MXPA01007516A - Potassium salt of (s - Google Patents

Abstract

The present invention relates to a novel form of 5- methoxy- 2- [[(4- methoxy- 3,5- dimethyl- 2- pyridinyl) methyl]sulfinyl]-1H- benzimidazole, known under the generic name omeprazole. More specifically, it relates to a novel crystalline form of the potassium salt of the (S)- enantiomer of 5- methoxy- 2- [[(4- methoxy- 3,5- dimethyl- 2- pyridinyl) methyl]sulfinyl]-1H- benzimidazole. The present invention also relates to processes for preparing such a form of the potassium salt of (S)- omeprazole and pharmaceutical compositions containing it.

Description

POTASSIUM SALT OF (S) -OMEPRAZOL FIELD OF THE INVENTION The present invention relates to a new form of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) -methyl] sulfinyl] -lH-benzimidazole, known under the generic name omeprazole. More particularly, it refers to a new crystalline form of the potassium salt of the (S) -enantiomer of 5-metsxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl ] -lH-benzimidazole. The present invention also relates to a process for the preparation of a potassium salt form of (S) -omeprazole and pharmaceutical compositions containing it.

BACKGROUND OF THE INVENTION AND PREVIOUS TECHNIQUE The compound 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -lH-benzimidazole, which has the generic name omeprazole, and the pharmaceutically acceptable salts thereof are described in EP 5129. The specific alkaline salts of omeprazole are described in EP 124 495. Omeprazole is a proton pump inhibitor, ie, effective in the inhibition of gastric acid secretion , and it is used as an antiulcer agent. In a more general sense REF: 131519, omeprazole can be used to prevent and treat diseases related to gastric acid in mammals and especially in man. Omeprazole is a sulfoxide and a chiral compound, where the sulfur atom is the stereogenic center. Thus, omeprazole is a racemic mixture of its two simple enantiomers, the (R) - and (S) -enantiomer of omeprazole, referred to herein as (R) -omeprazole and (S) -omeprazole. The absolute configurations of the omeprazole enantiomers have been determined by an X-ray study of a derivative N-alkylated from the (+) - enantiomer in the non-salt form. The (+) - enantiomer of the form other than salt and the (-) -enantiomer of the non-salt form is found to have the R and S configuration respectively. The conditions for measuring the optical rotation for each of these enantiomers are described in WO 94/27988. Certain salts of the simple enantiomers of omeprazole and their preparation are described in WO 94/27988. These compounds have improved the pharmacokinetic and metabolic properties that will provide an improved therapeutic profile such as a lower degree of interindividual variation.

WO 96/02535 describes a process for the preparation of the simple enantiomers of omeprazole and structurally related compounds as well as salts thereof. WO 96/01623 describes pharmaceutical dosage forms comprising, for example, magnesium salts of (R) - and (5) -omeprazole. WO 98/54171 describes a process for the preparation of the magnesium salt trihydrate of (S) -omeprazole, wherein the potassium salt of (S) -omeprazole is used as an intermediate. The potassium salt of (S) -omeprazole, according to the prior art, is crystallized as a methanol solvate. Certain salts of (5) -omeprazole, such as the potassium salt, are in general in compounds suitable for i.v. due to its intrinsic properties, such as high stability and high water solubility. Methanol solvates are however not suitable for i.v. administration, since the concomitant administration of methanol could be fatal to the recipient. Therefore, there is a need for a potassium salt of (S) -omeprazole that is free of methanol. The new form of the potassium salt of (S) -omeprazole according to the present invention is, therefore, referred to as the potassium salt of (S) -omeprazole form B. The form of the prior art of the Potassium salt of (S) -omeprazole described in WO 98/54171, is subsequently referred to as the potassium salt of (S) -o or eprazole of form A.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an X-ray powder diffractogram of the potassium salt of (S) -omeprazole prepared according to the present invention, ie in the form B. Figure 2 is a diffractogram of X-ray powder of the potassium salt of (S) -omeprazole prepared according to example 2 in WO 98/54171, that is, in form A.

DESCRIPTION OF THE INVENTION Surprisingly it has been found that the potassium salt of (S) -omeprazole is present in a number of structurally different forms. It is an object of the present invention to provide a substantially pure potassium salt of (S) -omeprazole of Form B. The potassium salt of (5) -omeprazole of Form B is advantageous because it is in the hydrate form, although the previously known form A is methanol solvate. The potassium salt of (S) -omeprazole form B is especially suitable for intravenous administration. The potassium salt of (S) -omeprazole of form B is further characterized as being crystalline, and preferably being highly crystalline. The potassium salt of (S) -omeprazole of form B, obtained according to the present invention, is substantially free of other forms of potassium salts of (S) -omeprazole, such as the corresponding form A described in the prior art . The potassium salt of (S) -omeprazole of form B obtained according to the present invention is also substantially free of potassium salts of. { R) -omeprazole. The potassium salt of (S) -omeprazole form B is characterized by the positions and intensities of the major peaks in the X-ray powder diffractogram, but it can also be characterized by conventional FT-IR spectroscopy. These characteristics are not exhibited by any other forms of potassium salt of (S) -omeprazole and therefore, the potassium salt of (S) -omeprazole of form B is easily distinguishable from any other forms of crystals of potassium salts of (S) -omeprazole described in the prior art. By the expression "any form" is meant anhydrates, hydrates, solvates, amorphous forms, and polymorphs. Such examples of any forms of potassium salt of (S) -omeprazole include, but are not limited to, anhydrates, monohydrates, dihydrates, sesquihydrates, trihydrates, alcoholates, such as methanolates and ethanolates, amorphous and polymorphic forms. The potassium salt of (S) -omeprazole form B can also be characterized by its unit cell. In a further aspect, the present invention provides a process for the preparation of the potassium salt of (5) -omeprazole of form B which comprises the step of converting (5) -omeprazole to the corresponding potassium salt in toluene or dichloromethane by treatment with a potassium source, such as potassium hydroxide or potassium methylate, followed by isolation of the salt formed. The crude (S) -omeprazole used in the process can be prepared, for example, by oxidation of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) ethyl] thio] -1H -benzimidazole in (S) -omeprazole, with an oxidation agent and a chiral titanium complex, optionally in the presence of a base in an organic solvent, such as toluene or dichloromethane, as described in the prior art, see WO 98 / 54171. The potassium salt of (S) -omeprazole of form B, prepared according to the present invention, characterized and differentiated from the previously known form A, is analyzed, X-ray pulvidifraction, a technique which is known per se. Another technique suitable to analyze, characterize and differentiate the potassium salt of (S) -omeprazole of form B from the corresponding form A, is by conventional "FT-IR." The amount of water in the potassium salt of (S) ) -omeprazole of form B is determined by thermogravimetric analysis (TGA), a technique which is known per se.The potassium salt of (S) -omeprazole form B is effective as a secretion inhibitor of gastric acid, and is useful as an antiulcer agent In a more general sense, it can be used for the treatment of conditions related to gastric acid in mammals and especially in man, including, for example, reflux esophagitis, gastritis, Duodenitis, gastric ulcer and duodenal ulcer can also be used for the treatment of other gastrointestinal disorders where the inhibitory effect of gastric acid is desirable, for example, in patients on therapy with non-steroidal anti-inflammatory drugs (NSAIDs), in patients with No Ulcer Dyspepsia, in patients with symptomatic gastroesophageal reflux disease, and in patients with gastrinomas. Potassium salt of (S) -omeprazole form B can also be used in patients in intensive care situations, in patients with acute upper gastrointestinal bleeding, pre- and post-operatively to prevent aspiration of gastric acid and treat ulceration by tension. In addition, the potassium salt of (S) -omeprazole form B may be useful in the treatment of psoriasis as well as in the treatment of infections with Helicobacter and related diseases. The potassium salt of (S) -omeprazole form B can also be used for the treatment of inflammatory conditions in mammals, including man. Any suitable route of administration can be employed to provide the patient with an effective dose of potassium salt of (S) -omeprazole of form B, according to the present invention. For example, peroral or parenteric formulations and the like can be used. Dosage forms include capsules, tablets, dispersions, suspensions and the like. The potassium salt of (S) -omeprazole form B, because it is highly soluble in water, is especially suitable for parenteral formulations, such as i.v. According to the invention there is further provided a pharmaceutical composition comprising the potassium salt of (S) -omeprazole of Form B, as an active ingredient, in association with a pharmaceutically acceptable carrier, diluent or excipient and optionally other therapeutic ingredients. Compositions comprising other therapeutic ingredients are of particular interest in the treatment of Helicobacter infections. The invention also provides the use of the potassium salt of (S) -omeprazole form B in the production of medicament for use in the treatment of a condition related to gastric acid and a method for the treatment of a condition related to Gastric acid this method comprises administering to a subject suffering from the condition a therapeutically effective amount of the potassium salt of (S) -omeprazole form B. The compositions of the invention include compositions suitable for peroral or perennial administration. The compositions may be conveniently presented in unit dosage forms, and prepared by any methods known in the pharmacy art. In the practice of the invention, the most suitable route of administration as well as the magnitude of a therapeutic dose of the potassium salt of (S) -omeprazole form B in any given case will depend on the nature and severity of the disease. be treated. The dose, and the frequency of the dose, may also vary according to the age, body weight, and response of the individual patient. Special requirements may be needed for patients who have Zollinger-Ellison syndrome, such as a need for higher doses than the average patient. Children and patients with liver diseases as well as patients under prolonged treatment will generally benefit from doses that are somewhat lower than the average. Thus, in some conditions it will be necessary to use doses outside the ranges established later. Both higher and lower doses are within the scope of the present invention. In general, a suitable dosage form can cover a range of doses from 5 mg to 120 mg of total daily dose, administered in a single dose or equally divided doses. A preferred dosage range is from 5 mg to 100 mg, and most preferably from 10 mg to 80 mg. A suitable administration dose is 20 mg to 40 mg for intravenous administration as well as oral administration. The compound of the invention can be combined when the active component in close mixture with a pharmaceutical carrier according to conventional techniques. Especially suitable oral formulations are described in WO 96/01623 and EP 247 983, the descriptions of which are incorporated here as a whole as a reference. Combination therapies comprising the potassium salt of (S) -omeprazole form B and other active ingredients in the separate dosage forms can also be used. Examples of such active ingredients include antibacterial compounds, non-steroidal anti-inflammatory agents, antacid agents, alginates and prokinetic agents. The examples which follow will further illustrate the preparation of the compound of the invention, ie, the potassium salt of (S) -omeprazole form B, but are not proposed to limit the scope of the invention as defined above or as claims later, Examples Potassium salt of (S) -omeprazole form B A solution of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] thio] -lH-benzimidazole (67 mmol) in toluene (4 ml / g of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] thio] -lH-benzimidazole) was charged with water (0.9 mmol) and tartrate of D- (-) -diethyl (14 mmol) at 50 ° C. After stirring for 20 minutes, titanium (IV) isopropoxide (6.5 mmol) was added and the solution was stirred for approximately 50 minutes. The reaction mixture was maintained at the temperature of 35 ° C and N, N-diisopropylethylamine (10 mmol) was added. Eumeno hydroperoxide (74 mmol) was then charged to the solution while maintaining the temperature at about 35 ° C. After 3 hours, the reaction mixture was diluted with toluene (2 ml / g 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] thio] -lH-benzimidazole ) and potassium methoxide (26 mmol) were added as a slurry in toluene (8 ml / g KOMe). The crystals obtained were filtered and dried (36 ° C, vacuum) overnight. Yield of 0.72 g (1.9 mmol, 7% with respect to KOMe). The solvent content obtained with Karl-Fischer titration and GC respectively (% w / w) Water 3.4 Methanol 0.01 TGA Approximately 2% (w / w) of the water content is incorporated into the crystal lattice (ie, ~ 0.5 H20) / Potassium salt molecule of (S) -omeprazole form B) XRD The X-ray powder diffractogram of the product measured from 1-40 ° in 2? with CuKcci radiation shows the following list of peak characteristics: In addition, the diffractogram contains several weak peaks that have been omitted for clarity. The peaks, identified with d values calculated from the Bragg formula and intensities, have been extracted from the diffractogram of the potassium salt of (S) - omeprazole form B. The relative intensities are less reliable and instead of the values numerical the following definitions are used; % Relative Intensity Definition 25-100 mf (very strong) 10-25 s (strong) 3-10 m (medium) 1-3 d (weak) It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (10)

CLAIMS Having described the invention as above, the contents of the following claims are claimed as property:

1. The potassium salt of (S) -omeprazole of form B, characterized in that it is in a hydrate form.

2. The potassium salt of (S) -omeprazole of form B according to claim 1, characterized in that it is crystalline.

3. The potassium salt of (S) -omeprazole form B, characterized in that it provides an X-ray powder diffraction pattern that substantially exhibits the following d values;

4. A process for the preparation of potassium salt of (S) -omeprazole form B as defined in any of claims 1-3, which comprises the step of converting (S) -omeprazole to the corresponding potassium salt in toluene or dichloromethane by treatment with a potassium source, such as potassium hydroxide or potassium methylate, followed by isolation of the formed salt.

5. A process according to claim 4, characterized in that it comprises the additional step of oxidizing 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] thio] -lH- benzimidazole, with an oxidizing agent and a chiral titanium complex, optionally in the presence of a base in an organic solvent, such as toluene or dichloromethane, to obtain (S) -omeprazole.

6. A pharmaceutical formulation characterized by comprising the potassium salt of (S) -omeprazole of form B as defined in any of claims 1-3 in admixture with a pharmaceutically acceptable excipient.

7. A pharmaceutical formulation suitable for i.v. administration, characterized in that it comprises the potassium salt of (S) -omeprazole of form B as defined in any of claims 1-3 in admixture with a pharmaceutically acceptable excipient.

8. The use of potassium salt of (S) -omeprazole of form B according to any of claims 1-3, as an active ingredient in the production of medicament for use in the treatment of gastrointestinal disorders.

9. The use of the potassium salt of (S) -omeprazole form B according to any of claims 1-3, in the manufacture of a pharmaceutical formulation for i.v.

10. A method of treating gastrointestinal disorders characterized in that it comprises the administration of a therapeutically effective amount of potassium salt of (S) -omeprazole of form B according to any of claims 1-3, to a patient suffering from gastrointestinal disorders.