give pure Omeprazole magnesium salt (4.1 g,). The crystallinity of compound is 9.77 % as characterized by PXRD
Example 2 Preparation of magnesium Omeprazole
In 5 lit round flask equipped with efficient stirrer is charged NaOH pellets (0.58 g) in 50 ml methanol (dry). The mixture is stirred to get a clear solution. The reaction mixture is cooled to room temperature and Omeprazole powder (5 g) is added in one lot followed by 25 ml methanol. The reaction mixture was stirred at 20-25° C for 30 minutes, to it was added solution of MgCl2 (anhydrous) 0.68 gms in methanol (10 ml) and washed with 15 ml methanol, stirred at 20-25° C for 1 hour, solvent distilled off at 35-37 °C under reduced pressure to obtained sticky solid. To the sticky mass was added 50 ml of water and stirred, solid filtered and washed with water and finally with PEG200 + water mixture, suck dried and subsequently dried at 50-55° C in vacuum oven, till constant weight, to give pure Omeprazole magnesium salt (4.2 g,). The crystallinity of the compound is 45 % as characterized by PXRD
Example 3 Preparation of magnesium Omeprazole
In 250 ml round flask equipped with efficient stirrer is charged NaOH pallets (0.58 g) in 5 ml water. The mixture is stirred to get a clear solution. The reaction mixture is cooled to room temperature, and to it was added butan-1-ol (25 ml), Omeprazole powder (5 g) was added in one lot followed by 25 ml butan-1-ol. The reaction mixture was stirred at 20-25° C for 30 minutes, & added to it a solution of MgCl26H20 (1.47 gms) in water (10 ml), stirred at 20-25° C for 17-22 hours, the solid obtained was filtered, and washed with water and finally with PEG200 + acetone mixture, suck dried and further dried at 50-55° C in vacuum oven, till constant weight, to give pure Omeprazole magnesium salt (7.7 g,). The crystallinity of the compound is 58 % as characterized by PXRD

Example 4 Preparation of Magnesium Omeprazole
In a 500ml round flask equipped with efficient stirrer is charged Omeprazole powder
{5 g) and a methanol (75 ml). The mixture is stirred for 10-15 min. To it was added
magnesium methoxide (1.24 g) at room temperature and stirred for 1-2 hrs. To the
mixture was added methanol (25 ml). & NaOH pellets (580mg) and stirred for half an
hour at 20-25° C to get clear solution. The organic solvent was then distilled at 40-45°
C to get a foam. Then added water (50ml) and stirred for half an hour, filtered and
washed with water. Finally washed with mixture of PEG200 (4ml) + 10ml water, suck
dried to obtain Omeprazole Mg (2.6g). The salt obtained is characterized by PXRD
peaks: % crystallinity (59.34%).
Example 5 Preparation of magnesium Omeprazole
In 500ml it round flask equipped with efficient stirrer is charged NaOH pallets (1.15 g) and ethanol (37ml), stirred well with N2 gas passing to get clear solution. Then added Omeprazole powder (5 g) through powder funnel. Funnel was washed with ethanol. Then stirred for half an hour at 20-25 ° C. Then added solution of. MgCl2 6H20 (1.32 gm) in ethanol (17.5ml) through addition funnel portion wise. Addition funnel washed with (7.5ml) ethanol. Then reaction mixture is stirred for 48 hrs at 20-25 °C. Solid filtered and washed with ethanol, dried at 50-55 °C, till constant weight, to give pure Omeprazole magnesium salt (1.1 g, ) The salt obtained is characterized by PXRD peaks. % crystallinity ( 51.56%).
Dated this the 18th day of October 2008