WO2004089935A1 - Novel crystalline forms of s-omeprazole magnesium - Google Patents

Novel crystalline forms of s-omeprazole magnesium Download PDF

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WO2004089935A1
WO2004089935A1 PCT/IN2003/000151 IN0300151W WO2004089935A1 WO 2004089935 A1 WO2004089935 A1 WO 2004089935A1 IN 0300151 W IN0300151 W IN 0300151W WO 2004089935 A1 WO2004089935 A1 WO 2004089935A1
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omeprazole
magnesium
hours
omeprazole magnesium
process according
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PCT/IN2003/000151
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French (fr)
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Reddy Bandi Parthasaradhi
Reddy Kura Rathnakar
Reddy Rapolu Raji
Reddy Dasari Muralidhara
Reddy Kesireddy Subash Chander
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Hetero Drugs Limitd
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Priority to PCT/IN2003/000151 priority patent/WO2004089935A1/en
Publication of WO2004089935A1 publication Critical patent/WO2004089935A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole

Definitions

  • the present invention relates to novel crystalline forms of S-omeprazole magnesium, to processes for their preparation and to pharmaceutical compositions containing them.
  • the object of the present invention is to provide stable novel crystalline forms of S-omeprazole magnesium, processes for preparing these forms and pharmaceutical compositions containing them.
  • a novel crystalline form of S-omeprazole magnesium trihydrate designated as form H1 , characterized by an x-ray powder diffraction spectrum having peaks expressed as 2 ⁇ at about 5.8, 6.7, 7.6, 12.9, 13.9, 16.9, 17.7, 19.4, 20.5, 22.2, 23.5, 24.4, 25.3, 28.6 and 40.7 degrees.
  • Figure 1 shows typical form H1 x-ray powder diffraction spectrum.
  • S-omeprazole magnesium trihydrate form H1 a process for preparation of S-omeprazole magnesium trihydrate form H1.
  • S- omeprazole magnesium, toluene, water and an alcohol are mixed in any order, the contents are maintained for 15 minutes to 4 hours at 0°C to 35°C and S- omeprazole magnesium trihydrate form H1 is precipitated from the solution so obtained by adding n-hexane.
  • S-Omeprazole magnesium used in the process may be in any crystalline form or in any hydrated form. Water should be added in such a quantity that the total amount of water in the solution is at least just sufficient to form S-omeprazole magnesium trihydrate.
  • the mixture of S-omeprazole magnesium, toluene, water and an alcohol is stirred for 20 minutes to 1 hour at 15°C to 30°C.
  • n-Hexane should be added to the solution in a quantity that causes the precipitation of S-omeprazole magnesium trihydrate form H
  • S-omeprazole magnesium trihydrate form H1 S-omeprazole or an alkali metal salt of S-omeprazole, a magnesium salt, toluene, water and an alcohol are mixed in any order, the contents are maintained for 30 minutes to 12 hours at 0°C to 35°C and S-omeprazole magnesium trihydrate form H1 is precipitated from the solution so obtained by adding n-hexane. Water should be added in such a quantify that the total amount of water in the solution is at least just sufficient to form S-omeprazole magnesium trihydrate.
  • a process for preparation of S-omeprazole magnesium hemihydrate.
  • S-omeprazole magnesium, ester solvent, water and dimethylformamide are mixed in any order, the contents are maintained for 5 hours to 36 hours at 0°C to 35°C and S- omeprazole magnesium hemihydrate is precipitated from the solution so obtained by adding n-hexane.
  • S-Omeprazole magnesium used in the process may be in any crystalline form or in any hydrated form. Water should be added in such a quantity that the total amount of water in the solution is at least just sufficient to form S-omeprazole magnesium hemihydrate.
  • the mixture of S-omeprazole magnesium, ester solvent, water and dimethylformamide is stirred for 8 hours to 15 hours at 15°C to 30°C.
  • n-Hexane should be added to the solution in a quantity that causes the precipitation of S- omeprazole magnesium hemihydrate.
  • an alternative process for preparation of S-omeprazole magnesium hemihydrate.
  • S- omeprazole or an alkali metal salt of S-omeprazole, a magnesium salt, ester solvent, water and dimethylformamide are mixed in any order, the contents are maintained for 5 hours to 36 hours at 0°C to 35°C and S-omeprazole magnesium hemihydrate is precipitated from the solution so obtained by adding n-hexane.
  • Water should be added in such a quantity that the total amount of water in the solution is at least just sufficient to form S-omeprazole magnesium hemihydrate.
  • the mixture of S-omeprazole or an alkali metal salt of S-omeprazole, magnesium chloride, ester solvent, water and dimethylformamide is stirred for 10 hours to 20 hours at 15°C to 30°C.
  • n-Hexane should be added to the solution in a quantity that causes the precipitation of S-omeprazole magnesium hemihydrate.
  • a novel crystalline form of S-omeprazole magnesium monohydrate characterized by an x-ray powder diffraction spectrum having peaks expressed as 2 ⁇ at about 5.6, 6.5, 7.4, 8.0, 13.8, 16.7, 17.4, 19.2, 19.7, 20.4 and 28.4 degrees.
  • FIG. 3 shows typical monohydrate x-ray powder diffraction spectrum.
  • a process is provided for preparation of S-omeprazole magnesium monohydrate.
  • S-omeprazole magnesium, toluene, water and an alcohol are mixed in any order, the contents are maintained for 5 hours to 36 hours at 0°C to 35°C and n-heptane is added to the solution and S-omeprazole magnesium monohydrate is precipitated from the solution so obtained by adding n-heptane.
  • S-Omeprazole magnesium used in the process may be in any crystalline form or in any hydrated form. Water should be added in such a quantity that the total amount of water in the solution is at least just sufficient to form S-omeprazole magnesium monohydrate.
  • an alternative process for preparation of S-omeprazole magnesium monohydrate.
  • S- omeprazole or an alkali metal salt of S-omeprazole, a magnesium salt, toluene, water and an alcohol are mixed in any order, the contents are maintained for 10 hours to 36 hours at 0°C to 35°C and n-Heptane is added to the solution and S- omeprazole magnesium monohydrate is precipitated from the solution so obtained by adding n-heptane.
  • Water should be added in such a quantity that the total amount of water in the solution is at least just sufficient to form S- omeprazole magnesium monohydrate.
  • the mixture of S-omeprazole or an alkali metal salt of S-omeprazole, magnesium chloride, toluene, water and an alcohol is stirred for 15 hours to 30 hours at 15°C to 30°C.
  • n-Heptane should be added to the solution in a quantity that causes the precipitation of S- omeprazole magnesium monohydrate.
  • Figure 2 is a x-ray powder diffraction spectrum of S-omeprazole magnesium hemihydrate.
  • Figure 3 is a x-ray powder diffraction spectrum of S-omeprazole magnesium monohydrate. x-Ray powder diffraction spectrum was measured on a Bruker axs D8 advance x-ray powder diffractometer having a copper-K ⁇ radiation.
  • Example 3 S-Omeprazole magnesium (5 gm), n-butyl acetate (150 ml), dimethylformamide (100 ml) and water (1.5 ml) are mixed and stirred for 12 hours between 20°C and 30°C. The solution is cooled to 5°C, n-hexane (50 ml) is added and the contents are stirred for 5 hours between 5°C and10°C. The separated crystals are filtered to give 3.5 gm of S-omeprazole magnesium hemihydrate.
  • Example 4 S-Omeprazole (10 gm), MgS0 4 .7H 2 0 (5.5 gm), n-butyl acetate (200 ml), dimethylformamide (150 ml) and water (2.0 ml) are mixed and stirred for 15 hours between 20°C and 30°C. The solution is cooled to 5°C, n-hexane (100 ml) is added and the contents are stirred for 5 hours between 5°C and10°C. The separated crystals are filtered to give 7.3 gm of S-omeprazole magnesium hemihydrate.
  • Example 6 S-Omeprazole magnesium (5 gm), toluene (100 ml), methanol (10 ml) and water (1.5 ml) are mixed and stirred for 24 hours between 25°C and 35°C. n-Heptane (150 ml) is added to the solution and stirred for 1 hour between 25°C and 35°C. The separated crystals are filtered to give 4.2 gm of S-omeprazole magnesium monohydrate.
  • Example 7 Example 6 is repeated substituting S-omeprazole magnesium trihydrate form H1 for S-omeprazole magnesium to give S-omeprazole magnesium monohydrate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to novel crystalline forms of S-omeprazole magnesium, to processes for their preparation and to pharmaceutical compositions containing them.

Description

NOVEL CRYSTALLINE FORMS OF S-OMEPRAZOLE MAGNESIUM
FIELD OF THE INVENTION
The present invention relates to novel crystalline forms of S-omeprazole magnesium, to processes for their preparation and to pharmaceutical compositions containing them.
BACKGROUND OF THE INVENTION
Omeprazole, chemically 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridinyl)methyl]sulfinyl] -1 H-benzimidazole and its therapeutic uses are disclosed in EP 5129. Certain salts of omeprazole are disclosed in EP 124496 and in WO 95/01977. The salts of the enantiomers of omeprazole are described in WO 94/27988.
S-Omeprazole or its salts are useful for inhibiting gastric acid secretion in mammals and man.
Preparation of S-omeprazole in two crystalline forms (form A and Form B) is disclosed in US 6,162,816. US 6,369,085 describes crystalline forms of S- omeprazole magnesium, S-omeprazole magnesium dihydrate, S-omeprazole magnesium trihydrate and S-omeprazole potassium.
We have discovered three stable novel crystalline forms of S-omeprazole magnesium and these forms are found to be suitable for handling and pharmaceutical preparations. The object of the present invention is to provide stable novel crystalline forms of S-omeprazole magnesium, processes for preparing these forms and pharmaceutical compositions containing them.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, there is provided a novel crystalline form of S-omeprazole magnesium trihydrate, designated as form H1 , characterized by an x-ray powder diffraction spectrum having peaks expressed as 2Θ at about 5.8, 6.7, 7.6, 12.9, 13.9, 16.9, 17.7, 19.4, 20.5, 22.2, 23.5, 24.4, 25.3, 28.6 and 40.7 degrees. Figure 1 shows typical form H1 x-ray powder diffraction spectrum.
In accordance with the present invention, a process is provided for preparation of S-omeprazole magnesium trihydrate form H1. Thus, S- omeprazole magnesium, toluene, water and an alcohol are mixed in any order, the contents are maintained for 15 minutes to 4 hours at 0°C to 35°C and S- omeprazole magnesium trihydrate form H1 is precipitated from the solution so obtained by adding n-hexane. S-Omeprazole magnesium used in the process may be in any crystalline form or in any hydrated form. Water should be added in such a quantity that the total amount of water in the solution is at least just sufficient to form S-omeprazole magnesium trihydrate. Preferably, the mixture of S-omeprazole magnesium, toluene, water and an alcohol is stirred for 20 minutes to 1 hour at 15°C to 30°C. n-Hexane should be added to the solution in a quantity that causes the precipitation of S-omeprazole magnesium trihydrate form H
In accordance with the present invention, an alternative process is provided for preparation of S-omeprazole magnesium trihydrate form H1. S- omeprazole or an alkali metal salt of S-omeprazole, a magnesium salt, toluene, water and an alcohol are mixed in any order, the contents are maintained for 30 minutes to 12 hours at 0°C to 35°C and S-omeprazole magnesium trihydrate form H1 is precipitated from the solution so obtained by adding n-hexane. Water should be added in such a quantify that the total amount of water in the solution is at least just sufficient to form S-omeprazole magnesium trihydrate. Preferably, the mixture of S-omeprazole or an alkali metal salt of S-omeprazole, magnesium chloride, toluene, water and an alcohol is stirred for 30 minutes to 3 hours at 15°C to 30°C. n-Hexane should be added to the solution in a quantity that causes the precipitation of S-omeprazole magnesium trihydrate form H1.
In accordance with the present invention, there is provided a novel crystalline form of S-omeprazole magnesium hemihydrate, characterized by an x-ray powder diffraction spectrum having peaks expressed as 2Θ at about 5.8, 7.2, 10.4, 11.3, 12.8, 16.0, 17.5, 18.3, 21.5, 28.4 and 40.5 degrees. Figure 2 shows typical hemihydrate x-ray powder diffraction spectrum.
In accordance with the present invention, a process is provided for preparation of S-omeprazole magnesium hemihydrate. Thus, S-omeprazole magnesium, ester solvent, water and dimethylformamide are mixed in any order, the contents are maintained for 5 hours to 36 hours at 0°C to 35°C and S- omeprazole magnesium hemihydrate is precipitated from the solution so obtained by adding n-hexane. S-Omeprazole magnesium used in the process may be in any crystalline form or in any hydrated form. Water should be added in such a quantity that the total amount of water in the solution is at least just sufficient to form S-omeprazole magnesium hemihydrate. Preferably, the mixture of S-omeprazole magnesium, ester solvent, water and dimethylformamide is stirred for 8 hours to 15 hours at 15°C to 30°C. n-Hexane should be added to the solution in a quantity that causes the precipitation of S- omeprazole magnesium hemihydrate.
In accordance with the present invention, an alternative process is provided for preparation of S-omeprazole magnesium hemihydrate. Thus, S- omeprazole or an alkali metal salt of S-omeprazole, a magnesium salt, ester solvent, water and dimethylformamide are mixed in any order, the contents are maintained for 5 hours to 36 hours at 0°C to 35°C and S-omeprazole magnesium hemihydrate is precipitated from the solution so obtained by adding n-hexane. Water should be added in such a quantity that the total amount of water in the solution is at least just sufficient to form S-omeprazole magnesium hemihydrate. Preferably, the mixture of S-omeprazole or an alkali metal salt of S-omeprazole, magnesium chloride, ester solvent, water and dimethylformamide is stirred for 10 hours to 20 hours at 15°C to 30°C. n-Hexane should be added to the solution in a quantity that causes the precipitation of S-omeprazole magnesium hemihydrate. In accordance with the present invention, there is provided a novel crystalline form of S-omeprazole magnesium monohydrate, characterized by an x-ray powder diffraction spectrum having peaks expressed as 2Θ at about 5.6, 6.5, 7.4, 8.0, 13.8, 16.7, 17.4, 19.2, 19.7, 20.4 and 28.4 degrees. Figure 3 shows typical monohydrate x-ray powder diffraction spectrum. In accordance with the present invention, a process is provided for preparation of S-omeprazole magnesium monohydrate. Thus, S-omeprazole magnesium, toluene, water and an alcohol are mixed in any order, the contents are maintained for 5 hours to 36 hours at 0°C to 35°C and n-heptane is added to the solution and S-omeprazole magnesium monohydrate is precipitated from the solution so obtained by adding n-heptane. S-Omeprazole magnesium used in the process may be in any crystalline form or in any hydrated form. Water should be added in such a quantity that the total amount of water in the solution is at least just sufficient to form S-omeprazole magnesium monohydrate. Preferably, the mixture of S-omeprazole magnesium, toluene, water and an alcohol is stirred for 15 hours to 30 hours at 15°C to 30°C. n-Heptane should be added to the solution in a quantity that causes the precipitation of S-omeprazole magnesium monohydrate.
In accordance with the present invention, an alternative process is provided for preparation of S-omeprazole magnesium monohydrate. Thus, S- omeprazole or an alkali metal salt of S-omeprazole, a magnesium salt, toluene, water and an alcohol are mixed in any order, the contents are maintained for 10 hours to 36 hours at 0°C to 35°C and n-Heptane is added to the solution and S- omeprazole magnesium monohydrate is precipitated from the solution so obtained by adding n-heptane. Water should be added in such a quantity that the total amount of water in the solution is at least just sufficient to form S- omeprazole magnesium monohydrate. Preferably, the mixture of S-omeprazole or an alkali metal salt of S-omeprazole, magnesium chloride, toluene, water and an alcohol is stirred for 15 hours to 30 hours at 15°C to 30°C. n-Heptane should be added to the solution in a quantity that causes the precipitation of S- omeprazole magnesium monohydrate.
Examples of alcohols are methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl alcohol. Preferable alcohols are methanol and ethanol.
Examples of ester solvents are ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate and methyl formate. Preferable ester solvents are n-butyl acetate and ethyl acetate.
Examples of magnesium salts are magnesium sulfate and magnesium chloride.
The term "alkali" refers to sodium or potassium. In accordance with the present invention, there is provided a pharmaceutical composition comprising S-omeprazole magnesium trihydrate form H1 and a pharmaceutically acceptable carrier or diluent. In accordance with the present invention, there is provided a pharmaceutical composition comprising S-omeprazole magnesium hemihydrate and a pharmaceutically acceptable carrier or diluent.
In accordance with the present invention, there is provided a pharmaceutical composition comprising S-omeprazole magnesium monohydrate and a pharmaceutically acceptable carrier or diluent.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a x-ray powder diffraction spectrum of S-omeprazole magnesium trihydrate form H1.
Figure 2 is a x-ray powder diffraction spectrum of S-omeprazole magnesium hemihydrate.
Figure 3 is a x-ray powder diffraction spectrum of S-omeprazole magnesium monohydrate. x-Ray powder diffraction spectrum was measured on a Bruker axs D8 advance x-ray powder diffractometer having a copper-Kα radiation.
The following examples are given for the purpose of illustrating the present invention and should not be considered as limitations on the scope of spirit of the invention.
Example 1 S-Omeprazole magnesium (5.0 gm), toluene (100 ml), methanol (10 ml) and water (1.5 ml) are mixed and stirred for 30 minutes at 30°C. n-Hexane (150 ml) is added to the solution so obtained and stirred for 36 hours at about 30°C. The separated crystals are filtered to give 4.0 gm of S-omeprazole magnesium trihydrate form H1.
Example 2 S-Omeprazole potassium (10 gm), gS04 .7H20 (5.8 gm), toluene (150 ml), methanol (20 ml) and water (2.0 ml) are mixed and stirred for 1 hour between 25°C and 30°C. n-Hexane (180 ml) is added and stirred for 36 hours between 25°C and 30°C. The separated crystals are filtered to give 7.0 gm of S- omeprazole magnesium trihydrate form H1
Example 3 S-Omeprazole magnesium (5 gm), n-butyl acetate (150 ml), dimethylformamide (100 ml) and water (1.5 ml) are mixed and stirred for 12 hours between 20°C and 30°C. The solution is cooled to 5°C, n-hexane (50 ml) is added and the contents are stirred for 5 hours between 5°C and10°C. The separated crystals are filtered to give 3.5 gm of S-omeprazole magnesium hemihydrate.
Example 4 S-Omeprazole (10 gm), MgS04 .7H20 (5.5 gm), n-butyl acetate (200 ml), dimethylformamide (150 ml) and water (2.0 ml) are mixed and stirred for 15 hours between 20°C and 30°C. The solution is cooled to 5°C, n-hexane (100 ml) is added and the contents are stirred for 5 hours between 5°C and10°C. The separated crystals are filtered to give 7.3 gm of S-omeprazole magnesium hemihydrate.
Example 5 Example 1 is repeated substituting S-omeprazole magnesium hemihydrate for S-omeprazole magnesium to give S-omeprazole magnesium trihydrate form H
Example 6 S-Omeprazole magnesium (5 gm), toluene (100 ml), methanol (10 ml) and water (1.5 ml) are mixed and stirred for 24 hours between 25°C and 35°C. n-Heptane (150 ml) is added to the solution and stirred for 1 hour between 25°C and 35°C. The separated crystals are filtered to give 4.2 gm of S-omeprazole magnesium monohydrate.
Example 7 Example 6 is repeated substituting S-omeprazole magnesium trihydrate form H1 for S-omeprazole magnesium to give S-omeprazole magnesium monohydrate.
Example 8 S-Omeprazole sodium (10 gm), MgS04 .7H20 (5.8 gm), toluene (150 ml), methanol (15 ml) and water (2.0 ml) are mixed and stirred for 24 hours between 25°C and 35°C. n-Heptane (150 ml) is added to the solution and stirred for 5 hours between 25°C and 35°C . The separated crystals are filtered to give 7.2 gm of S-omeprazole magnesium monohydrate.

Claims

We claim:
1. A crystalline S-omeprazole magnesium trihydrate form H1 , characterized by an x-ray powder diffraction spectrum having peaks expressed as 2Θ at about 5.8, 6.7, 7.6, 12.9, 13.9, 16.9, 17.7, 19.4, 20.5, 22.2, 23.5, 24.4, 25.3, 28.6 and 40.7 degrees.
2. A crystalline S-omeprazole magnesium trihydrate form H1 as defined in claim 1 , further characterized by an x-ray powder diffraction spectrum as in figure 1.
3. A process for preparation of S-omeprazole magnesium trihydrate form H1 as defined in claim 1 , which comprises the steps of: a) mixing S-omeprazole magnesium, toluene, water and an alcohol; b) maintaining for 15 minutes to 4 hours at 0°C to 35°C; and c) precipitating S-omeprazole magnesium trihydrate form H1 by adding n- hexane.
4. A process according to cla ,im 3, wherein the alcohol is methanol.
5. A process according to cla im 3, wherein the alcohol is ethanol.
6. A process according to cla liim 3, wherein the contents are stirred for 20 minutes to 1 hour at 15°C to 30°C in (b).
7. A process for preparation of S-omeprazole magnesium trihydrate form H1 as .defined in claim 1 , which comprises the steps of: a) mixing S-omeprazole or an alkali metal salt of S-omeprazole, a magnesium salt, toluene, water and an alcohol; b) maintaining for 30 minutes to 12 hours at 0°C to 35°C; and c) precipitating S-omeprazole magnesium trihydrate form H1 by adding n- hexane.
8. A process according to claim 7, wherein the alcohol is methanol.
9. A process according to claim 7, wherein the alkali metal is sodium or potassium and the magnesium salt is magnesium sulfate or magnesium chloride.
10. A process according to claim 7, wherein the contents are stirred for 30 minutes to 3 hours at 15°C to 30°C in (b).
11. A crystalline S-omeprazole magnesium hemihydrate, characterized by an x- ray powder diffraction spectrum having peaks expressed as 2Θ at about 5.8, 7.2, 8.0, 8.6, 10.4, 11.3, 12.8, 16.0, 17.5, 18.3, 21.5, 28.4 and 40.5 degrees.
12. A crystalline S-omeprazole magnesium hemihydrate as defined in claim 11 , further characterized by an x-ray powder diffraction spectrum as in figure 2.
13. A process for preparation of S-omeprazole magnesium hemihydrate as defined in claim 11 , which comprises the steps of: a) mixing S-omeprazole magnesium, an ester solvent, water and dimethylformamide; b) maintaining for 5 hours to 36 hours at 0°C to 35°C; and c) precipitating S-omeprazole magnesium hemihydrate by adding n-hexane.
14. A process according to claim 13, wherein the ester solvent is n-butyl acetate.
15. A process according to claim 13, wherein the ester solvent is ethyl acetate.
16. A process according to claim 13, wherein the contents are stirred for 8 hours to 15 hours at 15°C to 30°C in (b).
17. A process for preparation of S-omeprazole magnesium hemihydrate as defined in claim 11 , which comprises the steps of: a) mixing S-omeprazole or an alkali metal salt of S-omeprazole, a magnesium salt, dimethylformamide, water and an ester solvent; b) maintaining for 5 hours to 36 hours at 0°C to 35°C; and c) precipitating S-omeprazole magnesium hemihydrate by adding n-hexane.
18. A process according to claim 17, wherein the ester solvent is n-butyl acetate.
19. A process according to claim 17, wherein the alkali metal is sodium or potassium and the magnesium salt is magnesium sulfate or magnesium chloride.
20. A process according to claim 17, wherein the contents are stirred for 10 hours to 20 hours at 15°C to 30°C in (b).
21. A crystalline S-omeprazole magnesium monohydrate, characterized by an x- ray powder diffraction spectrum having peaks expressed as 2Θ at about 5.6, 6.5, 7.4, 8.0, 13.8, 16.7, 17.4, 19.2, 19.7, 20.4 and 28.4 degrees.
22. A crystalline S-omeprazole magnesium monohydrate as defined in claim 21 , further characterized by an x-ray powder diffraction spectrum as in figure 3.
23. A process for preparation of S-omeprazole magnesium monohydrate as defined in claim 21, which comprises the steps of: a) mixing S-omeprazole magnesium, toluene, water and an alcohol; b) maintaining for 5 hours to 36 hours at 0°C to 35°C; and c) precipitating S-omeprazole magnesium monohydrate by adding n-heptane.
24. A process according to claim 23, wherein the alcohol is methanol.
25. A process according to claim 23, wherein the alcohol is ethanol.
26. A process according to claim 23, wherein the contents are stirred for 15 hours to 30 hours at 15°C to 30°C in (b).
27. A process for preparation of S-omeprazole magnesium monohydrate as defined in claim 21, which comprises the steps of: a) mixing S-omeprazole or an alkali metal salt of S-omeprazole, a magnesium .salt, toluene, water and an alcohol; b) maintaining for 10 hours to 36 hours at 0°C to 35°C; and c) precipitating S-omeprazole magnesium monohydrate by adding n-heptane.
28. A process according to claim 27, wherein the alcohol is methanol.
29. A process according to claim 27, wherein the alkali metal is sodium or potassium and the magnesium salt is magnesium sulfate or magnesium chloride.
30. A process according to claim 27, wherein the contents are stirred for 15 hours to 30 hours at 15°C to 30°C in (b).
31. A pharmaceutical composition comprising S-omeprazole magnesium trihydrate form H1 of claim 1 and a pharmaceutically acceptable carrier or diluent.
32. A pharmaceutical composition comprising S-omeprazole magnesium hemihydrate of claim 11 and a pharmaceutically acceptable carrier or diluent.
33. A pharmaceutical composition comprising S-omeprazole magnesium monohydrate of claim 21 and a pharmaceutically acceptable carrier or diluent.
PCT/IN2003/000151 2003-04-10 2003-04-10 Novel crystalline forms of s-omeprazole magnesium WO2004089935A1 (en)

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Cited By (13)

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WO2005118567A2 (en) * 2004-05-28 2005-12-15 Aaipharma Inc. Magnesium complexes of s-omeprazole
WO2006001753A1 (en) * 2004-06-24 2006-01-05 Astrazeneca Ab New process for the preparation of crystal modifications for use in the preparation of esomeprazole sodium salt
WO2006003163A1 (en) * 2004-07-02 2006-01-12 Esteve Química, S.A. Solid forms of the magnesium salt of (s)-omeprazole and processes for their preparation
DE102005008412A1 (en) * 2005-02-24 2006-09-07 Ratiopharm Gmbh New piperazine salt of omeprazol is proton pump inhibitor useful to prevent/treat e.g. peptic ulcer, gastritis, gastroesophageal reflux, acute stress ulcer or dyspepsia
WO2007031845A2 (en) * 2005-09-14 2007-03-22 Glenmark Pharmaceuticals Limited Polymorphic forms of (s)-omeprazole magnesium salts and processes for their preparation
WO2009074997A2 (en) * 2007-12-10 2009-06-18 Lee Pharma Ltd. A novel process for the preparation of crystalline magnesium salt of (s)-omeprazole di hydrate
EP2147918A1 (en) 2008-07-21 2010-01-27 LEK Pharmaceuticals D.D. Process for the preparation of S-omeprazole magnesium in a stable form
EP2385046A1 (en) 2010-05-03 2011-11-09 Produits Chimiques Auxiliaires Et De Synthese Precursor phase and use thereof for preparing the magnesium salt tetrahydrate of an omeprazole enantiomer
US8063074B2 (en) 2006-05-04 2011-11-22 Dr. Reddy's Laboratories Limited Polymorphic forms of esomeprazole sodium
CN102319223A (en) * 2011-09-21 2012-01-18 石药集团欧意药业有限公司 Esomeprazole freeze-dried preparation and preparation method thereof
CN104356114A (en) * 2014-11-17 2015-02-18 江苏中邦制药有限公司 Preparation method of esomeprazole magnesium trihydrate
CN106397402A (en) * 2016-08-30 2017-02-15 山东罗欣药业集团股份有限公司 Esomeprazole magnesium crystal compound and preparation method thereof
CN106928193A (en) * 2017-03-09 2017-07-07 上海华源医药科技发展有限公司 Preparation meets the method for the esomeprazole magnesium trihydrate of standards of pharmacopoeia

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EP1273581A1 (en) * 1997-05-30 2003-01-08 AstraZeneca AB New process for the preparation of the trihydrate of the magnesium salt of S-omeprazole

Patent Citations (2)

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WO1994027988A1 (en) * 1993-05-28 1994-12-08 Astra Aktiebolag Optically pure salts of pyridinylmethyl sulfinyl-ih-benzimidazole compounds
EP1273581A1 (en) * 1997-05-30 2003-01-08 AstraZeneca AB New process for the preparation of the trihydrate of the magnesium salt of S-omeprazole

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005118567A3 (en) * 2004-05-28 2006-09-28 Aaipharma Inc Magnesium complexes of s-omeprazole
WO2005118567A2 (en) * 2004-05-28 2005-12-15 Aaipharma Inc. Magnesium complexes of s-omeprazole
WO2006001753A1 (en) * 2004-06-24 2006-01-05 Astrazeneca Ab New process for the preparation of crystal modifications for use in the preparation of esomeprazole sodium salt
US8658799B2 (en) 2004-06-24 2014-02-25 Astrazeneca Ab Process for the preparation of crystalline modifications for use in the preparation of esomeperazole sodium salt
US7902370B2 (en) 2004-07-02 2011-03-08 Esteve Quimica, S.A. Solid forms of the magnesium salt of S-omeprazole and processes for their preparation
WO2006003163A1 (en) * 2004-07-02 2006-01-12 Esteve Química, S.A. Solid forms of the magnesium salt of (s)-omeprazole and processes for their preparation
ES2246149A1 (en) * 2004-07-02 2006-02-01 Esteve Quimica, S.A. Solid forms of the magnesium salt of (s)-omeprazole and processes for their preparation
JP2008505160A (en) * 2004-07-02 2008-02-21 エステヴェ キミカ， エス．エー． Solid form of magnesium salt of (S) -omeprazole and method for producing the same
DE102005008412A1 (en) * 2005-02-24 2006-09-07 Ratiopharm Gmbh New piperazine salt of omeprazol is proton pump inhibitor useful to prevent/treat e.g. peptic ulcer, gastritis, gastroesophageal reflux, acute stress ulcer or dyspepsia
WO2007031845A2 (en) * 2005-09-14 2007-03-22 Glenmark Pharmaceuticals Limited Polymorphic forms of (s)-omeprazole magnesium salts and processes for their preparation
WO2007031845A3 (en) * 2005-09-14 2007-05-18 Glenmark Pharmaceuticals Ltd Polymorphic forms of (s)-omeprazole magnesium salts and processes for their preparation
US8063074B2 (en) 2006-05-04 2011-11-22 Dr. Reddy's Laboratories Limited Polymorphic forms of esomeprazole sodium
WO2009074997A2 (en) * 2007-12-10 2009-06-18 Lee Pharma Ltd. A novel process for the preparation of crystalline magnesium salt of (s)-omeprazole di hydrate
WO2009074997A3 (en) * 2007-12-10 2009-12-30 Lee Pharma Ltd. A novel process for the preparation of crystalline magnesium salt of (s)-omeprazole di hydrate
US8362259B2 (en) 2008-07-21 2013-01-29 Lek Pharmaceuticals, D.D. Process for the preparation of esomeprazole magnesium in a stable form
EP2147918A1 (en) 2008-07-21 2010-01-27 LEK Pharmaceuticals D.D. Process for the preparation of S-omeprazole magnesium in a stable form
EP2385046A1 (en) 2010-05-03 2011-11-09 Produits Chimiques Auxiliaires Et De Synthese Precursor phase and use thereof for preparing the magnesium salt tetrahydrate of an omeprazole enantiomer
US8592601B2 (en) 2010-05-03 2013-11-26 Produits Chimiques Auxiliaires Et De Synthese Precursor phase and use thereof for preparing the magnesium tetrahydrate salt of an omeprazole enantiomer
CN102319223A (en) * 2011-09-21 2012-01-18 石药集团欧意药业有限公司 Esomeprazole freeze-dried preparation and preparation method thereof
CN102319223B (en) * 2011-09-21 2013-06-19 石药集团欧意药业有限公司 Esomeprazole freeze-dried preparation and preparation method thereof
CN104356114A (en) * 2014-11-17 2015-02-18 江苏中邦制药有限公司 Preparation method of esomeprazole magnesium trihydrate
CN106397402A (en) * 2016-08-30 2017-02-15 山东罗欣药业集团股份有限公司 Esomeprazole magnesium crystal compound and preparation method thereof
CN106397402B (en) * 2016-08-30 2019-05-03 山东罗欣药业集团股份有限公司 A kind of esomeprazole magnesium crystal-form compound and preparation method thereof
CN106928193A (en) * 2017-03-09 2017-07-07 上海华源医药科技发展有限公司 Preparation meets the method for the esomeprazole magnesium trihydrate of standards of pharmacopoeia

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