SA99190998B1 - Crystal form of omeprazole - Google Patents

Abstract

Abstract: The present invention relates to a new crystalline form of: 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl-lH-benzimidazole known by the generic name omeprazole. The invention also relates to the use of the new crystalline form. From: 5-methoxt-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl-lH-benzimidazole for the treatment of stomach and intestine disorders, and pharmaceutical formulations containing the crystalline form of the aforementioned compound, and processes to prepare the new crystal form from: 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)mehyl]sulfinyl-lH-benzimidazole

Description

Y — _ crystal form of omeprazole FULL DESCRIPTION BACKGROUND: The present invention relates to a new crystal form of: 5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinyl]- 1 H-benzi midazole 5-meth- oxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benz imidazole 0 known by the name The general 'omeprazole' and a new crystalline form of this compound, hereinafter referred to as 'omeprazole A' - JI omeprazole. Pharmaceutical containing omeprazole "form M" and processes for its preparation, then in the European patent compound description number: 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl ]-1H-benz imidazole Vo, known by the generic name omeprazole ¢ and also the therapeutically acceptable salts of this compound. X- on the single crystalline compound and on the crystalline structure derived from it. Lad hereafter refers to this crystalline form of omeprazole as omeprazole (Figure 5). Vo General Description AA AA: Omeprazole is one of the proton pump inhibitor compounds; That is, it is an effective compound in discouraging the secretion of stomach acids. Hence, die can be used as an anti-ulcer. More comprehensively, omeprazole can be used in the treatment of diseases related to stomach acids in ela All, specifically in humans. 0 A brief explanation of the drawings: Figure No. (1) is a graph of the refraction of X-rays in the powder of the omeprazole compound, Figure M. Figure No. (1) is a graph of the refraction X-rays in the powder of omeprazole, figure 8.

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Detailed description:

It was unexpectedly found that omeprazole can exist in more than one crystalline form

One. The present invention is intended to provide omeprazole “form M”. And there is another goal

of the invention providing a process for the preparation of omeprazole "form M" which is largely free of

(XRPD) in other X-powder. The omeprazole diffractometer uses the oo forms of omeprazole

As a way to distinguish omeprazole "M-form" from other crystalline and non-crystalline forms

The non-crystalline form of omeprazole. In addition to that; The present invention aims to

Providing pharmaceutical formulations containing omeprazole "form JA

Omeprazole “form A” has the distinctive characteristics of being DAA-defined, more thermodynamically stable, and less hygroscopic than omeprazole.

Figure 8, specifically at room temperature. Omeprazole (form M) also shows degrees

Better than chemical, thermal and optical stability compared to omeprazole

Figure 5.

Under certain conditions, omeprazole (form 8) can be completely or partially transformed into omeprazole 01 (form M). Therefore, omeprazole (form M) is more stable than omeprazole.

Thermodynamic aspect compared to omeprazole "VB shape" Omeprazole is also characterized by

5 “Form omeprazole “Form M” being less hygroscopic than omeprazole

Omeprazole “A JSG” omeprazole has peak sites and intensities on a diffraction scale.

X-rays = in the powder; As well as being distinguished by unit cell variables. The dimensions of the unit cell were calculated from © through Guinier’s data and the X-ray diffractometers are different in the powder and also the unit cell variables in

omeprazole "Figure 8" compared to omeprazole "Figure A" and then it can be distinguished

omeprazole "Fig. A" compared to omeprazole "Fig. 8 using a diffractometer

X-rays in the powder.

According to the present invention, omeprazole “form A” is characterized by diffraction of X-rays in the powder according to the pattern shown in the figure Vm, and it shows the values of “L” and the intensity values shown in the following table:

—¢ - The peaks defined by the values of “0” were calculated from the “Bragg” equation, and the intensity values were extracted from the Guinier diffraction scale for omeprazole “Fig. SA. The intensity values are considered less reliable and instead of them the numerical values shown in The following: * Relative intensity values were derived from diffraction measurements using fixed longitudinal slits. 1,4

This — and according to the present invention omeprazole “Form A” is characterized by the following unit cell variables: I = 01.4100 (£) angstroms (£) by 01.78 (¥) angstroms (¥) = 5.776 (£) ANG 11.01 < » oo (?) degree 11.78 = 8 (©) degree avy = v (7) degree Omeprazole can be characterized as Fig. Unf did the Raman spectrometer, where omeprazole form “A” is distinguished by the absence of the band at “Fie name” A, which is observed with respect to

J cm 71 nominal A and £Y with a ratio between the relative strength values of 'B JSG' omeprazole to omeprazole 0 'form M'. omeprazole and for omeprazole

UB "omeprazole form in relation to omeprazole 1 while this value is greater than 1" (less than

SA "form omeprazole According to this invention it also provides a process for the preparation of omeprazole by slow crystallization; while "A" form omeprazole is obtained and omeprazole ve is obtained on omeprazole "form 73 by rapid crystallization. Omeprazole "form A" may be prepared by a reaction to crystallize or recrystallize any of the forms of omeprazole or mixtures of any of these forms in a suitable solvent, Jie methanol, at room temperature and for a period of time. Extended time She - from 2 hours to several weeks. Suitable solvents are alkyl alcohols; Specifically a young alcohol containing 1 - ; carbon atoms. 0 Lad omeprazole "Form A" may be prepared by suspending any of the omeprazole forms or mixtures thereof in a suitable solvent at room temperature for an extended period of time. Examples of suitable solvents include - but are not limited to - methanol; or ethanol ¢ or acetone; or ethyl acetate; or +- methyl t- methyl ; or butyl ether; or toluene; or mixtures thereof. As for the extended time periods, they range - Sia - What Yo - from two hours to several weeks. Omeprazole “form M” obtained according to the present invention is largely devoid of other crystalline and non-crystalline forms of omeprazole, such as omeprazole.

- +0

Form SB which means that omeprazole “form M” has less than 701; the better is less

Of the 75 other forms of omeprazole such as omeprazole (Figure 8).

There are also distinct properties associated with omeprazole (the "M" form) in mixture with a form or forms

Solid from omeprazole Jie omeprazole omeprazole "form 'B' and this is represented by the fact that

M0 the mixture is more Gl chemically compared to omeprazole 3" in its pure form. Also, the

Mixtures containing a certain amount of omeprazole "form A" on the basis of weight is Lead

More Bla from a chemical point of view compared to mixtures containing a smaller amount of omeprazole

Shape M based on weight. These mixtures containing omeprazole can be prepared

“Form M” by mixing omeprazole “Form M” prepared according to the present invention with 0 other solid forms of omeprazole “Jie omeprazole” Figure 713 prepared according to prior art.

The present invention also relates to mixtures containing “JAN omeprazole M” in a mixture with

JIE] is another solid form of omeprazole. Jie includes those mixtures that contain omeprazole

omeprazole "form M" on mixtures containing quantities of omeprazole "form A" can

Fig. 11, 77, 5, 211, 770, Save 146, 780, 216, AY 1, 786, 256, 75, ZA, or 74 by weight of omeprazole.

‎JA

There are examples of other solid forms of omeprazole; This includes - without limitation - to

Omeprazole (Fig. 8) and other amorphous and polycrystalline forms.

The amount of omeprazole “m-form” that can be detected is defined as that amount that can be detected using the conventional methods Jie Raman ¢ spectra, FT-IR and X-ray diffractometer in

Powder (XRPD) and the like.

The term "chemical stability" - without jas - includes thermo stability.

light stability and stability

The compound of the invention, i.e. omeprazole “form A” and distinguished from To omeprazole SAF omeprazole 8, is analyzed and characterized using the powder-3X ray diffraction method; And it's a method

known by itself. There is another suitable method for pads analysis of the properties of omeprazole

Figure M” and its distinction from omeprazole Figure 8, which is the Raman spectrometer method

ov - - Omeprazole (form A) is one of the effective compounds in inhibiting the secretion of stomach acids and can be used as an anti-ulcer. More comprehensively, this compound can be used in the treatment of pathological conditions related to stomach acids that affect mammals. Specifically, human », and these include cases of esophagitis resulting from reflux esophagitis ¢, gastritis », duodenitis ¢, gastric ulcer and duodenal ulcer, in addition to that This compound can be used in the treatment of various disorders of the stomach and intestines in which inhibition of the secretion of stomach acids is desirable. ie, for example, in patients being treated with an NSAID and in patients with dyspepsia not caused by an ulcer; in patients with gastroesophageal reflux; and in patients with stomach tumors. The compound of the invention may also be used to treat patients under concentrated Ale Jy.; in patients with bleeding in the upper part of the gastrointestinal tract; and before or after surgical procedures to prevent gastric acid resorption and to treat stress ulcers. In addition, the compound of the present invention may be useful in the treatment of psoriasis and in the treatment of Helicobacter infection and other related diseases. It is also possible to benefit from the compound of the invention in the treatment of inflammatory conditions in mammalian organisms. Including the human. vo and the patient can be given the omeprazole compound, “form M” according to this invention, by any of the appropriate methods in which an effective dose of this compound is given. For example, oral or non-intestinal formulations may be used. The dosage forms herein include capsules ¢, tablets ¢, dispersions ¢, suspensions and the like; also enteric-coated capsules and/or tablets; and capsules and/or tablets containing enteric-coated micro granules of omerazole ©. In all dosage forms, omeprazole (Form M) may be mixed with other suitable ingredients. li for this invention, it also presents a pharmaceutical composition that includes omeprazole "form L" as an active ingredient in association with a carrierdlala, a diluent, an excipient, or with other acceptable therapeutic ingredients pharmacist. Formulations containing Yo-components are particularly useful in the treatment of infections with Helicobacter bacteria.” The invention, Lad, shows the use of omeprazole “form M” in the manufacture of a drug used in the treatment of pathological conditions related to stomach acids; And a way to treat these cases includes giving the patient a therapeutically effective amount of omeprazole "form SA not

- -

The compositions of the invention include those which can be administered appropriately orally or non-gastrointestinally. Such formulations may conveniently be provided in unit doses; or prepared according to

Known methods in the field of pharmacy. In the practice of this invention depends on choosing the most appropriate way to take the compound as well as the amount of the therapeutic dose © of omeprazole "form M" for any of the known cases; This depends on the nature of the disease to be treated and its severity. The amount and frequency of the dose also varies according to the age of cpm all and body weight; and the patient's response to treatment. There may be special requirements when treating patients with Zollinger-Ellison syndrome ¢ as these require higher doses than in normal patients. Children and patients with liver disease, as well as those on extended treatment, benefit

0 generally from doses of the compound that are slightly less than the average dose. Accordingly, in some pathological cases it may be necessary to use doses outside the aforementioned old limits, and Jie those higher or lower doses are within the scope of the present invention. In general, the appropriate oral dose may range from © mg to You mg as a total daily dose given as one time or divided into several doses; It is preferable that the dose range between

No 10 mg 88 mg. The compound of the invention may be mixed as a basic component in a mixture containing a pharmaceutical substance Alda according to the traditional methods Jie Methods of making oral formulations described in International Patent No. 071777/96 and European Patent No. YEVAAY They are the patents used here as a technical reference for this invention.

0 Combination therapy comprising omeprazole "form M" with other active ingredients may also be used in separate dosage forms; or in fixed dose form. Examples of such active ingredients are antibacterial compounds, non-steroidal anti-inflammatory agents ¢, antacid agents ¢, alginate, and primary action agents.

Yo The following examples illustrate the processes for preparing the compound of the invention; It is omeprazole (form M), and the intent of these examples is to define the scope of the invention that was defined above or that will be mentioned later in the claims.

Examples

Example No. 1: Preparation of omeprazole (form fA) at room temperature omeprazole (©,0A) omeprazole g) was added to methanol (TEA) ml) containing ammonia VY ammonia mL; 778. The suspension was then stirred in 0 dark for about £6 h, then filtered. The VA filtrate was dried for 1 h at 17 dap under reduced pressure for 1 h. (less than 0 mbar). andl = 17.8 g Example No. ?: Preparation of omeprazole Figure 5: Omeprazole (+© g) added to (Je Vou) methanol contains 0 ammonia +,Y) ammonia mL; 270) at 0 degrees. The solution was then filtered; It was cooled for about 70 minutes to about zero degrees. The crystals formed were filtered out; Then these crystals were washed with ice-cooled methanol. Then it was dried. The filtrate was dried for YE 1 hour at 40°C under low pressure (less than ∼mbar). Product T = grams. Example No.: vo Determination of the properties of omeprazole “form A” and omeprazole ray-ray diffraction in the powder. X-ray diffraction analysis was performed according to the GORY standard which has been described in ref.: 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. described in Wemer, P.

E., Eriksson, L. and Westdahl, M., J.

Apple. Crystallogr. 18 (1985) 367-370 The fact that the positions of all peaks of the refraction graphs for omeprazole “M-form” and “Fig. 8” can be measured using unit-cell variables validates the unit-cell measurements; And that the refraction graphs of Yo are an indication of the presence of pure forms.Fig.-1 shows a graph of the diffraction of omeprazole “form A” prepared according to Example = 1 in the present invention; while the form of = ¥ Wily's drawing of the diffraction of omeprazole JAI "omeprazole 8 prepared according to the example AY of this invention. The peaks marked with the values of “0” calculated from the Bragg equation and the intensity values were extracted; This is from the diffraction graphs of each of the "m-shaped" Busa, which are given in Table -0, which is the table that shows ot

- 1.

Also, the unit cell variables for omeprazole are “form L” and “form SB.” The relative intensity values are less reliable, and Yau uses the numerical value in the following definitions:

0 There are some additional weak or very weak peaks found in the diffraction graphs; These have been omitted from Table - 1. Table 1: CR-ray diffraction data in the powder for both omeprazole form M and form B shown in Figures 0 7. All peaks that seen in omeprazole “A JS omeprazole,” Figure 5; And that to the cell units given in the table below:

- 11 0 ee | my bh wee fy 0 wees

Eee py we [ow

CT ee ath CT we [we

CT ee we a ee ow

TT ee re ee we As for the cell units, they are as follows:

Not

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Claims (1)

DS - Claims 1 1 - Omeprazole compound of "form M" its content ranges from 790 to 719 sly "of omeprazole A) omeprazole shows X-ray diffraction © and also shows ¥ values" The following: ¢ L value relative intensity L value relative intensity ° (angstroms) (angstroms) 1 m4 Very strong 1No strong l v,04 La Y,4 Moderate A l Weak YEA Moderate q l very strong mm strong ve medium lm weak 11 81 strong b strong 8 ,VY strong yay medium 5.1 VY strong yo) weak weak m weak \o 14 Fair 7 Weak 1 £1 Weak 1 Weak {or VY Weak Y,A Weak Ha 14 Fair Weak Weak {YY 14 Weak Y,vo Weak 7 £14 Weak Other Weak AL Y \ Weak M "Weak YY M Weak 7.1 Weak 1 ?- Omeprazole "Form A" according to Claim No. (1); Cua the substance "Omeprazole" is determined by the values of the tricyclic unit cell unit of 10 ah and the variables ov a; = 01.401 (£) angstroms ° bh 1015106 (9) angstrom A = x 5.77 (£) angstrom ° (7) ah la V uh d = y 4 ie 0f)* 1 ? - Omeprazole “form” A according to Claim No. (1), where the “omeprazole” substance is thermodynamically stable at room temperature. 1 ¢- Omeprazole JA "omeprazole M" according to Claim No. (1); where "omeprazole" is non-hygroscopic to a large extent. fae "form M" pursuant to claim No. (1); Where omeprazole - © 1 YX by weight of omeprazole is present in the compound. JAN pursuant to claim (1); Where "A" form omeprazole omeprazole - + 1 "_ by weight of the omeprazole substance present in the compound. P 7- Omeprazole "form M" according to Claim No. (1) 0 Where 799 Y by weight of omeprazole is present in compound 1 + = omeprazole “Form A” contains -400 7959 by weight of omeprazole Y; Cua characterization of omeprazole in the ALY spectrometer, and for the relative intensity values Taw 114 in the absence of the Raman Y band ; .cm Scope / 877 Taw Scope less than 1 1 1 - A pharmaceutical composition that includes a therapeutically effective amount of omeprazole. a J \ _ “M” according to claim No. (1) mixed with an inert, pharmaceutically acceptable excipient. Of omeprazole Form “A according to Claim No. (i 1 11 1) - a method for treating inflammatory diseases affecting the stomach and intestines;” and it includes giving the patient who needs treatment a therapeutically effective amount of omeprazole omeprazole ¥ form M "according to claim No. (1) 117 1 - A method for treating Helicobacter infection; comprising administration to a patient Y who needs treatment a therapeutically effective amount of omeprazole 2201:0060" Fig. Li, “A 1” of claim no. (i 1).