CZ426099A3 - Novel form of S-omeprazole - Google Patents

Abstract

In the present invention, there is described novel form of magnesium salt of S-enantiomer omeprazole trihydrate. Described are also processes for preparing this salt form as well as pharmaceutical compositions in which the salt is comprised. The invented salt can be used in the preparation of a medicament intended for the treatment of gastric acid related condition.

Description

A new form of S-omeprazole

Qblaefr. techniques

The present invention relates to a novel form of the (-) - enantiomers of 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, i.e. S-omeprazole. More particularly, it relates to a novel form of the magnesium salt of the S-enantiomer of omeprazole trihydrate. The present invention also relates to a process for the preparation of this form of the magnesium salt of S-omeprazole and to pharmaceutical compositions containing it. Furthermore, the present invention also relates to intermediates used in their preparation.

Bfflaasadní ... afc.av, techniques

The compound 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) sulfinyl] -1H-benzimidazole having the generic name omeprazole and its pharmaceutically acceptable salts is disclosed in EP 5129. Specific alkali salts of omeprazole Omeprazole is a proton pump inhibitor, i.e., it inhibits gastric acid secretion and is useful as an anti-ulcer agent, and more generally, omeprazole can be used to prevent and treat diseases of the mammal, and in particular human, associated with gastric acid related diseases.

Omeprazole is a sulfoxide and is a chiral compound in which the sulfur atom represents a stereogenic center. Thus, omeprazole is a racemic mixture of two individual enantiomers, the R- and S-enantiomer of omeprazole, referred to herein as R-omeprazole and S-omeprazole. The absolute configurations of the enantiomers of omeprazole are determined by X-ray studies of the N-alkylated derivative of the free form of the (+) - enantiomer. Free forms (+) - enan • ·

the thiomer and the free forms of the (-) - enantiomer have the B and S configurations respectively and the (+) - enantiomer of the magnesium salt and the (-) - enantiomer of the magnesium salt also have the B and S configurations, respectively.

S. Conditions for measuring the optical rotation of these enantiomers are described in WO 94/27988.

Certain salts of the individual enantiomers of omeprazole and their preparation are disclosed in WO 94/27988. These compounds have improved pharmacokinetic and metabolic properties that provide an improved therapeutic profile, such as a lower degree of inter-individual variation.

WO 96/02535 discloses a process for preparing the single enantiomers of omeprazole and salts thereof and WO 96/01623 describes suitable tableted dosage forms of, for example, magnesium salts of E and S-omeprazole.

BRIEF DESCRIPTION OF THE DRAWINGS

Giant. 1 shows an X-ray powder diffractogram of the magnesium salt of S-omeprazole trihydrate prepared according to the invention.

Giant. 2 shows an X-ray powder diffractogram of the potassium salt of S-omeprazole prepared and used in this application (see Examples 2 and 3).

Giant. 3 shows an X-ray powder diffractogram of the magnesium salt of S-omeprazole dihydrate prepared and used in this application (see Example 5).

Giant. 4 shows an X-ray powder diffractogram of the magnesium salt of S-omeprazole dihydrate, which is the polymorphic form of the dihydrate shown in FIG. 3 (see Example 6). This magnesium salt of S-omeprazole dihydrate is prepared and can be used in the preparation of the magnesium salt of S-omeprazole trihydrate according to the invention.

Giant. 5 shows an X-ray powder diffractogram of the magnesium salt of Example A in WO 96/01623.

Effects of the invention

Surprisingly, it has been found that the magnesium salt of S-omeprazole exists in a number of structurally different forms. It is an object of the present invention to provide a substantially pure magnesium salt of S-omeprazole trihydrate, hereinafter referred to as a compound of the present invention. This trihydrate can be obtained as a well-defined compound. The present invention also provides a method of obtaining and a method of distinguishing S-omeprazole magnesium trihydrate from other forms of S-omeprazole magnesium salts.

The compound of the present invention is preferred because it is more stable than the previously known corresponding magnesium salts and is therefore more convenient to handle and store. The compound of the invention can also be more easily defined as it exists in a well-defined state. In addition, the compound of the invention is readily prepared in a reproducible manner, and therefore large scale preparation is easier.

The magnesium salt of S-omeprazole trihydrate prepared according to the present invention is substantially free of magnesium salts of S-omeprazole. The magnesium salt of S-omeprazole trihydrate obtained according to the invention is practically free of other forms

4 magnesium salts of S-omeprazole, such as the corresponding magnesium salts described above and the dihydrates used in the preparation of the trihydrate compound of the invention.

The compound of the invention is characterized by the positions and intensities of large peaks in the X-ray powder diffractogram, but may also be characterized by conventional FT-IH spectroscopy. No other form of magnesium salt of S-omeprazole exhibits these properties, and the magnesium salt of S-omeprazole trihydrate thus differs from any other crystalline form of the described magnesium salt of S-omeprazole. The compound of the invention is highly crystalline, i.e., has a higher crystallinity than any other form of the magnesium salt of S-omeprazole described above. By any other form is meant anhydrous forms, hydrates, solvates and polymorphic or amorphous forms described herein. Examples of any other forms of magnesium salt of S-omeprazole include, but are not limited to, anhydrous forms, monohydrates, dihydrates, sesquihydrates, trihydrates, alcoholates such as methoxides and ethanates, and polymorphic or amorphous forms thereof.

A compound of the invention may also be characterized by its elemental cell.

In another aspect, the invention provides methods for preparing the magnesium salt of S-omeprazole trihydrate, comprising:

a) treating the magnesium salt of S-omeprazole of any form, for example a form prepared according to a method known in the art, such as Example A in WO 96/01623, which is incorporated herein by reference, with water at a suitable temperature after

at the appropriate time. By suitable temperature is meant the temperature which induces the transformation of the starting material into the product without decomposing these compounds. Examples of such suitable temperatures include, but are not limited to, room temperature and higher temperatures. By suitable time is meant the time that leads to a high conversion of the starting material to the product without decomposing any compounds, i.e., obtaining a good yield. This suitable time will vary depending on the temperature used in a manner well known to one of ordinary skill in the art. The higher the temperature, the shorter the time required to obtain the desired conversion. The amount of water is not critical and will depend on the conditions used. The magnesium salt of S-omeprazole trihydrate is then separated from the aqueous suspension, for example by filtration or centrifugation, and then dried to constant suspension weight or b / oxidation of 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2- pyridyl) methyl] thio] -1H-benzimidazole, with an oxidizing agent and a chiral titanium complex, optionally in the presence of a base. This oxidation is carried out in an organic solvent, for example toluene or dichloromethane.

The crude product is brought to the corresponding potassium salt by treatment with a potassium compound, such as methanolic potassium hydroxide solution or methanolic potassium methylate solution, followed by separation of the formed salt.

The resulting potassium salt of S-omeprazole is then converted to the corresponding magnesium salt by treatment with a magnesium compound such as magnesium sulfate dissolved in a lower alcohol such as methanol. Optionally, the solution is filtered and precipitation is induced by the addition of a non-aqueous solvent such as acetone. The product is filtered off and optionally washed with water and further processed according to A

A A

And description a) above. Alternatively, the potassium salt may be treated with a magnesium compound, such as magnesium sulfate in water, to separate the magnesium salt of S-omeprazole trihydrate, or any other conventional method for converting the potassium salt to the corresponding magnesium salt and this process is within the scope of this invention.

Another aspect of the invention is to provide a suitable intermediate used in the preparation of a compound of the invention as well as a process for its preparation. A suitable intermediate is the S-omeprazole potassium salt. The potassium salt of S-omeprazole can also be used as an active ingredient of a pharmaceutical composition for use in the treatment of gastrointestinal disorders.

The compound of the present invention, i.e. the magnesium salt of S-omeprazole trihydrate prepared according to the present invention, can be analyzed by X-ray powder diffraction, a method known per se.

The amount of water in the magnesium salt of S-omeprazole trihydrate is determined thermographically, a method known per se.

The compound of the invention is effective as an inhibitor of gastric acid secretion and can be used as an anti-ulcer agent. More generally, it can be used to prevent and treat gastric acid-related conditions in mammals, and in particular humans, including, for example, reflux esophagitis, gastritis, duodenitis, gastric ulcer, and duodenal ulcer. Furthermore, it can be used to treat other gastrointestinal disorders where gastric acid inhibitory effect is desirable, for example in patients treated with NSAIDs,

in patients with non-ulcer dyspepsia, in patients with symptomatic gastro-esophageal reflux disease and in patients with gastrinomas. The compound of the invention can also be used in intensive care patients, patients with acute upper gastrointestinal bleeding, before and after surgery to prevent gastric acid aspiration and to prevent and treat stress ulceration. Further, the compound of the invention may be used in the treatment of psoriasis and in the treatment of Helicobacter infection and diseases associated therewith. The compound of the invention can also be used to treat inflammatory conditions in mammals including humans.

Any suitable route of administration may be used to provide an effective dose of the magnesium salt of S-omeprazole trihydrate to a patient of the invention. For example, oral or parenteral preparations and the like can be used. Dosage forms include capsules, tablets, dispersions, suspensions, and the like.

Further provided is a pharmaceutical composition comprising the magnesium salt of S-omeprazole trihydrate of the invention as an active ingredient in association with a pharmaceutically acceptable carrier, diluent or excipient and optionally other therapeutic ingredients. Compositions containing other therapeutic ingredients are particularly important in the treatment of Helicobacter infections. The invention also provides the use of the magnesium salt of S-omeprazole trihydrate of the invention in the manufacture of a medicament for use in the treatment of gastric acid related conditions and a method of treating gastric acid related conditions comprising administering to an individual suffering from this condition a therapeutically effective amount of magnesium salt. S-omeprazole trihydrate according to the invention.

· E e e e e * * * * * * e e e e e e e e e e e e e e e '«F f f f f f f f f f

Compositions of the invention include compositions suitable for oral or parenteral administration. The most preferred route is oral administration. The compositions may conveniently be presented in unit dosage forms and prepared by any of the methods known in the art of pharmacy.

In the practice of the present invention, the most appropriate mode of administration, as well as the magnitude of the therapeutic dose of the magnesium salt of S-omeprazole trihydrate of the present invention in the present case, depends on the nature and severity of the disease being treated. The dose and frequency of administration may also vary depending on the age, weight and response of the individual patient. Special requirements may arise in patients with Zollinger-Ellison syndrome, such as higher dose requirements than the average patient. For children and patients with liver disease, generally lower than average doses will be preferable. Therefore, in some conditions, it may be necessary to use doses outside the range below, for example, long-term treatment may require dose reduction. These higher and lower doses are within the scope of this invention. These daily doses vary between 5 mg and 300 mg.

In general, a suitable oral dosage form of a compound of the invention may cover a total daily dosage range of 5 to 300 mg when administered in a single dose or in uniformly divided doses. A preferred dosage range is from 10 mg to 80 mg.

The compound of the invention may be combined as an active ingredient in admixture with a pharmaceutical carrier according to conventional methods such as the oral compositions described in WO 96/01623 and EP 247 983, the disclosures of which are incorporated herein by reference.

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Is incorporated herein by reference in its entirety.

Combination formulations containing the magnesium salt of S-omeprazole trihydrate and other active ingredients may also be used. Examples of such active ingredients include, but are not limited to, antibacterial agents, non-steroidal anti-inflammatory agents, antacids, alginates, and prokinetic agents.

The examples below further illustrate the preparation of a compound of the invention according to various methods and including novel intermediates. These examples are not intended to limit the scope of the invention as defined above or in the claims.

Examples of massaging-you-findingM

Example 1

S-5-methoxy-2 - [[4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole magnesium trihydrate.

Water (157 kg) was added to the wet crystals of the magnesium salt of S-omeprazole prepared according to Example 4 below. The mixture was heated to 38 ° C with stirring and allowed to stand for 3 h. The crystals were collected by filtration and dried in vacuo. Yield 31.6 kg.

X-ray powder diffraction analysis is performed on a crystal sample prepared above according to standard methods, which can be found, for example, in A. I. Kitaigorodsky, Molecular Crystals and Molecules, Academic Press, New York, (1973), C.V. Bunn, Chemical Crystallography, Clarendon

• · · · · · · · · · · · · · · · ···

Press, London, (1948) or Η. P. Klug and L. E. Alexander, X-Ray Difference Procedures, John Wiley and Sons, New York, (1974). The analysis provides a diiractogram shown in FIG.

1. The principal peaks with their positions and relative intensities read from the diffractogram in Figure 1 are given below in Table 1. Relative intensities are less reliable and the following definitions based on numerical values are used instead.

* · • • • * * * * * *

Relative intensity in X 25-100 10-25 3-10 1-3 <1

Definition vs (very strong) s (strong) m (medium) w (weak) vw (very weak) of Table 1, some other very weak peaks found on the diffractograms were omitted.

Table 1. Peak positions and intensities in the X-ray powder diffractogram of magnesium salt of S-omeprazole trihydrate.

value d (nm) Relative intensity 0.267 m 0.279 m 0.327 m 0.352 with 0.382 with 0.396 vs 0.414 m 0.52 m 0.56 m 0.67 vs 0.69 with 0.83 w 1.66 vs

• ΦΦΦ · φ

Example 2

S-5-methoxy-2-CC (4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole potassium salt.

A solution of 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridyl) -methyl-3-thio] -1H-benzimidazole (15.4 g, 46.8 mmol) in toluene (70 mL) was heated. to 50 ° C and water (0.05 mL, 2.8 mmol) and D - (-) - diethyltartarate (2.02 g, 9.82 mmol) were added. The reaction mixture was stirred for 20 min. Titanium (IV) isopropoxide (1.34 g, 4.68 mmol) was added and the reaction mixture was stirred for 45 min. The mixture was cooled to 30 ° C and diiaopropylethylamine (0.91 g, 7.01 mmol) was added followed by cumene hydroperoxide (9.52 g, 51.89 mmol). The resulting mixture was stirred at 30 ° C for 3 h. Methanol (40 mL) was added followed by potassium hydroxide (3.05 g, 46.8 mmol) in methanol (30 mL). Seed crystals were added and the reaction mixture was stirred at 35 ° C overnight. The precipitated product is collected by filtration, washed with methanol and toluene and dried under vacuum. Yield: 9.74 g (54%).

Example 3

S-5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] -3-sulfinyl-13H-benzimidazole potassium salt.

Water (157.6 μΐ) is added to a solution of 5-methoxy-2 - (((4-methoxy-3,5-dimethyl-2-pyridyl) methyl) thio-3H-benzimidazole in toluene (370 ml, 211.5 g / 1) with a water content of 0.031% by weight, followed by the addition of D - (-) - diethyl tartrate (8.55 ml), heated to 50 ° C and stirred at this temperature for 20 min. 15 ml) and the reaction mixture is left at 50 ° C for 45 min, the temperature is lowered to 30 ° C and diisopropylethylamine is added.

9 9

9 9 9

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99 (6.2 mL). Add cumene hydroperoxide at an appropriate rate to maintain the temperature between 28 ° C and 34 ° C. The temperature was raised to 35 ° C after 2 h and potassium methoxide (24.55 g) in methanol (222 mL) was added. The mixture was filtered for 14 h and the crystals were washed with methanol: toluene (240 mL, 1: 1) and methanol (120 mL) and dried. Yield: 79 g (74 35), ee> 99.9 35.

[α] D ²⁰ - +28.7 ° (c = 1% water).

Analysis: 89 35 The substance is potassium salt of S-5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (11% is methanol).

1 H-NMR (200 MHz, DMSO-d 6, δ ppm): 2.23 (s, 3H), 2.24 (s, 3H), 3.71 (s, 3H), 3.75 (s, 3H) 4.40 (d, 1H), 4.78 (d, 1H), 6.58 (dd, 1H), 7.00 (d, 1H), 7.35 (d, 1H), 8.25 (with,

1H).

The products of Examples 2 and 3 analyzed by X-ray powder diffractometry as described in Example 1 provide the diffractogram shown in Figure 2 and the results shown in the Table

2. Some very weak peaks in the diffractogram were deleted from Table 2.

Table 2. Peak positions and intensities in the X-ray powder diffractogram of the potassium salt of S-omeprazole.

• · · φ · φ · · · φ · · · · φ · φφφφφφφφφφφφφφφφφφφ

value d Relative value d Relative (nm) intensity (nm) intensity 1.36 vs 0.352 m 1.06 vw 0.342 w 0.78 m 0.338 w 0.68 m 0.334 m 0.65 m 0.328 w 0.62 w 0.320 m 0.61 m 0.312 w 0.58 3 0,306 w 0.54 m 0.303 w 0.53 w 0.297 w 0.52 w 0.293 vw 0.50 vw 0.289 w 0.475 m 0.285 m 0.471 w 0.276 w 0.452 w 0.271 vw 0.442 w 0.256 vw 0.432 w 0.258 w 0.427 m 0.257 w 0.398 vw 0.256 w 0.392 w 0.252 vw 0.389 w 0.247 vw 0.387 w 0.245 vw 0.381 w 0.243 vw 0.374 m 0.240 vw 0.360 m 0.238 vw 0.355 m 0.231 vw

α1 = 0.154060 nm

• · · · · · · ·

Example 4

S-5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole magnesium salt.

Methanol (148 kg) was added to the potassium salt of S-5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (71 kg, methanol content 13). 35). Magnesium sulfate heptahydrate (40 kg) was added with stirring. After 70 min, the mixture was filtered and the filtrate was washed with methanol (46 kg). The solution was evaporated to a volume of 100 L, acetone (253 kg) was added and the resulting mixture was allowed to stand for 4 h. The precipitated product was filtered off, washed with acetone and water. Large crystals were used immediately as described in Example 1.

Example 5

S-5-methoxy-2- [E (4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole dihydrate.

5.0 g of the wet product of Example 4 with an approximate dry matter content of 74 35 were dried under vacuum at 35 ° C overnight to give 3.58 g (2.68 mmol) of S-5-methoxy-2- magnesium salt dihydrate. [(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole called Form B.

The product is analyzed using X-ray powder diffraction as described in Example 1 and the analysis provides the diffractogram shown in Figure 3 with the values given in Table 3 below. Some other low intensity peaks have been omitted from Table 3 values.

- 16 · · · 16 16 16 16 16 16 16 16

Table 3. Peak positions and intensities in the X-ray powder diffractogram of magnesium salt of S-omeprazole dihydrate, Form B.

value d (nm) Relative intensity 0.419 m 0.445 m 0.468 m 0.479 with 0.491 with 0.498 with 0.51 m 0.54 with 0.55 m 0.56 m 0.58 m 0.63 m 0.67 with 0.79 m 0.81 with 1.10 m 1.18 m 1.49 vs

Conversion of S-omeprazole magnesium dihydrate to trihydrate

This material is then processed to S-5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridyl) magnesium salt trihydrate] A A

A ·· • 9 A A · A AAA ·

A A A A

A A A A A A A

N-thylsulfinyl] -1H-benzimidazole according to the method described for the wet substance in Example 1.

Example 6

S-5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole magnesium dihydrate.

A methanol solution of S-5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1 H -benzimidazole salt is prepared as described in Example 4. Magnesium salt solution S-5-methoxy-2- [C (4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (1.86 g) in 5 mL of methanol was evaporated so that 1.58 ml of methanol remained. 1.6 ml of water and 6.32 ml of acetone are then added. The solution is left to crystallize for 26 h at room temperature. The resulting crystals were collected by filtration and dried at 40 ° C under reduced pressure to give S-5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, called Form A.

The product is analyzed by X-ray powder diffraction as described in Example 1 and provides the diffractogram shown in Figure 4 with the values given in Table 4. Some other low intensity peaks found in the diffractogram were omitted in Table 4.

Table 4. Positions and intensities of the major peaks of the X-ray powder diffractogram of the magnesium salt of S-omeprazole dihydrate, Form A.

value d (nm) Relative intensity 0,304 with 0.314 with 0.318 m 0.405 with 0.419 with 0.432 m 0.454 with 0.469 vs 0.52 with 0.53 with 0.58 with 0.62 vs 0.66 with 1.55 vs

Example 7

Magnesium salt of S-5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] -3-sulfinyl 13-1H-benzimidazole.

22.0 g (29.1 mmol) of S-5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] -3-sulfinyl-1H-benzimidazole potassium salt are dissolved in 40 ml of water. The solution was seeded with 0.11 g (0.1 mmol) of S-5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl 13-1H-benzimidazole trihydrate. 22 ml (69.5 mmol) of aqueous magnesium sulfate are added over 3 h. The suspension is filtered and the precipitate is treated with water for about 30 min, the crystals are filtered off and dried in vacuo at 35 ° C. Yield: 9.15 g (11.6 mmol, 80%). The substance has a purity of 99.8% by HPLC, a magnesium content of 3.40% by weight and an ee of 99.8 as.

The results of the X-ray powder diffraction analysis of the products correspond to Fig. 1 and Table 1.

Reference sample

S-5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole magnesium salt.

The method used corresponds to that described in Example A of WO 96/01623.

The magnesium (0.11 g, 4.5 mmol) was dissolved and treated with methanol (50 mL) at 40 ° C with a catalytic amount of methylene chloride. The reaction proceeds under a nitrogen atmosphere and is complete after 5 h. At room temperature, a mixture of both [90 X (-) - isomer and 10 X (+) - isomer of 5-methoxy-2 - [[(4)] is added to the magnesium methoxide solution. -methoxy-3,5-dimethyl-2-pyridyl] methyl] sulfinyl-3H-benzimidazole (2.84 g, 8.2 mmol) The mixture was stirred for 12 h and then a small amount of water (0.1 mL) was added to precipitation of inorganic magnesium salts After stirring for 30 minutes, the inorganic salts are separated by filtration and the solution is rotary evaporated, the residue now being a concentrated methanol solution of the enantiomeric mixture (i.e., the title compound contaminated with the (+) - isomer), with optical purity (enantiomeric). This mixture was diluted with acetone (100 mL) and a white precipitate was obtained after stirring at room temperature for 15 min, further stirring for 15 min followed by filtration yielded 1.3 g (50%). ) the title compounds in the form of white k Chiral analyzes of crystals and mother liquor are performed by analytical chiral column chromatography. The optical purity of the crystals and mother liquor is from 98.4 e.e. and 64.4% e.e.

The optical purity (e.e.) was thus increased from 80% to 98.4 seconds with the simple crystallization of the magnesium salt from a mixture of acetone and methanol. The product is crystalline as shown by powder X-ray diffraction and the magnesium content is 3.44 as shown by atomic absorption spectroscopy.

[α] D ⁼ 131.5 ° (c = 0.5%, methanol).

The product is analyzed by X-ray powder diffraction as described in Example 1 and provides a diiractogram shown in Figure 5 with the values given in Table 5 below. Some other very weak peaks found in the diffractograms have been omitted from Table 5.

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Table 5. Peak positions and intensities in the X-ray powder diffractogram of Figure 5.

value d (nm) Kelativní intensity 0.290 with 0.341 with 0.390 with 0.413 and 0.479 vs 0.500 vs 0.54 vs 0.57 with 0.63 with 0.68 with 0.78 with 0.84 vs 1.08 with 1,22 with 1.51 vs

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Claims (17)

Magnesium salt of S-omeprazole trihydrate. The magnesium salt of S-omeprazole trihydrate according to claim 1, characterized by a high degree of crystallization. The magnesium salt of S-omeprazole trihydrate according to claim 1, characterized in that it is stable. The magnesium salt of S-omeprazole trihydrate according to claim 1, characterized by the following major peaks in its X-ray powder diffractogram: value d (nm) Relative intensity 0.267 m 0.279 m 0.327 m 0.352 with 0.382 with 0.396 vs 0.414 m 0.52 m 0.56 m 0.67 vs 0.69 with 0.83 w 1.66 vs 5. Process for the preparation of the magnesium salt of S-omeprazole trihydrate náhradní φ náhradní náhradní náhradní náhradní náhradní náhradní náhradní náhradní náhradní náhradní The process according to any one of claims 1 to 4, wherein the magnesium salt of S-omeprazole in any other form is treated with water. A process for preparing the magnesium salt of S-omeprazole trihydrate according to any one of claims 1 to 4, characterized in that it comprises the following steps: a) mixing the potassium salt of S-omeprazole with an organic solvent, b) converting the potassium salt of S-omeprazole into the corresponding magnesium salt of S-omeprazole by treating the potassium salt with a magnesium source, c) precipitation of the magnesium salt of S-omeprazole by addition of a non-aqueous solvent, (d) separating the magnesium salt of S-omeprazole obtained; (e) treating the obtained magnesium salt of S-omeprazole with water; and f) separating and drying the magnesium salt of S-omeprazole trihydrate obtained in this way. The process of claim 6, wherein said organic solvent used in step a) is methanol. Process according to any one of claims 6 and 7, characterized in that the non-aqueous solvent used in step c) is acetone. (spare page) - 24 · · · 24 24 24 24 24 24 24 24 24 24 24 24 24 Method according to claim 6, characterized in that steps a) to e) are replaced by one step: i) converting the potassium salt of S-omeprazole into the corresponding magnesium salt of S-omeprazole by treating the potassium salt with a magnesium source in water. A process according to any one of claims 6 to 9, wherein the magnesium source used in step b) of claims 6 to 8 or step i) of claim 9 is magnesium sulfate. A process for preparing the potassium salt of S-omeprazole for use in any one of claims 6 to 10, comprising the steps of: (a) oxidation of 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] thio] -1H-benzimidazole to S-omeprazole in an organic solvent, b) converting S-omeprazole into the corresponding potassium salt of S-omeprazole by treating S-omeprazole with a potassium source, c) separating the thus obtained potassium salt of S-omeprazole. Process according to claim 11, characterized in that said organic solvent used in step a) is toluene. A method according to any one of claims 11 and 12, characterized in that said potassium source used (spare side) 9 (9) 9 9 9 · 9 9 9 9 99 9999 98 99 • 9 9 9 9 9 9 9 9 • 9 99 25 in step b) is a methanolic potassium methoxide solution or a methanolic potassium hydroxide solution. The S-omeprazole potassium salt prepared according to claim 11, characterized by the following peaks in the X-ray powder diffractogram: 44 44 4 4 4 4 4 4 4 4 4 · 4 4 4 44 4444 (replacement page) • 4 44 4 4 · · 4444 4 4 4 444 4 • 4 44 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 value d Relative value d Relative (nm) intensity (nm) intensity 1.36 vs 0.352 m 1.06 vw 0.342 w 0.78 m 0.338 w 0.68 m 0.334 m 0.65 m 0.328 w 0.62 w 0.320 m 0.61 m 0.312 w 0.58 with 0,306 w 0.54 m 0.303 w 0.53 w 0.297 w 0.52 w 0.293 vw 0.50 vw 0.289 w 0.475 m 0.285 m 0.471 w 0.276 w 0.452 w 0.271 vw 0.442 w 0.266 vw 0.432 w 0.258 w 0.427 m 0.257 w 0.398 vw 0.256 w 0.392 w 0.252 vw 0.389 w 0.247 vw 0.387 w 0.245 vw 0.381 w 0.243 vw 0.374 m 0.240 vw 0.360 m 0.238 vw 0.355 m 0.231 vw 0.154060 nm (replacement side) ·! * * * * * * * * *! • · · · · · · · · · · · - 27 A pharmaceutical composition comprising the magnesium salt of S-omeprazole trihydrate according to any one of claims 1 to 4 as an active ingredient in association with a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. Use of the magnesium salt of S-omeprazole trihydrate according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of a condition associated with gastric acid. 17. A method of treating a gastric acid related condition, comprising administering to an individual suffering from the condition a therapeutically effective amount of the magnesium salt of S-omeprazole trihydrate according to any one of claims 1 to 4.