MXPA99011674A - Omeprazole sodium salt - Google Patents

Abstract

This invention relates to a novel form of the sodium salt of 5-methoxy-2-[ [(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl]sulfinyl]-1H-benzimidazole, known under the generic name of omeprazole sodium salt. This invention also relates to processes for its preparation of omeprazole sodium form B which is thermodynamically stable, as well as pharmaceutical compositions containing it and its use in the treatment of gastrointestinal disorders.

Description

SODIUM SALTS FROM OMEPRAZOL Field of the Invention The present invention relates to a novel form of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -IH-benzimidazole, known under the generic name of omeprazole. More specifically, it relates to a new form of the omeprazole sodium salt, especially a salt of the well-defined omeprazole sodium monohydrate, hereinafter referred to as the omeprazole salt form B, and to its use in the treatment of gastrointestinal disorders, to pharmaceutical compositions containing it and to the preparation thereof.

Background of the invention and prior art The compound 5-methoxy-2- [(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -lH-benzimidazole having the generic name of omeprazole, as well as therapeutically acceptable salts thereof , are described in EP 5129. The specific alkaline salts of omeprazole, such as the sodium salt, are described in EP Ref.032311 124 495. The sodium salt of omeprazole produced according to examples 1 and 2 of EP 124 495 It is a mixture of crystalline forms and amorphous material. One of the crystalline forms present in this mixture, referred to hereinafter as form A of the salt of omeprazole, is a hydrate with one or two water molecules, of which one molecule of water is strongly bound in the crystalline structure while the other is easily removed by drying. The resulting dry substance, which contains a strongly bound water molecule, is very hygroscopic and absorbs water rapidly under normal conditions. Omeprazole is a proton pump inhibitor, that is, it is effective in inhibiting the secretion of gastric acid, and is useful as an antiulcer agent. In a more general sense, omeprazole can be used for the treatment of diseases related to gastric acid in mammals and especially in man.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a diffractogram of X-ray powder of form B of omeprazole sodium.

Figure 2 is a diffractogram of X-ray powder of form A of omeprazole sodium. Figure 3 is an X-ray powder diffractogram of omeprazole sodium prepared according to the prior art.

Description of the invention It has surprisingly been found that the sodium salt of omeprazole exists in a number of different crystalline forms. It is an object of the present invention to provide a well-defined, thermodynamically stable form at room temperature, and industrially useful from omeprazole sodium, especially form B of omeprazole sodium. Another object of the present invention is to provide a process for the preparation of form B of omeprazole sodium, substantially free of other forms of the omeprazole sodium salt. X-ray powder diffraction (XRPD) is used as a method of differentiating form B from omeprazole sodium from other forms of the omeprazole sodium salt. It has been found that the sodium salt of omeprazole can crystallize into at least two different forms, of which form B of omeprazole sodium is one. Another form is form A of omeprazole sodium with one to two moles of water. Form A of omeprazole sodium is one of the crystalline forms present in the mixture of crystalline forms and the amorphous material obtained in example 1 and example 2 in EP 124 495. However, there is no form B of omeprazole sodium present in the mixture of the forms obtained when preparing the salt of -omeprazole sodium as described in either example 1 or example 2 in EP 124 495. Form B of omeprazole sodium is a crystalline form exhibiting advantageous properties, such as be stable, be well defined, and be a true monohydrated crystalline form. Form B of omeprazole sodium is thermodynamically more stable than form A of omeprazole sodium. Form B of omeprazole sodium is essentially non-hygroscopic and therefore in industrial processes, such as pharmaceutical manufacturing processes, can be loaded in a fixed amount in contrast to form A of omeprazole sodium which must be loaded in amounts calculated from a recent omeprazole test or indirectly from a recent test of its content of water. Other advantages include easier preparation and higher reproducibility between batches. This is especially important in the scale of production and leads to a higher production capacity.

Form A of omeprazole sodium, which is thermodynamically unstable, under certain circumstances can be converted completely or partially to form B of omeprazole sodium. Form B of omeprazole sodium is presently characterized because it is thermodynamically more stable than form A of omeprazole sodium and any other form of omeprazole sodium prepared according to the prior art. Form B of omeprazole sodium is further characterized because it is essentially non-hygroscopic. By the term "any other form" are meant the anhydrates, hydrates, solvates and amorphous materials described in the prior art. Examples of any other forms of the sodium salts of omeprazole include, but are not limited to, anhydrates, monohydrates, dihydrates, sesquihydrates, trihydrates, alcoholates, and polymorphous and amorphous forms thereof. The form B of omeprazole sodium is characterized by the positions and intensities of the peaks in the diffractogram of the X-ray powder, as well as by the parameters of the cell or unit cell which have been calculated from the positions of the peak. The corresponding data for form A of omeprazole sodium are completely different, while form B is easily distinguishable from form A. Form B of omeprazole sodium according to the present invention is characterized in that it provides a powder diffraction pattern of X-ray that exhibits substantially the following values d; The form B of omeprazole sodium according to the present invention is characterized in that it has a monocyclic unit with the parameters a = 15.09 A, b = 12.83 A, c = 9.82 A, ß = 94.4 Á.

According to the invention, a process for the preparation of form B of omeprazole sodium as well as a process for the preparation of form A of omeprazole sodium is additionally provided. Form B of omeprazole sodium can also be characterized by FT-IR. Form B of omeprazole sodium is prepared by treating omeprazole with an aqueous base, Na + B ~, where Na denotes sodium and B denotes hydroxide or alkoxide, in a suitable solvent, such as isopropanol optionally containing some water, at room temperature . Once the mixing has been carried out, the whole mixture can be stirred, for example, by swinging it, for an additional period of time, for example about 0-2 hours, at room temperature. The crude mixture can optionally be filtered in this step. Sowings of form B of omeprazole sodium can be added to the crystallization solution to induce crystallization. The slurry or slurry was further stirred after this for a period of about 10-24 hr to ensure as complete a crystallization as possible. It is also possible to cool the mixture to complete the crystallization and thereby improve the yield. The form B of omeprazole sodium is separated after this, for example by filtration or centrifugation, followed by washing with a suitable solvent, preferably the same solvent as previously used, and thereafter drying at a constant weight. Form B of omeprazole sodium can also be prepared by recrystallizing the sodium salt of omeprazole in any form, or mixtures thereof, in a suitable solvent such as ethanol or isopropanol, optionally containing some water. The form B of the omeprazole sodium obtained according to the present invention is substantially free from other forms of the sodium salts of omeprazole, such as form A of omeprazole sodium. The compound of the invention, ie the form B of omeprazole sodium, prepared according to the present invention is analyzed, characterized and differentiated from the form A of omeprazole sodium by X-ray powder diffraction, a technique which is known per se. Another suitable technique for analyzing, characterizing and differentiating form B of omeprazole sodium from form A of omeprazole sodium is by conventional FT-IR. The amount of water in form B of omeprazole sodium and in form A of omeprazole sodium is determined by thermogravimetric analysis, a technique which is known per se. The water content can also be determined by Karl Fischer. Form B of omeprazole sodium is effective as an inhibitor of gastric acid secretion, and is useful as an antiulcer agent. In a more general sense, it can be used for the treatment of related conditions, with gastric acid in mammals and especially in man, including for example reflux esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer. In addition, it can be used for the treatment of other gastrointestinal disorders where the inhibitory effect of gastric acid is desirable, for example in patients on NSAID therapy, in patients with Non-Ulcerative Dyspepsia, in patients with symptomatic gastro-esophageal reflux disease. , and in patients with gastrinomas. The compound of the invention can also be used in patients in intensive care situations, in patients with acute upper gastrointestinal bleeding, pre- and postoperatively to prevent aspiration of gastric acid and to treat ulceration caused by stress. In addition, the compound of the invention may also be useful in the treatment of psoriasis as well as in the treatment of infections caused by Helicobacter and related diseases. The compound of the invention can also be used for the treatment of inflammatory conditions in mammals, including man. Any suitable administration route can be employed, providing the patient with an effective dosage of form B of Omeprazole sodium according to the invention. For example, peroral or parenteral formulations and the like may be employed. Dosage forms include capsules, tablets, dispersions, solutions, suspensions and the like. Form B of omeprazole sodium, because it is highly soluble in water, is especially suitable for parenteral formulations, such as for intravenous administration. According to the invention there is further provided a pharmaceutical composition comprising form B of omeprazole sodium, 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 infections caused by Helicobacter. The invention also provides the use of Form B of omeprazole sodium in the manufacture of a medicament for use in the treatment of a condition related to gastric acid and a method of treating a condition related to gastric juice, such method being characterized in that it comprises administering to a subject suffering from said condition, a therapeutically effective amount of the form B of omeprazole sodium. Compositions of the invention include compositions suitable for peroral or parenteral administration. The compositions may be conveniently presented in unit dosage forms, and prepared by any methods known in the pharmacy art. Combination therapies comprising form B of omeprazole sodium and other active ingredients in 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. In the practice of the invention, the most suitable administration route as well as the magnitude of a therapeutic dose of form B of omeprazole sodium in any given case will depend on the nature and severity of the disease to 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. Individual requirements may be necessary for patients who have Zollinger-Ellison syndrome, such as a need for higher doses than the average patient. Children and patients with liver disease as well as patients on long-term treatment will generally benefit from doses that are somewhat lower than average. Therefore, in some conditions it may be necessary to use doses outside the intervals established later. Such higher and lower doses are within the scope of the present invention. In general, a suitable dosage range for parental administration is from 10 mg to 300 mg, and preferably from 20 mg to 80 mg. A suitable oral dosage form can cover a dose ranging from 5 mg to 300 mg of total daily dose, administered in a single dose or equally divided into divided doses. A preferred dosage range is from 10 mg to 80 mg. The compound of the invention can be combined as the active component intimately mixed with a carrier or pharmaceutical carrier according to conventional techniques, such as the oral formulations described in WO 96/01623 and EP 247 983, the descriptions of which are incorporated herein as a whole for reference. The following examples will further illustrate the preparation of the compound of the invention, ie the form B of omeprazole sodium, but are not intended to limit the scope of the invention as defined herein above or as claimed below.

Examples Example 1 Preparation of form B of omeprazole sodium from omeprazole 120 grams of omeprazole, 480 ml of isopropanol and 13.2 grams of NaOH (s) dissolved in 26.7 grams of water are added to a 3-neck glass vessel. The suspension is stirred for about 40 minutes at room temperature. The obtained solution is filtered through a lightening filter and the filter is washed with 20 ml of isopropanol. The isopropanol wash is combined with the previous isopropanol solution containing the product. The solution is seeded with 6 grams of form B of omeprazole sodium in 25 ml of isopropanol. The suspension is stirred for an additional 25 hours and the product is filtered and dried at 40 ° C. Performance 84.5%.

Example 2 Preparation of form B of omeprazole sodium from form A of omeprazole sodium 30 grams of form A of omeprazole sodium, prepared according to example 3 below, and 25 ml of ethanol are added to a glass container of 3 mouths The suspension is seeded with form B of omeprazole sodium and then stirred for an additional 24 hours at room temperature. The product is then filtered and dried at 50 ° C. Performance: 80% Example 3 Preparation of form A of omeprazole sodium from omeprazole 14. 8 kg of sodium hydroxide dissolve in 42 1 of water in a separate container. 120 kg of omeprazole are added to 927 1 of isopropanol in a 4000 l glass coated rector. The aqueous sodium hydroxide is charged to the suspension. The omeprazole is dissolved and the clear solution is filtered on a closed pressure filter to a 1200 liter glass-lined reactor. The solution is heated and 228 liters of methanol are charged at 50 ° C to initiate crystallization. The batch is seeded with a suspension of 1.2 kg of omeprazole sodium methanol moistened in isopropanol. The solution is cooled from 51 ° C to -8 ° C. The formed suspension is maintained at -8 to -9 ° C for 4 hours with moderate agitation. The centrifuged substance is washed with a cold mixture of isopropanol and methanol, 76 liters and 20 liters respectively, and then dried in a rotary dryer at approximately 35 mbar with a jacket temperature of 65 ° C. The dry substance was devoid of the lumps in a mill. Yield: 126.0 kg of omeprazole sodium methanol wet. A sample of the wet omeprazole sodium methanol (32.3 kg) is loaded in a rotary dryer. A vapor equilibrium process to remove the methanol was carried out at 39-87 mbar with a jacket temperature of 50 ° C. The equilibrium process took 3 days. The balanced substance was devoid of lumps in a mill. Production: 25.7 kg.

Example 4 Characterization of form B of omeprazole sodium and form A of omeprazole sodium using X-ray powder diffraction (XRPD) A diffraction analysis of the X-ray powder was carried out according to standard methods which can be found for example in Bunn, CW (1948), Chemical Crystallography, Clarendon Press, London, or Klug, HP & Alexander, L. E. (1974), X-Ray Diffraction Procedures, John Wiley and Sons, New York. The cell or unit cell parameters for Forms A and B have been calculated from X-ray powder diffractograms using the "TREOR" program by Werner, P.E., Eirksson, L. and Westdahl, M., J. Appl. Crystallogr. 18 (1985) 367-370. The fact that the positions in all the peaks in the diffractograms for form A and form B can be calculated using the parameters of the respective cell or unit cell, provides that the cells or unit cells be correct and that the diffractograms are indicative of the pure forms. The diffractogram of form B of omeprazole sodium, prepared according to Example 1 in the present application, is shown in Figure 1 and the diffractogram of form A of omeprazole sodium, prepared according to Example 3, is shown in Figure 2. The peaks, identified with the calculated values of the Bragg formula and the intensities, have been extracted from the diffractograms for form A, form B and the diffractogram obtained from the material produced in accordance with the prior art, and are provided in Table 1. This table also gives the parameters of the cell or unit cell for forms A and B. The relative intensities are less reliable and instead of numerical values the following definitions are used; % Relative Intensity Definition 25-100 vs (very strong) 10-25 s (strong) 3-10 m (medium) 1-3 w (weak) < 1 vw (very weak) Some additional very weak peaks found in the diffractograms have been omitted from table 1.

Reference Example A Preparation of omeprazole sodium according to the prior art according to the method described in Example 2 in EP 124 495 Omeprazole (1300 g, 3.77 moles) is added under vigorous mechanical stirring to a mixture of tetrahydrofuran (13 1) and 50% aqueous NaOH (296 g, 3.7 moles) and stirring is continued for 45 minutes. Trichlorethylene (5.7 1) is added and stirring is continued overnight at room temperature. The mixture is cooled to +5 ° C and then stirred for 3 hours. The precipitate is removed by filtration and the filter cake is washed with trichlorethylene (51) and dried under reduced pressure at 50 ° C to give the sodium salt of omeprazole (1314 g, 95%), m.p. 208-210 ° C. The product was analyzed using X-ray powder diffraction and gave the diffractogram shown in Figure 3 and given later in Table 1. Some additional very weak peaks found in the diffractograms have been omitted from Table 1.

Table 1. Diffraction data of X-ray powder for form A of omeprazole sodium, form B and according to the prior art. Only peaks below 2T = 40 ° have been included. All the peaks indicated for form A and form B can be indexed with the cells or unit cells given later.

Form A of the unit cell: a = 15 .757 (3) Á b = 8 .: 126 (1) Á c = 15 .671 (6) Á ß = 94 .21 (2) ° Form B of the unit cell: a = 15 .086 (6) Á b = 12 .835 (4) A or c = 9.1 315 (3). A or ß = 94 .41 (3) Table 1, continued Table 1, continued It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, it is claimed as property that contained in the following

Claims (13)

1. Form B of omeprazole sodium, characterized because it is thermodynamically stable.

2. Form B of omeprazole sodium, characterized because it is essentially non-hygroscopic.

3. Form B of omeprazole sodium according to claim 1 or claim 2, characterized in that it provides a diffraction pattern of the X-ray powder which exhibits substantially the following values of intensities;

4. The form B of omeprazole sodium according to any of claims 1-3, characterized in that it has a monocyclic unitary cell with the parameters a = 15.09 A, b = 12.83 A, c = 9.82 A, ß = 94.4 A.

5. A process for the preparation of form B of omeprazole sodium as defined in any of claims 1-4, characterized in that it includes the steps of, a) preparing the sodium salt of omeprazole by the addition of an aqueous base to omeprazole in a mixture of solvents comprising an alcohol and water, b) allowing the solution to crystallize, optionally using form B of omeprazole sodium to induce crystallization; and c) isolate form B of the omeprazole sodium thus obtained.

6. A process according to claim 5, characterized in that the aqueous base used in step a) is sodium hydroxide.

7. A process according to any of claims 5-6, characterized in that the alcohol used in step a) is isopropanol.

8. A process for the preparation of form B of omeprazole sodium as defined in any of claims 1-4, characterized in that it comprises the steps of: a) dissolving omeprazole sodium in any form, or a mixture of any forms, in a mixture of solvents comprising alcohol and water; b) allow the solution to crystallize, optionally using form B of omeprazole sodium to induce crystallization, and c) isolate form B of the omeprazole sodium thus obtained.

9. A pharmaceutical formulation, characterized in that it comprises form B of omeprazole sodium as defined in any of claims 1-4 admixed with a pharmaceutically acceptable excipient.

10. A pharmaceutical formulation suitable for i.v. administration, characterized in that it comprises the form B of omeprazole sodium as defined in any of claims 1-4 mixed with a pharmaceutically acceptable excipient.

11. The use of Form B of omeprazole sodium according to any of the claims 1-4, as an active ingredient in the manufacture of a medicament for use in the treatment of gastrointestinal disorders.

12. The use of form B of omeprazole sodium as defined in any of claims 1-4 in the manufacture of a pharmaceutical formulation for i.v.

13. A method of treating gastrointestinal disorders, characterized in that it comprises the administration of a therapeutically effective amount of the form B of omeprazole sodium as defined in any of claims 1-4, to a patient suffering from gastrointestinal disorders.