Further, processes for preparing the zinc salt, pharmaceutical compositions comprising the salt and a method of treatment or prevention of gastrointestinal ulcers comprising administration of the salt are provided.

Background of the Invention Omeprazole is a gastric acid secretion inhibitor, useful as an anti-ulcer agent.

United States Patent No. 5,714, 504 describes alkaline salts of (S) -omeprazole, such as sodium, magnesium, lithium, potassium, calcium or tetraalkylammonium salts. However, only the preparation of sodium and magnesium salts of (S) -omeprazole has been<BR> exemplified, besides (S) -omeprazole freebase in this patent. The potassium salt of (S)- omeprazole has been prepared in WO 98/54171 and WO 00/44744. Commercially magnesium salt of (S) -omeprazole is used for treating and preventing peptic ulcers, gastroesophageal reflux disease (GERD or heartburn), erosive esophagitis, other conditions involving excessive stomach acid production, and for treating bacterial infections caused by helicobacter pylori.

Summary of the Invention Herein is provided the zinc salt of (S) -omeprazole, that is, (S) -omeprazole zinc.

Another aspect relates to esomeprazole zinc in an amorphous form.

In yet another aspect, a process for preparing (S) -omeprazole zinc is provided,<BR> which comprises contacting (S) -omeprazole freebase or its sodium/potassium salt with<BR> zinc salt of an acid in a suitable solvent to form (S) -omeprazole zinc, wherein the process is carried out in the presence of a base whenever (S)-omeprazole freebase is used.

Further aspects include methods for treating or preventing gastrointestinal ulcers which comprise administering (S) -omeprazole zinc, or a pharmaceutical composition that<BR> comprises (S) -omeprazole zinc, along with pharmaceutically acceptable excipients.

The term" (S)-omeprazole zinc, "as used herein, means any salt comprised of (S)- omeprazole anions and zinc cations. For instance, solid as well as dissolved forms are <BR> <BR> included, and so are crystalline and amorphous forms. (S) -omeprazole zinc may exist in an anhydrous and/or solvent-free form or as a hydrate and/or a solvate.

The expression"S-omeprazole,"as used herein, refers to an omeprazole-containing material which is substantially free of the R-enantiomer of omeprazole, for example, it has an enantiomeric excess of 80%, or for example an enantiomeric excess of 90%. In some particular embodiments, S-omeprazole is in enantiomeric excess of at least about 95%, or at least about 98%, or at least about 99.5%, or at least about 99.8%.

!<BR> Further, the term" (S)-omeprazole zinc, "as used herein, encompasses<BR> stoichiometric as well as non-stoichiometric ratios of (S) -omeprazole anion and zinc<BR> cation. The ratio of (S) -omeprazole to zinc is not required to be 1: 1 in order to be termed<BR> (S) -omeprazole zinc. In a particular embodiment (S) -omeprazole zinc is formed as a salt<BR> having a 2: 1 molar ratio between (S) -omeprazole anion and zinc cation even when an<BR> excess of (S) -omeprazole or an excess of zinc salt of an acid is used in the salt formation.

Brief Description of the Figures Figure 1 is an X-Ray diffractogram of (S) -omeprazole zinc.

Figure 2 is an infrared spectrum of (S)-omeprazole zinc.

Figure 3 is a differential scanning calorimetry spectrum of (S) -omeprazole zinc.<BR> <P>Figure 4 is an X-Ray diffractogram of (S) -omeprazole zinc.

Figure 5 is an infrared spectrum of (S)-omeprazole zinc.

Figure 6 is a differential scanning calorimetry spectrum of (S) -omeprazole zinc.<BR> <P>Figure 7 is an X-Ray diffractogram of (S) -omeprazole zinc.

Figure 8 is an infrared spectrum of (S)-omeprazole zinc.

Figure 9 is a differential scanning calorimetry spectrum of (S) -omeprazole zinc.<BR> <P>(S) -omeprazole zinc obtained in amorphous form is non-hygroscopic. Amorphous

form may be advantageous in comparison with the crystalline form as it can be obtained in a finely powdered form with better solubility properties.

Examples of bases which may be used in the process for preparing (S)-omeprazole zinc using (S) -omeprazole freebase include alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkali metal bicarbonates such as sodium bicarbonate, and ammonium hydroxide.

The zinc salt of an acid to be used in the process can be the salt of any inorganic or organic acid. Examples of such salts include zinc chloride, zinc nitrate, zinc sulphate, zinc phosphate, zinc carbonate, zinc oxalate, zinc acetate, zinc lactate, zinc succinate, zinc citrate, and zinc tartrate.

Examples of suitable solvents for carrying out the process include water, ketones such as acetone and methyl isobutyl ketone, esters such as ethyl acetate and isopropyl acetate, chlorinated hydrocarbons such as methylene chloride and ethylene dichloride, cyclic ethers such as dioxan and tetrahydrofuran, alcohols such as methanol, ethanol and isopropanol, nitriles such as acetonitrile, dipolar aprotic solvents such as dimethylsulfoxide and dimethylformamide, and mixtures thereof.

In water the reactants are more soluble than the (S) -omeprazole zinc product. In this way, the salt-fonning reaction is accompanied by spontaneous precipitation of the produced zinc salt out of the solution.

Alternatively, the precipitation may be facilitated by reducing the volume of the solution and/or by adding an antisolvent, that is, a solvent in which the (S)-omeprazole zinc is insoluble or sparingly soluble. The precipitation can also be induced by reducing the temperature of the solvent, especially if the initial temperature at contact is elevated.

Examples of anti solvents that may be added to precipitate out (S) -omeprazole zinc include lower alkyl ethers such as diethyl ether, and diisopropyl ether; hydrocarbons such as hexane and heptane and mixture (s) thereof.

The (S) -omeprazole freebase or its sodium/potassium salt to be used in the preparation processes can be obtained by methods known in the art including those

described in United States Patent Nos. 5,714, 504,5, 948, 789, and US 6,162, 816, and International Patent Applications WO 00/44744, WO 98/54171, W092/08716. The <BR> <BR> starting (S) -omeprazole freebase or its sodium/potassium salts may be obtained as a<BR> solution directly from a reaction in which (S) -omeprazole is formed, and used as such.

The precipitated zinc salt may be isolated in a solid state by conventional methods such as filtration or centrifugation, optionally followed by washing and/or drying.

(S) -omeprazole zinc is a useful proton pump inhibitor and an antibacterial, and thus can be used to treat any condition that would be benefited by administration of a gastric acid secretion inhibitor. In particular, (S) -omeprazole zinc can be used for the treatment or prophylaxis of gastric acid-related diseases and gastrointestinal inflammatory diseases in mammals and man, such as erosive or ulcerative gastroesophageal reflux disease (GERD), gastric ulcer, duodenal ulcer, reflux esophagitis, and gastritis.

Furthermore, it may be used for treatment of other gastrointestinal disorders where gastric antisecretory effect is desirable, for example in patients on NSAID therapy, in patients with gastrinomas, and in patients with acute upper gastrointestinal bleeding. It may also be used in patients in intensive care situations, and pre-and postoperatively to prevent acid aspiration and stress ulceration. Further, (S) -omeprazole zinc may be useful in the treatment of helicobacter infections and diseases related to these.

The salt can be administered as a component of a pharmaceutical composition.

Accordingly, in a further aspect, there is provided a pharmaceutical composition that comprises (S)-omeprazole zinc and pharmaceutically acceptable carriers, diluents or excipients and optionally other therapeutic ingredients. The salt may be conveniently formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms. Any suitable route of administration may be employed for example, peroral or parental.

In the following section preferred embodiments are described by way of examples to illustrate the process of the invention. However, these are not intended in any way to limit the scope of the present invention. Several variants of these examples would be evident to persons ordinarily skilled in the art.

Examples General Experimental Details-Powder XRD X-Ray Diffraction (XRD) patterns were taken with an diffractometer manufactured by Rigaku Corporation, specifically the model RU-H3R. The goniorneter was a CN2155A3, and the X-Ray tube was equipped with Cu target anode. The settings for the divergence slits were 1 0, for the receiving slit 0. 15mm, and for the scatter slit 1 0. The operating power was 40 KV, 100 mA, the scanning speed was 2 deg/min step: 0.02 deg, and the wavelength was 1.5406 A.

General Experimental Details-FT Infrared Infrared spectra were taken with a Perkin Elmer, 16 PC, with scan parameters of 16 scans, 4.0 cm~l, according to the USP 25, general test methods page 1920. Infrared absorption spectra were obtained by the potassium bromide pellet method.

General Experimental Details-Differential Scanning Calorimetry Differential Scanning Calorimetry was done by the model DSC821 e, manufactured by Mettler Toledo, with sample weights of 3-5 mg, and the sample temperature range of 25-100° C, heating rate of 1° C/min, nitrogen flow of 80.0 mL/min, with one hole in the crucible.

Example 1: A first preparation of (S !-omeprazole zinc (-)-5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridinyl) -methyl] sulfinyl]-lH- benzimidazole, zinc salt was prepared as follows.

The potassium salt of (S)-omeprazole (5. 0g) was stirred in acetone (50ml) at 25 to 30°C and anhydrous zinc chloride (1. 8 g) was added. The reaction mixture was stirred for 1 to 2 hours. The solid that separated out was filtered through filter aid under vacuum and the wet cake was washed with acetone (20ml). The filtrate was concentrated under reduced pressure at 40-45°C to a semisolid material. Methanol (50 ml) was added, the suspension stirred further for 1-2 hours at 20-25°C. The solid obtained was filtered, washed with methanol and air dried at 40 to 45°C for 7 to 8 hours to get (S)-omeprazole zinc (5.2g).

HPLC Purity = 98.56 %, Chiral Purity by HPLC= 99.89 %. MC% w/w by KF = 3.35 %, Zn content (w/w): 10.99% ; Powder XRD, IR in KBr and DSC spectra are as shown in Figure 1,2 and 3 respectively, as shown in the accompanying drawings.

Example 2: (-)-5-methoxy-2- [ [ (4-metlioxy-3, 5-dimethyl-2-pyridinyl) -methyl] sulfinyl]-1H- benzimidazole, zinc salt was also prepared as follows.

The potassium salt of (S)-omeprazole (5g,) was dissolved in water (60ml) at at 25- 30° C to get a clear solution. Anhydrous zinc chloride (1.8g) dissolved in water (5ml) was slowly added to the above solution in 10 minutes at 25-30°C. The reaction mixture was further stirred for 1 to 2 hours, the obtained solid was filtered and washed with water. The product was air dried at 40 to 45°C for 8 to 10 hours to get (S) -omeprazole zinc (4.9g).

MC% w/w by KF = 3.31 %, Zn content (w/w): 9.42% ; XRD, IR spectra, and DSC spectra are as shown in Figure 4,5 and 6 respectively, as shown in the accompanying drawings.

Example 3: (-)-5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridinyl) -methyl] sulfinyl]-lH- benzimidazole, zinc salt was also prepared as follows.

The potassium salt of (S)-omeprazole (5g,) was dissolved in water (60ml) at at 25- 30° C to get a clear solution. Zinc sulphate heptahydrate (3.8 g) dissolved in water (10ml) was slowly added to the above solution in 10 minutes at 25-30°C. The reaction mixture was further stirred for 1 to 2 hours, the obtained solid was filtered and washed with water.

The product was air dried at 40 to 45°C for 8 to 10 hours to get (S) -omeprazole zinc (4.2g).

HPLC Purity = 98. 97 %, Chiral Purity by HPLC= 99.92%. MC% w/w by KF = 0.10 %. XRD and IR spectra are similar to those shown for Example 1 in Figure 1 and 2 respectively.

Example 4: (-)-5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl)-methyl] sulfinyl]-1H- benzimidazole, zinc salt was also prepared as follows.

The potassium salt of (S)-omeprazole (100. 0g) was stirred in acetone (1500ml) at 25 to 30°C and zinc sulphate pentahydrate (75.0 g) was added. The reaction mixture was stirred for 5-6 hours. The solid that separated out was filtered through filter aid under vacuum and the wet cake was washed with acetone (200ml). The filtrate was concentrated under reduced pressure at 40-45°C to a semisolid material. Methanol (400 ml) was added, the solution so obtained was stirred with activated carbon (5.0 g) for another 30 minutes at 20-25°C. The carbon was filtered off and the filtrate concentrated under vacuum to a semisolid material. Water (500ml) was then added and the mixture was stirred at 25 to 30°C for 2 to 3 hours. Solid thus obtained was filtered, washed with water and air dried at 40 to 45°C for 7 to 8 hours to get (S)-omeprazole zinc (59.0).

HPLC Purity = 99.69 %, Chiral Purity by HPLC= 99.96 %. MC% w/w by KF = J 3.44 %, Zn content (w/w): 6.04% ; Powder XRD, IR in KBr and DSC spectra are as shown in Figure 7,8 and 9 respectively, as shown in the accompanying drawings.