RS49871B - NEW CRYSTALLlNE FORM OF OMEPRAZOLE - Google Patents

Abstract

Omeprazole form A, which gives an X-ray powder diffraction pattern showing the following essential d-values Form A Form A d-value (A) Relative intensity d-value (A) Relative intensity 9.5 vj 3.71 j 7.9 j 3.59 s 7.4 sl 3.48 s 7.2 vj 3.45 j 6.0 s 3.31 sl 5.6 j 3.22 j 5.2 j 3.17: s 5.1 j 3.11 sl 4.89 sl 3.04 sl 4.64 s 3.00 sl 4.60 s 2.91 sl 4.53 sl 2.86 sl 4.49 s 2.85 sl 4.31 s 2.75 sl 4.19 sl 2.67 sl 4.15 sl 2.45 sl 3.95 sl 2.41 sl and the absence of the band at 1364 cm-1 in Raman spectroscopy.

Description

Field of invention

This invention relates to a new crystalline form of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)^5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]]sulfinyl-1H-benzimidazole is known by the generic name omeprazole and its new crystalline form is referred to below as omeprazole form A. Further, this invention also relates to the use of omeprazole form A for the treatment gastrointestinal disorders, pharmaceutical compositions containing omeprazole form A and procedures for obtaining omeprazole form A.

State of the art

The compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]]sulfinyl-1H-benzimidazole, which has the generic name omeprazole, as well as its therapeutically acceptable salt, are described in EP 5129. Single crystal X-ray data and the deduced molecular structure of the only known crystalline form of omeprazole are described by Ohishi et al. Acta Cryst

(1989), C45, 1921-1923. This disclosed crystalline form of omeprazole is referred to below as omeprazole form B.

Omeprazole is a proton pump inhibitor, i.e. it is effective in inhibiting the secretion of gastric acid and is used as an antiulcer agent. In a more general sense, omeprazole can be used to treat diseases related to stomach acid in mammals and especially in humans.

Short description of the image

Figure 1 is an X-ray diffractogram of omeprazole form A powder.

Figure 2 is an X-ray diffractogram of Form B omeprazole powder.

Description of the invention

Surprisingly, it was found that the substance omeprazole can exist in more than one crystalline form. Object of the present invention to provide omeprazole form A: Another object of the present invention is to provide a process for obtaining omeprazole form A, substantially free from other forms of omeprazole. X-ray powder diffraction (XRPD) was used as a method to distinguish omeprazole form A from other crystalline or non-crystalline forms of omeprazole. Additionally, it is an object of the present invention to provide a pharmaceutical formulation comprising omeprazole form A.

Omeprazole form A is a crystalline form that shows favorable properties, such as good definition, higher thermodynamic stability and lower hygroscopicity than omeprazole form B, especially at room temperature. Omeprazole form A also shows better chemical stability, such as thermal and light stability, than omeprazole form B.

Omeprazole form B can under certain conditions be completely or partially converted to omeprazole form A. Omeprazole form A is therefore characterized by greater thermodynamic stability than omeprazole form B.

Omeprazole Form A is further characterized as being essentially non-hygroscopic.

Omeprazole form A was characterized by the position and intensity of the signal in the X-ray powder diffractogram, as well as the unit cell parameters. The dimensions of the unit cell were calculated from the exact Guinier data. X-ray powder diffraction data as well as unit cell parameters for omeprazole form B are different compared to omeprazole form A. Omeprazole form A can therefore be distinguished from omeprazole B using X-ray powder diffraction.

Omeprazole Form A, according to the present invention, is characterized by providing an X-ray powder diffraction pattern as in Figure 1, showing the following essential d-values and intensities;

Signals, identified with d-values calculated from Bragg's formula and intensities, were extracted from the Guinier diffractogram of omeprazole form A. Relative intensities are less reliable and instead of numerical values the following definitions were used;

♦Relative intensity is derived from the diffractogram measured using fixed slits.

Omeprazole Form A of the present invention is further characterized by triclinic unit cell parameters;

a=10.410(4)A

b=l 0.468(3) A

c=9.729(4) A

a=111.51(3)°

p=16.78(3)°

y=90.77(3)<0>

Omeprazole form A can also be characterized by Raman spectroscopy, where omeprazole form A is characterized by the absence of the band at 1364 cm"<1>, which is observed in omeprazole form B, and the ratio of the relative intensities of the bands at 842 and 836 cm"<1>. The ratio (intensity of band 842 cm"<5>/ intensity of band 836 cm"<1>) is <1 for omeprazole form A, while the ratio is >1 for omeprazole form B.

According to the invention, there is further provided a process for obtaining omeprazole form A.

Omeprazole form A was obtained after slow crystallization and omeprazole form B was obtained by rapid crystallization. Omeprazole Form A can be prepared by reacting the crystallization or recrystallization of omeprazole in any form, or a mixture of any forms, in a suitable solvent, such as for example methanol, at ambient room temperature and for an extended period of time. Examples of an extended period of time include, but are not limited to, several hours, such as 2 hours, up to several weeks. Suitable solvents are alkyl alcohols and especially lower alcohols containing 1-4 carbon atoms.

Omeprazole Form A may also be prepared by suspending omeprazole of any form, or mixtures of any forms, in a suitable solvent at ambient room temperature for an extended period of time. Examples of suitable solvents include, but are not limited to, methanol, ethanol, acetone, ethyl acetate, methyl tert-butyl ether, toluene, or any mixture thereof. Examples of extended periods of time include, but are not limited to, several hours, such as 2 hours, up to several weeks.

The omeprazole form A obtained according to the present invention is essentially free from other crystalline and non-crystalline forms of omeprazole, such as omeprazole form B. Essentially free from other forms of omeprazole should be understood to mean that omeprazole form A contains less than 10%, preferably less than 5% of any form of omeprazole, e.g. omeprazole form B.

Omeprazole form A in mixture with other solid form/forms of omeprazole, e.g. with omeprazole form B, also exhibits beneficial properties, such as greater chemical stability than pure omeprazole form B. Mixtures containing a certain amount of omeprazole form A in relation to weight are also chemically more stable than other mixtures containing a lower amount of omeprazole form A in relation to weight. These mixtures containing omeprazole form A can be prepared, for example, by mixing omeprazole form A prepared according to the present invention with other solid forms of omeprazole, such as form B, obtained according to the prior art.

The present invention also relates to a mixture of omeprazole form A with other solid forms of omeprazole. Such compositions preferably contain more than 50% by weight of omeprazole form A. Other embodiments include, for example, compositions containing an established amount of omeprazole form A that is 1%, 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99% of omeprazole form A in relation to on weight.

Examples of other solid forms of omeprazole include, but are not limited to, omeprazole form B, amorphous forms, and other polymorphs.

A detectable amount of omeprazole form A is an amount that can be detected using conventional techniques, such as FT-ER, Raman spectroscopy, XRPD and the like.

Expressed chemical stability includes, but is not limited to, thermal stability and light stability.

The compound according to the invention, i.e. omeprazole form A prepared according to the present invention is analyzed, characterized and distinguished from omeprazole form B by X-ray powder diffraction, known in the art. Another suitable technique for analyzing, characterizing and distinguishing omeprazole form A from omeprazole form B is Raman spectroscopy.

Omeprazole form A is effective as an inhibitor of gastric acid secretion, and used as an antiulcer agent. More generally, it can be used to treat conditions related to stomach acid in mammals, particularly humans, e.g. including reflux esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer. Furthermore, it can be used for the treatment of other gastrointestinal disorders where the effect of gastric acid inhibitors is desirable, for example in patients on NSAID therapy, in patients with non-ulcer dyspepsia, in patients with symptoms of gastro-oesophageal reflux disease and patients with gastrinomia. The compound of the invention may also be used in intensive care patients, in patients with acute upper gastrointestinal bleeding, pre- and post-operatively to prevent aspiration of gastric acid and treat stress ulceration. Furthermore, the compound of the invention may be useful in the treatment of psoriasis as well as in the treatment of Helicobacter pylori and related diseases. The compounds of the invention may also be used to treat inflammatory conditions in mammals, including humans.

Any convenient route of administration may be included to provide the patient with an effective dose of omeprazole form A according to pronal. For example, oral or parenteral formulation and the like can be used. Dosage forms include capsules, tablets, dispersions, suspensions and the like, e.g. enteric coated capsules and/or tablets, tablets and/or capsules containing coated pellets of omeprazole. In all dosage forms, omeprazole form A may be mixed with other suitable ingredients.

According to the invention there is further provided a pharmaceutical composition containing omeprazole form A, as an active ingredient, together with pharmaceutically acceptable carriers, diluents or excipients and optionally other therapeutic ingredients. Compositions containing other therapeutic ingredients are of particular interest in the treatment of Helicobacter pylori infections. The invention also provides the use of omeprazole form A in the manufacture of a medicament for use in the treatment of a gastric acid-related condition and a method of treating a gastric acid-related condition comprising administering to a subject suffering from said condition a therapeutically effective amount of omeprazole form A.

Compositions according to the invention include compositions suitable for oral or parenteral use. The compositions may be conveniently formulated as unit dosage forms and prepared by any known method known in the art or pharmacy.

In the practice of the invention, the most suitable route of administration as well as the size of the therapeutic dose of omeprazole form A in any given case will depend on the nature and severity of the disease being treated. The dose and frequency of doses 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 the need for higher doses than the average patient. Children and patients with liver disease as well as patients under long-term treatment will generally benefit from slightly lower than average doses. Therefore, in some conditions it may be necessary to use doses outside the range listed below. Such higher or lower doses are within the scope of the present invention.

In general, a suitable oral dosage form can cover a dosage range of 5 mg to 250 mg of the total daily dose, taken as a single dose or in equally divided doses. The preferred dosage range is from 10 mg to 80 mg.

The compound of the invention can be combined as an active component in intimate mixtures with pharmaceutical carriers according to conventional techniques, such as the oral formulation described in WO 96/01623 and EP 247 983, the inventions of which are incorporated herein by reference in their entirety.

Combination therapies containing omeprazole form A and other active ingredients in separate dosage forms or in one continuous dosage form may also be used. Examples of these active ingredients include anti-bacterial compounds, non-steroidal anti-inflammatory agents, antacid agents, alginates and prokinetic agents.

The following examples will further illustrate the preparation of compounds according to the invention, ie. omeprazole form A, but are not intended to limit the scope of the invention as defined herein above or in the claims below.

Examples

Example 1

Preparation of omeprazole form A

Omeprazole (55.8 g) was added at room temperature to methanol (348 ml) containing ammonia (1.3 ml; 25%). Afterwards, the suspension was stirred in the dark for approximately 45 hours and then filtered. The filtrate was dried for 28 hours at 30°C under reduced pressure (<5 mbar). Yield: 43.9 g.

Example 2

Preparation of omeprazole form B

Omeprazole (50g) was added to methanol (750ml) containing ammonia (0.7ml; 25%) at 50°C. The solution was then filtered and cooled over 20 minutes to approximately 0°C. The formed crystals were filtered and washed with ice-cold methanol and then dried. The filtrate was dried for 24 hours at 40°C under reduced pressure (<5 mbar). Yield: 39 g.

Example 3

Characterization of omeprazole form A and omeprazole form B by use

X-ray powder diffraction

X-ray diffraction analysis was performed according to standard methods that can be found in e.g. Bunn, C.W. (1948), Chemical Crystallography, Clarendon Press, London; or Klug, H. P. & Alexander, L. E. (1974), X-Ray Diffraction Procedures, John Wiley and Sons, New York. Unit cell parameters of omeprazole forms A and B calculated from Guinier X-ray powder diffraction patterns using the "TREOR" program Werner, P. E., Eriksson, L. and Westdahl, M, J. Appl. Crystallogr. 18 (1985) 367-370. The fact that the position of all the signals on the diffractogram of omeprazole form A and form B can be calculated using the appropriate unit cell parameters proves that the unit cells are correct and that the diffractograms are indicative of the pure forms. The diffractogram of omeprazole form A, prepared according to Example 1 of this application, is shown in Figure 1 and the diffractogram of omeprazole form B, prepared according to Example 2 of this application is shown in Figure 2.

Signals, identified with δ-values calculated from the Bragg formula and intensities, were extracted from the diffractograms of omeprazole form A and form B, and are given in Table 1. In this table, the unit cell parameters for omeprazole form A and B are also given. Relative intensities are less reliable and instead of numerical values the following definitions are used;

Some additional weak or very weak signals found in the diffractogram are omitted from Table 1.

Triclinic unit cells are:

Claims (12)

1. Omeprazole form A, indicated by the X-ray diffraction pattern beam on powder showing the following essential d-values and the absence of a band at 1364 cm"<1> in Raman spectroscopy. 2. Omeprazole form A according to claim 1, characterized in that it has a triclinic unit cell with parameters a—10.410(4) A, b=10.468(3) A, c=9.729(4) A; o=111.51(3)°, 0=1 16.78(3)°,7=90.77(3)°. 3. Composition of omeprazole, characterized in that it contains more than 80% by weight of omeprazole form A defined according to claim 1. 4. Omeprazole composition according to claim 3, characterized in that it contains 90% by weight of omeprazole form A. 5. Omeprazole composition according to claim 3, characterized in that it contains 95% by weight of omeprazole form A. 6. Omeprazole composition according to claim 3, characterized in that it contains 98% by weight of omeprazole form A. 7. Omeprazole composition according to claim 3, characterized in that it contains 99% by weight of omeprazole form A. 8. A process for obtaining omeprazole form A defined according to any of claims 1 or 2, characterized by the fact that it includes a) dissolving or suspending omeprazole of any form, or a mixture of any form, in a suitable solvent at 15-25 °C; b) allowing the solution to crystallize for 2 hours and c) isolating the omeprazole form A thus obtained. 9. The method according to claim 8, characterized in that the solvent used in step a) is selected from the group consisting of methanol, ethanol, acetone, ethyl acetate, methyl tert. butyl ether, toluene or any mixture thereof. 10. A process according to any one of claims 8-9, characterized in that step b) is carried out using omeprazole form A to induce crystallization. 11. A pharmaceutical formulation containing omeprazole form A defined according to any one of claims 1-7 in admixture with pharmaceutically acceptable excipients. 12. Use of omeprazole form A defined according to any of claims 1-7, as an active ingredient in the production of a drug for use in the treatment of gastrointestinal disorders.