KR100572297B1 - New Crystalline Form of Omeprazole - Google Patents

Abstract

The present invention relates to 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1 H -benz, known as the novel crystalline form of the generic name omeprazole. It is about imidazole. In addition, the present invention is directed to the stomach of novel crystalline form of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1 H -benzimidazole Use for the treatment of disorders, pharmaceutical compositions containing the same, as well as novel crystalline forms of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl]- A method for preparing 1 H -benzimidazole.

5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole, omeprazole, gastrointestinal disorders

Description

New crystalline form of omeprazole

The present invention relates to novel crystalline form of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1 H -benzimidazole. 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1 H -benzimidazole is known by the generic name omeprazole and its novel crystalline The form is referred to as omeprazole Form A below. The present invention also relates to the use of omeprazole Form A for the treatment of gastrointestinal disorders, pharmaceutical compositions containing omeprazole Form A, and methods of preparing the new crystalline form of omeprazole Form A.

Compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1 H -benzimidazole as a common name omeprazole, as well as its therapeutically acceptable Salts are described in EP 5129. Single crystal X-ray data and derived molecular structures of omeprazole in crystalline form so far known are described in Ohishi et al., Acta Cryst. (1989), C45, 1921-1923. The crystal form of this disclosed omeprazole is referred to as omeprazole form B below.

Omeprazole is effective in inhibiting proton pump inhibitors, ie gastric acid secretion, and is useful as an antiulcer agent. More generally, omeprazole can be used to treat gastric acid related diseases in mammals, particularly humans.

1 is an X-ray powder diffractogram of omeprazole Form A. FIG.

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

Surprisingly, the inventors have found that the substance omeprazole may exist in one or more crystalline forms. It is an object of the present invention to provide omeprazole Form A. It is another object of the present invention to provide a process for preparing omeprazole Form A which is substantially free of other forms of omeprazole. X-ray powder diffraction (XRPD) is used as a method of distinguishing omeprazole form A from other crystalline and non-crystalline forms of omeprazole. It is also an object of the present invention to provide a pharmaceutical formulation comprising omeprazole Form A.

Omeprazole Form A is a crystalline form that is well defined and exhibits advantages such as being thermodynamically more stable and less hygroscopic than omeprazole Form B. Omeprazole Form A also shows better chemical stability, such as thermal stability and light stability, than omeprazole Form B.

Omeprazole Form B may be converted completely or partially to Omeprazole Form A under certain conditions. Omeprazole Form A is thus characterized as more thermodynamically stable than omeprazole Form B.

Omeprazole Form A is also characterized as being inherently nonhygroscopic.

Omeprazole Form A is characterized by unit cell parameters as well as peak position and intensity in the X-ray powder diffractogram. Unit cell dimensions were calculated from accurate Guinea data. The unit cell parameters as well as the X-ray powder diffractogram data of omeprazole form B are different from omeprazole form A. Thus, omeprazole form A can be distinguished from omeprazole form B by X-ray powder diffraction.

Omeprazole Form A according to the present invention is characterized by providing an X-ray powder diffraction pattern as shown in Figure 1 which substantially exhibits the following d-values and intensities.

Form A Form A d-value (Å) Relative strength d-value (Å) Relative strength 9.5 vs 3.71 s 7.9 s 3.59 m 7.4 w 3.48 m 7.2 vs 3.45 s 6.0 m 3.31 w 5.6 s 3.22 s 5.2 s 3.17 m 5.1 s 3.11 w 4.89 w 3.04 w 4.64 m 3.00 w 4.60 m 2.91 w 4.53 w 2.86 w 4.49 m 2.85 w 4.31 m 2.75 w 4.19 w 2.67 w 4.15 w 2.45 w 3.95 w 2.41 w

The peak identified by the d-value calculated from the Bragg equation and intensity was extracted from the gon diffractogram of omeprazole form A. Relative strength is unreliable and the following definition is used instead of numerical values:

% Relative strength ^* Justice 25-100 vs (very strong) 10-25 s (strong) 3-10 m (middle) 1-3 w (weak) ^* Relative intensity is derived from diffractogram measured by fixed slit.

Omeprazole Form A according to the invention also has a parameter

a triplet system with a = 10.410 (4) Å, b = 10.468 (3) Å, c = 9.729 (4) Å, α = 111.51 (3) °, β = 116.78 (3) °, γ = 90.77 (3) ° Characterized in unit cells.

Omeprazole Form A is also characterized by Raman spectroscopy, which is free of bands at 1364 cm ⁻¹ observed in omeprazole Form B and is characterized by the ratio of the relative intensities of the 842 and 836 cm ⁻¹ bands. The ratio of the intensity of the 842 cm ⁻¹ band / the intensity of the 836 cm ⁻¹ band is less than 1 in omeprazole Form A, but greater than 1 in omeprazole Form B.

According to the invention there is also provided a process for the preparation of omeprazole Form A.

Omeprazole Form A is obtained upon slow crystallization and Omeprazole Form B is obtained upon rapid crystallization. Omeprazole Form A may be prepared by crystallization or recrystallization of any form of omeprazole or any form of a mixture for a prolonged period of time at about room temperature in a suitable solvent such as methanol. Examples of extended time periods include, but are not limited to, several hours, for example two hours to several weeks. Suitable solvents are alkyl alcohols and especially lower alcohols having 1 to 4 carbon atoms.

Omeprazole Form A may also be prepared by suspending any form of omeprazole or any form of a mixture in a suitable solvent for an extended period of time at about room temperature. 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 time periods are, but are not limited to, several hours, for example two to several weeks.

Omeprazole Form A obtained according to the present invention is substantially free of other crystalline and non-crystalline forms of omeprazole, for example omeprazole Form B. It is to be understood that substantially free of other forms of omeprazole means that omeprazole Form A contains less than 10%, preferably less than 5% of other forms of omeprazole, for example omeprazole Form B.

Omeprazole form A in a mixture with other solid forms / other forms of omeprazole, for example omeprazole form B, also shows the advantage of being more chemically stable than, for example, pure omeprazole form B. Mixtures containing certain weights of omeprazole Form A are also chemically more stable than other mixtures containing less weight omeprazole Form A. Such mixtures comprising omeprazole form A can be prepared by mixing omeprazole form A prepared according to the present invention with other forms of omeprazole prepared according to the prior art, for example form B.

The invention also relates to a mixture comprising omeprazole Form A together with other solid forms of omeprazole. Such mixtures comprising omeprazole Form A are for example detectable amounts (1%, 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%) by weight %, 70%, 80%, 90%, 95%, 98% or 99% by weight) of omeprazole Form A.

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

Detectable amounts of omeprazole Form A are amounts detectable using conventional techniques such as FT-IR, Raman spectroscopy, XRPD and the like.

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

Compounds of the invention prepared according to the invention, ie omeprazole form A, were analyzed from omeprazole form B by X-ray powder diffraction, a technique known per se, characterized and distinguished. Another suitable technique for analyzing, characterizing and distinguishing omeprazole form A from omeprazole form B is by Raman spectroscopy.

Omeprazole Form A is effective as a gastric acid secretion inhibitor and useful as an antiulcer agent. More generally, it can be used to treat gastric acid related conditions including reflux esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer in mammals, especially humans. In addition, treatment of other gastrointestinal disorders in which gastric acid inhibitory effects are desirable, such as patients receiving NSAID therapy, patients with non-ulcer dyspepsia, patients with symptomatic gastroesophageal reflux disease, and gastrinoma It can be used for patients who are present. The compounds of the present invention may also be used in patients in intensive care situations, patients with acute upper gastrointestinal bleeding, to prevent aspiration of gastric acid and to treat stress ulcer formation. In addition, the compounds of the present invention may be useful for treating psoriasis as well as for treatment of Helicobacter infections and related diseases. The compounds of the invention can also be used to treat inflammatory conditions in mammals, including humans.

Any suitable route of administration can be used to provide the patient with an effective dosage of omeprazole Form A according to the present invention. For example, oral or parenteral preparations can be used. Dosage forms include capsules, tablets, dispersions, suspensions and the like, for example enteric coated capsules and / or tablets, capsules containing enteric coated pellets of omeprazole and / or tablets. In all dosage forms, omeprazole Form A can be mixed with other suitable ingredients.

According to the present invention there is provided a pharmaceutical composition comprising omeprazole Form A as an active ingredient with a pharmaceutically acceptable carrier, diluent or excipient, and optionally other therapeutic ingredients. Compositions comprising other therapeutic ingredients are particularly important for the treatment of Helicobacter infection. The present invention also provides the use of omeprazole Form A in the manufacture of a medicament for the treatment of gastric acid related conditions, and a method of treating gastric acid related conditions comprising administering a therapeutically effective amount of omeprazole Form A to a patient in a gastric acid related condition.

Compositions of the present invention include compositions suitable for oral or parenteral administration. The composition may conveniently be presented in unit dosage form and may be prepared by any method known in the art of pharmacy.

In the practice of the present invention, the degree of therapeutic dose of omeprazole Form A as well as the most suitable route of administration in any given case will depend on the nature and severity of the disease to be treated. Dosage and frequency will also vary with each patient's age, weight and response. Patients with Sollinger-Ellison syndrome will need special requirements, such as administering more than the average patient. A slightly lower than average dose will generally benefit patients with long-term treatment as well as patients with children and liver disease. Thus, in some conditions it may be necessary to use dosages outside the ranges described below. Such higher or lower dosages are within the scope of the present invention.

In general, suitable oral dosage forms can range from a total daily dose of 5 mg to 250 mg administered in a single dose or in a uniformly divided dose. Preferred dosage ranges are from 10 mg to 80 mg.

The compounds of the present invention can be combined as active ingredients in dense mixtures with pharmaceutical carriers according to conventional techniques, such as oral preparations described in WO 96/01623 and EP 247 983.

Combination therapy may also be used comprising omeprazole Form A and other active ingredients in separate dosage forms or in one fixed dosage form. Examples of such active ingredients are antibacterial compounds, nonsteroidal anti-inflammatory agents, antacids, alginates and prokinetic agents.

The following examples will also illustrate formulations of the compounds of the invention, ie omeprazole Form A, but are not intended to limit the scope of the invention as defined above or as claimed below.

<Example 1>

Preparation of Omeprazole Form A

Omeprazole (55.8 g) was added to methanol (348 ml) containing ammonia (1.3 ml, 25%) at room temperature. Thereafter, the suspension was stirred in the dark for about 45 hours and then filtered. The filtrate was dried under reduced pressure (<5 mbar) for 18 hours. Yield: 43.9 g.

<Example 2>

Preparation of Omeprazole Form B

Omeprazole (50 g) was added at 50 ° C. to methanol (750 ml) containing ammonia (0.7 ml, 25%). Then the solution was filtered and cooled to about 0 ° C for about 20 minutes. The crystals formed were filtered off, washed with ice cold methanol and dried. The filtrate was dried at 40 ° C. under reduced pressure (less than 5 mbar) for 24 hours. Yield: 39 g.

<Example 3>

Characteristics of Omeprazole Form A and Omeprazole Form B Using X-Ray Powder Diffraction

See, eg, Bunn, C. W. (1948), Chemical Crystallography, Clarendon Press, London; Or X-ray diffraction analysis according to standard methods found in Klug, H. P. & Alexander, L. E. (1974), X-Ray Diffraction Procedures, John Wiley and Sons, New York. Werner, P. E., Eriksson, L. and Westdahl, M., J. Appl. Crystallogr. 18 (1985) 367-370, using the program "TREOR", was used to calculate unit cell parameters for omeprazole forms A and B from the gyroscope X-ray powder diffractogram. The fact that the positions of all peaks in the diffractograms for omeprazole Form A and Form B can be calculated using each unit cell parameter demonstrates that the unit cell is accurate and the diffractogram displays pure form. The diffractogram of omeprazole form A prepared according to example 1 of the present application is shown in FIG. 1, and the diffractogram of omeprazole form B prepared according to example 2 of the present application is shown in FIG. 2.

Peaks identified by the d-value calculated from the Bragg equation and intensity were extracted from the diffractograms for omeprazole Form A and Form B, which are shown in the table below. This table also shows unit cell parameters for omeprazole forms A and B. Relative strength is unreliable and the following definition is used instead of numerical values:

% Relative strength Justice 25-100 vs (very strong) 10-25 s (strong) 3-10 m (middle) 1-3 w (weak)

Some additional weak or very weak peaks shown in the diffractograms are omitted in Table 1 below.

X-ray powder diffraction data for omeprazole Form A and Form B shown in FIGS. 1 and 2. All peaks indicated for omeprazole Form A and Form B can be indexed in unit cells given below. Form A Form B d-value (Å) Relative strength d-value (Å) Relative strength 9.5 vs 9.6 vs 7.9 s 8.0 m 7.4 w 7.9 m 7.2 vs 7.5 w 6.0 m 7.1 vs 5.6 s 5.9 m 5.2 s 5.6 m 5.1 s 5.3 s 4.89 w 5.1 s 4.64 m 4.54 m 4.60 m 4.48 s 4.53 w 4.41 m 4.49 m 4.14 w 4.31 m 3.75 s 4.19 w 3.57 m 4.15 w 3.47 s 3.95 w 3.40 w 3.71 s 3.28 s 3.59 m 3.22 m 3.48 m 3.02 w 3.45 s 2.97 w 3.31 w 2.87 w 3.22 s 2.37 w 3.17 m 3.11 w 3.04 w 3.00 w 2.91 w 2.86 w 2.85 w 2.75 w 2.67 w 2.45 w 2.41 w

The triclinic unit cell was as follows.

Unit cell form A Unit cell form B a = 10.410 (4) a = 10.257 (10) b = 10.468 (3) b = 10.717 (6) c = 9.729 (4) c = 9.694 (10) α = 111.51 (3) ° α = 112.14 (7) ° β = 116.78 (3) ° β = 115.56 (5) ° γ = 90.77 (3) ° γ = 91.76 (7) °

Claims (19)

delete delete Omeprazole Form A characterized by providing an X-ray powder diffraction pattern exhibiting substantially the following d-values. Form A Form A d-value (Å) Relative strength d-value (Å) Relative strength 9.5 vs 3.71 s 7.9 s 3.59 m 7.4 w 3.48 m 7.2 vs 3.45 s 6.0 m 3.31 w 5.6 s 3.22 s 5.2 s 3.17 m 5.1 s 3.11 w 4.89 w 3.04 w 4.64 m 3.00 w 4.60 m 2.91 w 4.53 w 2.86 w 4.49 m 2.85 w 4.31 m 2.75 w 4.19 w 2.67 w 4.15 w 2.45 w 3.95 w 2.41 w The method of claim 3 wherein the parameter is a triplet system with a = 10.410 (4) Å, b = 10.468 (3) Å, c = 9.729 (4) Å, α = 111.51 (3) °, β = 116.78 (3) °, γ = 90.77 (3) ° Omeprazole Form A characterized by having a unit cell. Omeprazole composition, characterized in that it contains at least 70% by weight of omeprazole Form A according to claim 3. a) dissolving or suspending omeprazole form A, omeprazole form B, amorphous form and other polymorphs, or mixtures thereof in a suitable solvent, b) crystallizing the solution by inducing crystallization with or without omeprazole Form A, c) isolating the omeprazole Form A obtained. A process for the preparation of omeprazole Form A according to claim 3 comprising a. The process of claim 6 wherein the solvent used in step a) is methanol, ethanol, acetone, ethyl acetate, methyl tert. And butyl ether, toluene or mixtures thereof. The process according to claim 6, wherein step a) is carried out at 15 to 25 ° C. 7. The method of claim 6, wherein step b) is performed for at least 2 hours. delete Omeprazole Form A prepared by the process according to claim 6. A pharmaceutical formulation for the treatment of gastrointestinal disorders comprising the omeprazole according to claim 3 together with a pharmaceutically acceptable excipient. delete A method of treating a gastrointestinal disorder, comprising administering to a mammal suffering from a gastrointestinal disorder, excluding a human, a therapeutically effective amount of omeprazole according to claim 3. Omeprazole composition characterized by containing at least 80% by weight of omeprazole Form A according to claim 3. An omeprazole composition comprising at least 90% by weight of omeprazole Form A according to claim 3. Omeprazole composition characterized by containing at least 95% by weight of omeprazole Form A according to claim 3. An omeprazole composition comprising at least 98% by weight of omeprazole Form A according to claim 3. An omeprazole composition comprising at least 99% by weight of omeprazole Form A according to claim 3.

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