WO2009074997A2

WO2009074997A2 - A novel process for the preparation of crystalline magnesium salt of (s)-omeprazole di hydrate

Info

Publication number: WO2009074997A2
Application number: PCT/IN2008/000063
Authority: WO
Inventors: Venkat Reddy Alla; Raghumitra Alla; Jagan Mohan Gopi Setti; Aruna Kumari Sirigiri; Sreenivasa Reddy Bodapati; Venkat Rami Reddy Nara
Original assignee: Lee Pharma Ltd
Current assignee: Lee Pharma Ltd
Priority date: 2007-12-10
Filing date: 2008-02-01
Publication date: 2009-06-18
Anticipated expiration: 2010-06-10
Also published as: WO2009074997A3

Abstract

Disclosed herein is process for preparation of crystalline form of (S)-5-methoxy-2-[[(4- methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolemagnesium dihydrate which comprises: dissolving (S)-Omeprazole potassium in dimethyl formamide; reacting with magnesium chloride hexa hydrate; removing the salts from the mixture; and precipitating the (S)-Omeprazole magnesium di hydrate crystalline form by adding anti solvent. The anti-solvent used in the above process is selected from the group consisting of ketones such as acetone or methyl isobutyl ketone; esters such as ethyl acetate, and ethers like methyl tertiary butyl ether.

Description

A NOVEL PROCESS FOR THE PREPARATION OF CRYSTALLINE MAGNESIUM SALT OF (S)-OMEPRAZOLE DI HYDRATE

Technical field:

The present invention relates generally to the Field of pharmaceutical agents that are effective as inhibitors of gastric acid secretion. More particularly, the invention relates to a novel process for the preparation of stable crystalline (S)-Omeprazole magnesium dihydrate.

Back ground and prior art:

Omeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease, (PUD), gastroesophageal reflux disease (GORD/GERD) and Zollinger Ellison syndrome. Omeprazole generally refers to rac-5-methoxy-2-{[(4-methoxy-3,5- dimethylpyridin-2-yl)methyl]sulfinyl}-lH-benzimidazole, was first disclosed in US4255431 and marketed by Astrazeneca as omeprazole magnesium under the trade names Losec and Prilosec. More recent developments in the art pertain to optically pure isomers of omeprazole, specifically S-omeprazole, and its related pharmaceutical salts, which are less influenced by liver metabolism, exerting less adverse effect, as compared to the omeprazole racemate. Certain disclosures ascribe particularly efficacious pharmaceutical activity to a magnesium salt of S-omeprazole, which is currently being marketed by AstraZeneca under the brand name of Nexium.

US4255431, for example, contemplates benzimidazole-substituted compounds, their pharmaceutical salts, and optical isomers thereof.

US5714504 to Lindberg et al. discloses a pharmaceutical formulation that comprises a pure solid state alkaline salt of the (-)-enantiomer of 5-methoxy-2-[[(4-methoxy-3,5- dimethyl-2-pyridyl)methyl]sulfinyl]-lH-benzimidazole. The '504 patent discloses in this regard certain optically pure magnesium salts of S-omeprazole and processes of making the same.

US 2006/0166986 describe a process for the resolution of racemic 5-methoxy-2-[(3,5- dimethyl)-4-rnethoxy-2-pyridyl)methyl thio]-lH-benzimidazole by using (R)-camphor sulfonyl chloride in presence of methylene dichloride then the corresponding camphor SLilfonyl derivative is oxidized with meta chloro per benzoic acid. Corresponding camphor sulfonate derivative of Omeprazole is hydrolyzed with sodium hydroxide it gives R-Omeprazole mother liquor is on concentration gave (S)-Omeprazole. (S)- Omeprazole potassium is converted to (S)-Omeprazole magnesium di hydrate by using magnesium chloride in presence of water.

WO 2007/013743 describes a process for preparation of optically pure (S)-Omeprazole and its salts by dissolving (S)-(-) binol, a weak base and the racemic form of Omeprazole in a mixture of a water-compatible organic solvent & water at high temperature; crystallizing the obtained inclusion complex of (S)-Omeprazole & (S)-(-) binol and removing the (S)-(-) binol moiety from the crystallized inclusion complex. The inclusion complex of (S)-Omeprazole & (S)-(-) binol is treated with magnesium chloride solution in presence of isopropyl acetate & sodium hydroxide solution, followed by crystallization from methanol & acetone gave (S)-Omeprazole magnesium dihydrate.

WO 2005/105786 describes the preparation of (S)-Omeprazole by resolving racemic Omeprazole with (S)-camphor sulfonyl chloride to form diastereomeric mixture. These diastereomers are separated by fractional crystallization followed by deprotection to give (S)-Omeprazole. (S)-Omeprazole magnesium dihydrate is prepared by converting (S)- Omeprazole potassium salt with magnesium chloride solution in presence of water. Another

method describes that by reacting (S)-Omeprazole base with magnesium methoxide in presence of methanol further crystallized from acetone. US 2003/0004190 describes a process for the preparation of (S)-Omeprazole magnesium trihydrate, wherein (S)-Omeprazole potassium is reacted with magnesium sulphate in presence of methanol & acetone which upon drying it gives (S)-Omeprazole magnesium dihydrate form B. This application also describes the conversion of (S)-Omeprazole magnesium dihydrate to trihydrate by doing process of water leaching.

In another method, the methanolic solution of (S)-Omeprazole magnesium is evaporated to obtain a residue, which on crystallization from acetone gives (S)-Omeprazole magnesium salt dihydrate, Form A.

US 2004/0167173 describes the preparation of trihydrate of (S)-Omeprazole magnesium in the form of amorphous solid. (S)-Omeprazole base is reacted with magnesium metal in presence of methanol & dichloromethane, followed by quenching the reaction mass into water material, which is precipitated, filtered & finally crystallized from methanol & ethyl acetate.

US 2005/0267157 describes the recrystallization of (S)-Omeprazole magnesium tri hydrate by using dimethyl formamide (or) methanol (or) acetone (or) methanol/acetone mixture (or) ethanol/acetone (or) dimethyl sulfoxide. This patent application describe solvate forms of (S)-Omeprazole magnesium coordination complex having formula [Mg(Solv_a)_X (Solvb)y I mg (S-Omeprazolato)₃]₂ (Solv_c)_z. Where in Solv_a,b,c may be dimethyl formamide, acetone, dimethyl sulfoxide, methanol, ethanol, dimethyl formamide/water, dimethyl sulfoxide/water.

US 2007/0149573 discloses a process for the preparation of amorphous (S)-Omeprazole magnesium substantially free of neutral Omeprazole having water content less than about 4.8% by weight.

WO 2004/089935 discloses the preparation of (S)-Omeprazole magnesium tri hydrate form Hl , (S)-Omeprazole magnesium hemi hydrate, (S)-Omeprazole magnesium monohydrate by using (i) toluene, methanol & water mixture (ii) dimethyl formamide, and water & hexane mixture. Thus, there is a need in the art to provide an alternate process for preparation of stable crystalline salt of (S)-Omeprazole magnesium dihydrate, which is simple, cost-effective and easy to scale up.

Objectives of the invention:

Therefore, the objective of the present invention is to provide a cost effective (or) industrially/economically feasible processes for the preparation of crystalline (S)-Omeprazole magnesium dihydrate.

Another objective of the invention is to provide crystalline form of (S)-Omeprazole magnesium dihydrate which is stable.

Summary of the invention:

In accordance to meet the above objectives, the invention provides process for preparation of stable crystalline form of S)-Omeprazole magnesium dihydrate in a consistent and reproducible manner.

Accordingly, the process for preparation of crystalline form of (S)-5-methoxy-2-[[(4- methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole magnesium dihydrate comprises of: i. dissolving (S)-Omeprazole potassium in dimethylformamide; ii. reacting with magnesium chloride hexa hydrate; iii. removing the salts from the mixture; and iv. precipitating the (S)-Omeprazole magnesium di hydrate crystalline form by adding anti solvent.

In another process variant, the conversion of (S)-Omeprazole magnesium trihydrate to crystalline (S)-Omeprazole magnesium dihydrate comprising the steps of:

i. dissolving (S)-Omeprazole magnesium trihydrate in dimethyl formamide; ii. removing the salts from the resulting mixture; iii. precipitating the (S)-Omeprazole dihydrate crystalline form by adding anti solvent The anti-solvent used in the above processes is selected from the group consisting of ketones such as acetone or methyl isobutyl ketone; esters such as ethyl acetate, and ethers like methyl tertiary butyl ether.

Brief Description of the drawings:

Fig-1: Shows the Thermo gravimetric analysis spectrum of the crystalline magnesium salt of (S)-Omeprazole di hydrate (Example-1)

Fig-2: Shows the Differential scanning calorometry spectrum of the crystalline magnesium salt of (S)-Omeprazole di hydrate (Example-1)

Fig-3: Shows the X-ray diffraction spectrum of the crystalline magnesium salt of (S)-

Omeprazole di hydrate (Example-1)

Fig-4: Shows the Thermo gravimetric analysis spectrum of the crystalline magnesium salt of (S)-Omeprazole di hydrate (Example-2)

Fig-5: Shows the Differential scanning calorometry spectrum of the crystalline magnesium salt of (S)-Omeprazole di hydrate (Example-2)

Fig-6: Shows the X-ray diffraction spectrum of the crystalline magnesium salt of (S)-

Omeprazole di hydrate (Example-2)

Fig-7: Shows the Thermo gravimetric analysis spectrum of the crystalline magnesium salt of (S)-Omeprazole di hydrate (Example-3)

Fig-8: Shows the Differential scanning calorometry spectrum of the crystalline magnesium salt of (S)-Omeprazole di hydrate (Example-3)

Fig-9: Shows the X-ray diffraction spectrum of the crystalline magnesium salt of (S)-

Omeprazole di hydrate (Example-3)

Fig-10: Shows the Thermo gravimetric analysis spectrum of the crystalline magnesium salt of (S)-Omeprazole di hydrate (Example-4)

Fig-11 : Shows the Differential scanning calorometry spectrum of the crystalline magnesium salt of (S)-Omeprazole di hydrate (Example-4)

Fig-12: Shows the X-ray diffraction spectrum of the crystalline magnesium salt of (S)-

Omeprazole di hydrate (Example-4)

Fig-13: Shows the Thermo gravimetric analysis spectrum of the crystalline magnesium salt of (S)-Omeprazoie di hydrate (Example-5)

Fig- 14: Shows the Differential scanning calorometry spectrum of the crystalline magnesium salt of (S)-Omeprazole di hydrate (Example-5) Fig- 15: Shows the X-ray diffraction spectrum of the crystalline magnesium salt of (S)- Omeprazole di hydrate (Example-5)

Description of the Invention:

While the invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated, it is not intended to limit the invention to these particular embodiments.

The above objectives and advantages will be clear from the description of the embodiment, which is outlined in a broad sense and alternatively featured in the present invention, so that those skilled in the art may better understand the detailed description of the invention that follows. Additional features of the invention will be described herein after, that form the subject of claims of the invention. Those skilled in the art should appreciate that they can readily use the disclosed concept and specific embodiment as a basis for carrying out the same process of the present invention and realize that such equivalent conception do not depart from the spirit and scope of the invention in its broadest sense.

According to the present invention, the preparation of crystalline form of (S)-Omeprazole magnesium dihydrate salt can be prepared consistently starting from (S)-Omeprazole potassium salt or (S)-Omeprazole magnesium trihydrate salt.

In all the embodiments described herein below, the above mentioned starting materials are dissolved in dimethyl formamide, followed by treating with magnesium chloride hexa hydrate and precipitated using variety of anti-solvents selected from ketones, esters or ether solvents to yield substantially identical crystalline form of (S)-Omeprazole magnesium di hydrate.

Accordingly, in one preferred embodiment, the preparation of crystalline form of (S)-5- methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole magnesium dihydrate comprises steps of: dissolving (S)-Omeprazole potassium in dimethyl formamide; reacting with magnesium chloride hexa hydrate; removing the salts from the mixture; and precipitating the (S)-Omeprazole magnesium di hydrate in crystalline form by adding anti solvent.

In yet another embodiment, the conversion of (S)-Omeprazole magnesium trihydrate to crystalline form of (S)-Omeprazole magnesium dihydrate comprises dissolving the (S)- Omeprazole magnesium trihydrate in dimethyl formamide; and precipitating the (S)- Omeprazole dihydrate in crystalline form by adding anti solvent like acetone.

The anti-solvent used in the above processes is selected from the group consisting of ketones such as acetone or methyl isobutyl ketone; esters such as ethyl acetate, and ethers like methyl tertiary butyl ether.

Thus, the processes of the present invention is reliable, convenient and easily reproducible on industrial scale and also give substantially identical crystalline form of (S)-Omeprazole magnesium dihydrate, which is exemplified through the following examples.

The following examples, which include preferred embodiments, is intended to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative- discussion of preferred embodiments of the invention.

Examples:

Preparation of crystalline (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)- methyl]sulfinyl]-lH-benzimidazole magnesium salt dihydrate Example 1 :

(S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfmyl]-lH- benzimidazole magnesium salt dihydrate crystalline form.

Dimethyl formamide (180 ml) was added to (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl- 2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole potassium salt (30 gm) and magnesium chloride hexa hydrate ( 9 gm) was added to the mixture while stirring; after 60 min the mixture was filtered and washed with dimethyl formamide. To this solution acetone (600 ml) was added and the resulting mixture was left over for 2 hrs. The precipitated product was filtered off and slurry washed with acetone (100 ml). The product was dried at 40-45° C over night to obtain 18 gm of crystalline (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl- 2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole magnesium salt di hydrate.

The resulting crystals were characterized by X-ray powder diffraction, differential scanning calorometry (endotherm at 173.9⁰C, sample degrades at 183.29⁰C) and thermo gravimetric analysis (5.84% weight loss at 177.19⁰C). Specific optical rotation -128.32° (C=O.5% in methanol). Peak positions and relative intensities for the X-ray power diffraction are given in Table- 1.

Table- 1

Example-2:

Dimethyl formamide (180 ml) was added to (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl- 2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole potassium salt (30 gm) and magnesium chloride hexa hydrate ( 9 gm) was added to the mixture with stirring. After 1 hr maintenance, the mixture was filtered and washed with dimethyl formamide. To this solution, ethyl acetate (600 ml) added and the reaction mixture was left over for 3 hrs at 30-35° C. The precipitated product was filtered off and slurry washed with ethyl acetate (100 ml). The product was dried at 40-45° C over night to give 20 gm of (S)-5-methoxy- 2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole magnesium salt dihydrate.

The resulting crystals were characterized by X-ray powder diffraction, differential scanning calorometry (endotherm at 175.58°C, sample degrades completely at 179.59⁰C) and thermo gravimetric analysis (4.47% weight loss at 177.08⁰C). Specific optical rotation -133.54° (C=O.5% in methanol). Peak positions and relative intensities for the X-ray power diffraction are given in Table-2.

Table-2

Example-3:

Dimethyl form amide (180 ml) was added to (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl- 2-pyridinyl)-methyi]sulfinyl]-lH-benzimidazole (30 gm) and magnesium chloride hexa hydrate (9 gm) was added to the mixture along with stirring. After 1 hr maintenance, the mixture was filtered and washed with dimethyl formamide. To the solution, methyl tertiary butyl ether (600 ml) was added and the reaction mixture was stirred for 3 hr at 30-32° C. The isolated product was filtered off and slurry washed with methyl tertiary butyl ether (100 ml). The product was dried at 40-45° C over night to give 26 gm of (S)-5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfmyl]-lH-benzimidazole magnesium dihydrate. The resulting crystals were characterized by X-ray powder diffraction, differential scanning calorometry (endotherm at 175.7⁰C, sample degrades completely at 179.84°C) and thermo gravimetric analysis (4.65% weight loss at 176.12°C). Specific optical rotation -133.04° (C-0.5% in methanol). Peak positions and relative intensities for the X-ray power diffraction are given in Table-3.

Table-3

Example-4:

Dimethyl formamide (180 ml) was added to (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl- 2-pyridinyI)-methyl]sulfmyl]-lH-benzimidazole potassium salt (30 gm). Magnesium chloride hexa hydrate (9 gm) was added to the mixture along with stirring. After 1 hr maintenance, the mixture was filtered off and washed with dimethyl formamide. To the solution methyl iso butyl ketone (600 ml) was added and the resulting mixture was stirred for 3 hr at 30-32° C. The precipitated product was filtered off and slurry washed with methyl iso butyl ketone (100 ml). The product obtained was dried at 40-45° C over night to obtain 20 gm of (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfmyl]- lH-benzimidazolemagnesium dihydrate.

The resulting crystals were characterized by X-ray powder diffraction, differential scanning calorometry (endotherm at 176.65°C, sample degrades completely at 179.74°C) and thermo gravimetric analysis (5.84% weight loss at 177.19⁰C). Specific optical rotation -130.66° (C=O.5% in methanol). Peak positions and relative intensities for the X-ray power diffraction are given in Table-4.

Table-4

Example-5:

Conversion of (S)-Omeprazole salt of magnesium trihydrate to crystalline di hydrate: Dimethyl formamide (180 ml) was added to (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl- 2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole magnesium salt of hexa hydrate (9 gm). The resulting mixture was filtered off to remove inorganic salts and washed with dimethyl formamide. To the filtrate, acetone (600 ml) was added and the resulting mixture was stirred for 3 hr at 30-32° C. The precipitated product was filtered off and slurry washed with acetone (100 ml). The product obtained was dried at 40-45° C over night to obtain 16 gm of (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridmyl)- methyl]sιilfinyl]-l H-benzimidazole magnesium dihydrate.

The resulting crystals were characterized by X-ray powder diffraction, differential scanning calorometry (endotherm at 175.1O⁰C, sample degrades completely at 179.39°C) and thermo gravimetric analysis (4.47% weight loss at 177.08°C). Specific optical rotation -128.00° (C=O.5% in methanol). Peak positions and relative intensities for the X-ray power diffraction are given in Table-5.

Table-5

Claims

We claim,

1. A process for preparation of the crystalline form of magnesium salt of (S)- Omeprazole dihydrate comprising the steps of: a) dissolving potassium salt of (S)-Omeprazole in dimethyl formamide; b) adding magnesium chloride hexa hydrate to the solution of step (a); c) removing salts by filtration; d) precipitating the magnesium salt of (S)-Om eprazole by addition of anti solvent; e) isolating the magnesium salt of (S)-Omeprazole; f) slurry washing the magnesium salt of (S)-Omeprazole with anti solvent; and g) isolating followed by drying the isolated product to obtain crystalline magnesium salt of (S)-Omeprazole dihydrate.

2. A process according to claim 1, wherein the anti solvent is selected from the group consisting of ketones like acetone or methyl isobutyl ketone; ester like ethyl acetate or ether such as methyl tertiary butyl ether.

3. A process according to claim 1, wherein, the anti solvent used in slurry washing of the magnesium salt of (S)-Omeprazole is selected from the group consisting of ketones like acetone or methyl isobutyl ketone; ester like ethyl acetate or ethers such as methyl tertiary butyl ether.

4. The process according to claims 1 to 3, wherein, the crystalline (S)-Omeprazole magnesium dehydrate obtained by using acetone as anti solvent is characterized by X-ray powder diffraction, differential scanning calorometry (endotherm at 173.9⁰C, sample degrades at 183.29°C) and thermo gravimetric analysis (5.84% weight loss at 177.19°C), specific optical rotation -128.32° (C=0.5% in methanol).

5. The process according to claims 1 to 3, wherein, the crystalline form of magnesium salt of (S)-Omeprazole dihydrate obtained by using ethyl acetate as anti solvent is characterized by X-ray powder diffraction, differential scanning calorometry (endotherm at 175.58°C, sample degrades completely at 179.59°C) and thermo gravimetric analysis (4.47% weight loss at 177.08°C), specific optical rotation -133.54° (C=0.5% in methanol).

6. The process according to claims 1 to 3, wherein, the crystalline form of magnesium salt of (S)-Omeprazole dihydrate obtained by using methyl tertiary butyl ether as anti solvent is characterized by X-ray powder diffraction, differential scanning calorometry (endotherm at 175.7°C, sample degrades completely at 179.84°C) and thermo gravimetric analysis (4.65% weight loss at 176.12°C), specific optical rotation - 133.04° (C=0.5% in methanol).

7. The process according to claims 1 to 3, wherein the crystalline form of magnesium salt of (S)- Omeprazole di hydrate obtained by using methyl iso butyl ketone as anti solvent is characterized by X-ray powder diffraction, differential scanning calorometry (endotherm at 176.65°C, sample degrades completely at 179.74⁰C) and thermo gravimetric analysis (5.84% weight loss at 177.19⁰C), specific optical rotation - 130.66° (C=0.5% in methanol).

8. A process for the conversion of magnesium salt of (S)-Omeprazole trihydrate to crystalline form of magnesium salt of (S)-Omeprazole dihydrate which comprised the following steps: a) dissolving magnesium salt of (S)-Omeprazole trihydrate in dimethyl formamide; b) precipitating the magnesium salt of (S)-Omeprazole by the addition of acetone solvent and c) isolating followed by drying the precipitate to obtain crystalline form of magnesium salt of (S)-Omeprazole di hydrate.

9. The process according to claim (8), where in crystalline form of magnesium salt of (S)-Omeprazole is characterized by X-ray powder diffraction, differential scanning calorometry (endotherm at 175.10°C, sample degrades completely at 179.39°C) and thermo gravimetric analysis (4.47% weight loss at 177.08⁰C), specific optical rotation - 128.00° (C=0.5% in methanol).