FORM 2
THE PATENTS ACT 1970 (Act 39 of 1970)
&
THE PATENTS RULE 2003 (SECTION 10 and rule 13)
PROVISIONAL SPECIFICATION
"NOVEL POLYMORPH OF ESOMEPRAZOLE POTASSIUM AND PROCESS FOR THE PREPARATION THEREOF"
Glenmark Pharmaceuticals Limited an Indian Company, registered under the Indian company's Act 1957 and
having its registered office at
Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai - 400 099
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION


FIELD OF THE INVENTION
The present invention relates to a novel crystalline form of 5-Methoxy-2-[(S)-(4-methoxy-3, 5-dimethyl-2-pyridinylmethyl) sulfinyl]-lH-benzimidazole potassium salts generally known as esomeprazole potassium. The present invention also relates to processes for preparing such crystalline form of potassium salt of esomeprazole and pharmaceutical compositions containing it.
BACKGROUND OF THE INVENTION
The compound 5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl]-lH-benzimidazole, having the generic name omeprazole, and therapeutically acceptable salts thereof, are described in EP 5129. The specific alkaline salts of omeprazole are disclosed in EP 124 495. Omeprazole is a proton pump inhibitor, i.e. effective in inhibiting gastric acid secretion, and is useful as an antiulcer agent. In a more general sense, omeprazole may be used for prevention and treatment of gastric-acid related diseases in mammals and especially in man.
Omeprazole is a sulfoxide and a chiral compound, wherein the sulfur atom is the stereogenic center. Thus, omeprazole is a racemic mixture of its two single enantiomers, the (R) - and (S)-enantiomer of omeprazole, herein referred to as (R)-omeprazole and (S)-omeprazole.
Certain salts of the single enantiomers of omeprazole and their preparation are disclosed in WO 94/27988. These compounds have improved pharmacokinetic and metabolic properties which will give an improved therapeutic profile such as a lower degree of inter individual variation.
WO 96/02535 discloses a process for the preparation of the single enantiomers of omeprazole and structually related compounds as well as salts thereof WO 96/01623 discloses pharmaceutical dosage forms comprising for instance magnesium salts of (R)-and (S)-omeprazole.
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WO 98/54171 discloses a process for the preparation of the trihydrate of magnesium salt of esomeprazole, wherein the potassium salt of esomeprazole is used as an intermediate.
US Pat. No. 6,677,455 and US Pat. No. 6,511,996 further discloses two different crystalline forms of potassium salt of esomeprazole.
The novel form of the potassium salt of esomeprazol according to the present invention is hereinafter referred to as Form X.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an X-ray powder diffractogram of Esomeprazole Potassium Form- X.
DESCRIPTION OF THE INVENTION
It has surprisingly been found that the potassium salt of esomeprazole occurs in a number of structurally different forms. It is an object of the present invention to provide a substantially pure potassium salt of esomeprazole form X.
Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated
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as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances and the safety and efficacy of drug products.
For crystalline compounds, XRD (x-ray powder diffraction) is a useful technique. Each XRD is unique for the particular crystalline form. Each crystalline form exhibits a diffraction pattern with a unique set of diffraction peaks that can be expressed in 2 theta angles, d-spacing values and relative peak intensities. 2 theta diffraction and corresponding d-spacing values account for positions of various peaks in the XRD pattern and d-spacing values may be calculated with observed 2 theta angles by well known methods using the Bragg equation.
It has surprisingly been found that the potassium salt of esomeprazole occurs in different crystalline polymorphic forms. It is an object of the present invention to provide novel crystalline form of potassium salt of esomeprazole i.e. Form X.
The process of the present invention makes the best use of the novel crystalline form and their properties by making it possible to produce esomeprazole potassium in a more effective and efficient way.
The present process is advantageous since it allows esomeprazole potassium salt to be prepared directly from the corresponding salts in high yield and good quality. Additional merits are high reproducibility, good process ability including safety
The process of the present invention comprises essentially of the following steps:
i) dissolving esomeprazole neutral form in a suitable solvent Si;
ii) addition of an additional solvent S2;
iii) addition of potassium source;
iv) concentrating the reaction mass under vacuum;
v) adding an additional suitable antisolvent S3 and
vi) isolating esomeprazole potassium salt
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In one embodiment of the present invention esomeprazole neutral form is prepared either from the corresponding esomeprazole salts such as potassium, sodium, magnesium, lithium, alkyl ammonium salt and more or less immediately processed through the subsequent steps defined above. If so, the esomeprazole salt as mentioned above can be prepared by any of the method as disclosed in thr art and thereafter suspended in solvent Si. The pH shall thereafter be adjusted to produce esomeprazole in its neutral form. This pH adjustment can be made by the addition of about 1 molar equivalent of a suitable acid HA, preferably as an aqueous solution. Examples of such acid HA comprises but not limited to, all mineral acids that forms a water soluble potassium salt, e.g. hydrochloric acid, and acetic acid. The aqueous phase is thereafter discarded and the organic phase is optionally washed with water or brine. Esomeprazole neutral form is now ready to be used, more or less immediately, in steps ii) to v) defined above.
The solvent Si can be selected from organic solvents include, but are not limited to aromatic solvents such as benzene or alkyl, aryl, halo substituted benzenes, chlorinated olefins such as dichloro methane, dichloro ethane, chloroform, carbon tetrachloride, perchloroethylene, etc. Ketone such as acetone, methyl iso butyl keotne, iso butyl ketone, etc.
The solvent S2 can be selected from organic solvents, but are not limited acetonitrile CM alcohols such as methanol, ethanol, n-butanol, n-propanol, acetonitrile. Ketone such as acetone, methyl iso butyl keotne, iso butyl ketone, etc.
The solvent S3 can be selected form cyclic and acyclic hydrocarbons such as n-pentane, n-hexane, n-heptane, n- octane, cycloheptane, cyclohexane, etc.
The potassium source is potassium hydroxide. The esomeprazole potassium salt is affected by optional seeding.
Esomeprazole potassium salt obtained by the present process can be dried using conventional drying process, as appropriate.
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The phrase "more or less immediately" used in the present invention is to be understood to mean that the subsequent step or action shall be performed at such a time to avoid degradation of the active compound. The subsequent step can be performed considerably later in time provided that due care has been taken to avoid degradation of the active compound.
It is an aspect of the present invention to provide esomeprazole potassium having novel crystalline Form X. Another object of the present invention is to provide a process for the preparation of novel polymorphic Form X. Esomeprazole potassium salt Form X is characterized by X ray powder diffraction pattern as in Figure 1, exhibit d spacing value as shown in table 1.

d-spacing 2 - Theta Intensity (%)
16.6674 5.3 ±-0.2 100
In another aspect of the present invention provides esomeprazole potassium form X, having a chemical purity of 96% or more as measure by HPLC, preferably 99% or more, more preferably 99.5% or more.
In yet another aspect of the present invention, when a pharmaceutical composition comprising esomeprazole potassium form X prepared according to the present invention is formulated for oral administration. Accordingly, D50 and D90 particle size of the unformulated esomeprazole potassium form X used as starting material in preparing a pharmaceutical composition generally is less than 300 microns preferably less than about 200 microns, more preferably less than 150 microns, still more preferably less than about 50 microns and still more preferably less than about 10 microns.
Any milling, grinding micronizing or other particle size reduction method known in the art can be used to bring the solid state esomeprazole potassium form X thereof into any desired particle size range as set forth above.
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The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.
Example 1
5-Methoxy-2-[(S)-(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-lH-benzimidazole potassium
10 grams of potassium salt of esomeprazole were dissolved in 20 ml of water, which was then followed by addition of 20 ml of methylene chloride at 20 to 30° C and pH of the aqueous layer was adjusted about 7-8.5 by the addition of acetic acid. The aqueous layer was separated and extracted with 20 ml of methylene chloride. The organic layer was combined and followed by washing with water. This was further followed by addition of 50 ml of acetonitrile to the organic layer, which was then allowed to cool, followed by addition of potassium hydroxide solution (1.4 grams of potassium hydroxide dissolved in 1.4 ml of water). The resulted solution was stirred for 60 minutes and concentrated under vacuum below 40°C. This was followed by the addition of 50 ml of acetone to the resulted residue and the solvent was again evaporated under vacuum. 100 ml of heptane was added to the resulted residue and the reaction mass were stirred overnight. The resulted mass was filtered and dry to afford potassium salt of esomeprazole. Yield: 5 grams
XRD confirms to Form X having characteristic d-spacing values at 16.6 and 2-Theta value 5.3.
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Example 2
5-Methoxy-2-[(S)-(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-lH-benzimidazole potassium
10 grams of sodium salt of esomeprazole were dissolved in 20 ml of water, which was then followed by addition of 20 ml of methylene chloride at 20 to 30°C and pH of the aqueous layer was adjusted about 7-8.0 by addition of acetic acid. The aqueous layer was separated and extracted with 20 ml of methylene chloride. The organic layer was combined and followed by washing with water. This was further followed by addition of 50 ml of acetonitrile to the organic layer, which was then allowed to cool, followed by addition of potassium hydroxide solution (1.5 grams of potassium hydroxide dissolved in 1.5 ml of water). The resulted solution was stirred for 60 minutes and concentrated under vacuum below 40°C. This was followed by the addition of 50 ml of acetone to the resulted residue and the solvent was again evaporated under vacuum. 100 ml of heptane was added to the resulted residue and the reaction mass were stirred overnight. The resulted mass was filtered and dry to afford potassium salt of esomeprazole. Yield: 5.6 grams
XRD confirms to Form X having characteristic d-spacing values at 16.6 and 2-Theta value 5.3.
Dated this Twenty-First (21st) day of June, 2006

(Signed).
VISHAL A SODHA
SENIOR MANAGER-IPM
GLENMARK PHARMACEUTICALS LIMITED
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