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WO2010097583A1 - Polymorphe de l'ésoméprazole de potassium et sa préparation - Google Patents

Polymorphe de l'ésoméprazole de potassium et sa préparation Download PDF

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Publication number
WO2010097583A1
WO2010097583A1 PCT/GB2010/000333 GB2010000333W WO2010097583A1 WO 2010097583 A1 WO2010097583 A1 WO 2010097583A1 GB 2010000333 W GB2010000333 W GB 2010000333W WO 2010097583 A1 WO2010097583 A1 WO 2010097583A1
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WO
WIPO (PCT)
Prior art keywords
potassium
esomeprazole
ethanol solvate
esomeprazole potassium
solvent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB2010/000333
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English (en)
Inventor
Dharmaraj Ramachandra Rao
Srinivas Laxminarayan Pathi
Rajendra Narayanrao Kankan
Philip Anthony Curtis
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cipla Ltd
Original Assignee
Cipla Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cipla Ltd filed Critical Cipla Ltd
Publication of WO2010097583A1 publication Critical patent/WO2010097583A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the present invention relates to a crystalline form of 5-methoxy-2-[(S)-[(4-methoxy-3,5- dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H-benzimidazole potassium (esomeprazole potassium), a process for its preparation and pharmaceutical compositions thereof.
  • Omeprazole chemically known as 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridinyl)methyl]sulfinyl]-1 H-benzimidazole, is a proton pump inhibitor and exists as a racemic mixture containing equal amounts of both (R) and (S)-enantiomers. As compared to a racemic mixture, (S)-enantiomer of omeprazole has shown to possess improved efficacy and hence is mostly used in pharmaceutical compositions.
  • WO2005/023797 discloses a preparation of salts of the (R)- and (S)-enantiomers of omeprazole.
  • WO98/54171 discloses a synthesis of the magnesium salt of esomeprazole trihydrate, wherein the potassium salt of esomeprazole is used as an intermediate.
  • the intermediate esomeprazole potassium which is a methanol solvate, is hereinafter designated as Form A.
  • WO2000/044744 discloses Form B characterized as being a hydrate of esomeprazole potassium, the process for its preparation and pharmaceutical compositions thereof.
  • WO2007/148213 discloses Form X of esomeprazole potassium which is crystallised using a dichloromethane solvent.
  • Form C a new crystalline form of esomeprazole potassium which is hereinafter designated as "Form C”.
  • Crystalline Form C of esomeprazole potassium is an ethanol solvate.
  • the amount of ethanol in the polymorph may range from about 5% to about 25% by weight of the esomeprazole potassium, typically from about 10% to about 20% by weight of the esomeprazole potassium. In an embodiment, the amount of ethanol in the polymorph may be about 15% by weight of the esomeprazole potassium.
  • the Form C ethanol solvate may be characterised by having an X-ray powder diffraction (XRPD) pattern comprising peaks at 13.1 and 14.0 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the XRPD pattern may further comprise peaks at 6.3, 14.8, 16.0 and 16.3 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the XRPD pattern may comprise yet further peaks at 8.0 and 12.7 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the XRPD pattern may comprise still further peaks at 18.0, 18.8, 23.0, 23.9 and 25.7 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the XRPD pattern may comprise peaks at 6.3, 8.0, 12.7, 13.1 , 14.0, 14.8, 16.0, 16.3, 18.0, 18.8, 23.0, 23.9 and 25.7 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the XRPD pattern may comprise still yet further peaks at 20.0, 24.4, 25.0, 27.0, 28.3, 29.7, 30.3 and 34.8 2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the XRPD pattern may yet further comprise peaks at 11.1 , 19.5, 22.1 , 22.4, 26.4, 28.8, 30.8, 31.9, 32.4, 32.7, 34.0, 34.4, 35.9, 36.6, 37.7, 38.7 and 39.1 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • crystalline Form C of esomeprazole potassium ethanol solvate is characterised by having an X-ray powder diffraction (XRPD) pattern comprising peaks at the °2 ⁇ positions ( ⁇ C 2 ⁇ ) as shown in Table 1.
  • XRPD X-ray powder diffraction
  • crystalline Form C of esomeprazole potassium ethanol solvate is characterised by having an X-ray powder diffraction (XRPD) pattern as shown in Figure 1.
  • crystalline Form C of esomeprazole potassium ethanol solvate is characterised by having an infrared spectrum with characteristic IR spectra peaks at about
  • crystalline Form C of esomeprazole potassium ethanol solvate is 15 characterised by having an IR spectrum as shown in Figure 2.
  • crystalline Form C of esomeprazole potassium ethanol solvate is characterized by having a DSC thermogram exhibiting a significant exothermic peak at 112.71 0 C and endothermic peak at 206.99 0 C.
  • the DSC of crystalline esomeprazole potassium Form C is shown in Figure 3.
  • crystalline Form C of esomeprazole potassium ethanol solvate has a 5 purity of greater than or equal to about 95%, preferably greater than or equal to about 99%, more preferably greater than or equal to about 99.8%.
  • the process comprises treating esomeprazole with a potassium source to obtain the esomeprazole potassium salt, dissolving the salt in a first solvent, adding ethanol to the reaction mass and isolating the crystalline Form C.
  • the process comprises concentrating the solution of the salt in the first solvent to obtain a residue, adding the ethanol to the residue, and isolating the crystalline Form C.
  • the potassium source may be selected from methanolic potassium hydroxide, ethanolic potassium hydroxide or methanolic potassium methoxide.
  • the first solvent used for dissolving esomeprazole potassium may be a polar aprotic solvent which may be selected from dichloromethane, tetrahydrofuran, acetonitrile, acetone, methyl isobutyl ketone and methyl ethyl ketone.
  • the first solvent used in the process is acetone.
  • the solution of esomeprazole potassium in the first solvent may be concentrated under vacuum to yield a residue.
  • the residue obtained on concentration may be stirred at a temperature ranging from about 20 0 C + o about 25 0 C in the ethanol.
  • the solution thus obtained is typically cooled to a temperature ranging from about O 0 C to about 10 0 C, preferably from about O 0 C to about 5 0 C.
  • the resulting solid may be dried under vacuum at a temperature ranging from about
  • the esomeprazole free base starting material may be prepared in accordance with the procedures described in WO2008/102145.
  • crystalline Form C of esomeprazole potassium prepared according to the process described above.
  • a pharmaceutical composition comprising esomeprazole potassium Form C as described above together with one or more pharmaceutically acceptable excipients.
  • esomeprazole potassium Form C described above for use in medicine, particularly for use as a gastric acid secretion suppressant.
  • esomeprazole potassium Form C described above for use in suppressing gastric acid secretion.
  • a method of suppressing gastric acid secretion comprising administering a therapeutically effective amount of esomeprazole potassium Form C described above to a patient in need thereof.
  • Figure 1 shows the powder X-ray diffractogram (XRPD) pattern of crystalline Form C of esomeprazole potassium ethanol solvate.
  • Figure 2 shows the FT-IR (KBr) spectrum of crystalline Form C of esomeprazole potassium ethanol solvate.
  • Figure 3 shows the Differential Scanning Calorimetry (DSC) thermogram of crystalline Form C of esomeprazole potassium ethanol solvate.
  • the present invention relates to a new stable polymorphic form of esomeprazole potassium which is hereinafter designated as Form C.
  • the present invention provides a process for preparing stable esomeprazole potassium Form C, having good flow characteristics, in high yield and purity.
  • the present invention provides crystalline Form C of esomeprazole potassium ethanol solvate characterized by having an XRPD pattern with d-values as listed in Table 2. In an embodiment, the present invention provides crystalline Form C of esomeprazole potassium ethanol solvate characterized by having an XRPD pattern with peaks at the °2 ⁇ positions ( ⁇ 0.2 °2 ⁇ ) as listed in Table 2.
  • the present invention provides crystalline Form C of esomeprazole0 potassium ethanol solvate characterized by having a differential scanning calorimetry thermogram exhibiting a significant exothermic peak at 112.71 0 C and endothermic peak at 206.99 0 C.
  • the DSC of Form C of esomeprazole potassium of the present invention is depicted in Figure 3. 5
  • the present invention provides a process for preparing crystalline esomeprazole potassium which comprises: (a) preparing the potassium salt of esomeprazole by treating esomeprazole with a potassium source;
  • the crystalline forms prepared according to the above process also form another aspect of the present invention.
  • the potassium source used for preparing the esomeprazole potassium salt may be selected from methanolic potassium hydroxide, ethanolic potassium hydroxide or methanolic potassium methoxide.
  • the first solvent used for dissolving esomeprazole potassium may be a polar aprotic solvent which may be selected from dichloromethane, tetrahydrofuran, acetonitrile, acetone, methyl isobutyl ketone and methyl ethyl ketone.
  • the first solvent used in the process is acetone.
  • the solution of esomeprazole potassium is concentrated under vacuum to yield the residue.
  • the process of the present invention is simple, economical and highly reproducible and provides Form C esomeprazole potassium ethanol solvate in relatively high purity of greater than or equal to about 95%, preferably greater than or equal to about 99%, more preferably greater than or equal to 99.8%.
  • Residual ethanol content - 10 - 20% (determined by gas chromatography)
  • Example 3 Toluene (125 ml) was charged followed by D-(-)-diethyl tartrate (4.75 g), titanium (IV) isopropoxide (3.25 g) and stirred for 15 minutes. To this water was charged up to 0.4% based on the moisture content of reaction mass. The reaction mass was stirred for 30 minutes at 25 - 3O 0 C to form a chiral titanium complex. Further, 5-methoxy-2-[[(4-methoxy- 3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole (25 g) was charged to the complex and the contents were heated to 7O 0 C over a period of 1 hour and maintained at 70 - 75 0 C for 30 minutes. The reaction mass was then cooled to 10 - 15 0 C, cumene hydroperoxide (28.5 g) was slowly added at 10 - 15 0 C over a period of 3 hours.
  • Residual ethanol content - 10 - 20% (determined by gas chromatography)

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un polymorphe de l'ésoméprazole de potassium appelé « Forme C », qui se trouve sous la forme d'un solvate d'éthanol. L'invention concerne également des procédés de préparation de la forme C de l'ésoméprazole de potassium et des compositions pharmaceutiques la comprenant.
PCT/GB2010/000333 2009-02-24 2010-02-24 Polymorphe de l'ésoméprazole de potassium et sa préparation Ceased WO2010097583A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN413MU2009 2009-02-24
IN413/MUM/2009 2009-02-24

Publications (1)

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WO2010097583A1 true WO2010097583A1 (fr) 2010-09-02

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111072633A (zh) * 2019-12-19 2020-04-28 山东达因海洋生物制药股份有限公司 一种埃索美拉唑镁三水合物的制备方法

Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5693818A (en) 1993-05-28 1997-12-02 Astra Aktiebolag Process for preparing pure salts of pyridinylmethyl-sulfinyl-1H-benzimidazole
WO1998054171A1 (fr) 1997-05-30 1998-12-03 Astra Aktiebolag Nouvelle forme de s-omeprazole
EP0897386A1 (fr) 1996-04-26 1999-02-24 Astra Aktiebolag Procede de preparation d'un sel de magnesium d'un heterocycle sulfinyl substitue
US5948789A (en) 1994-07-15 1999-09-07 Astra Aktiebolag Process for synthesis of substituted sulphoxides
WO2000044744A1 (fr) 1999-01-28 2000-08-03 Astrazeneca Ab Sel de potassium, de ($i(s))-omeprazole
WO2002098423A1 (fr) * 2001-06-06 2002-12-12 Cipla Limited Compose d'inclusion de s-omeprazole (esomeprazole) avec des cyclodextrines
WO2004037253A1 (fr) * 2002-10-22 2004-05-06 Ranbaxy Laboratories Limited Forme amorphe de sels d'esomeprazole
WO2005023797A1 (fr) 2003-09-04 2005-03-17 Astrazeneca Ab Nouveaux sels d'omeprazole et d'esomeprazole ii
WO2005082888A1 (fr) 2004-03-01 2005-09-09 Milen Merkez Ilac Endustrisi A.S. Procede de preparation d'un sel magnesique d'omeprazole
EP1801110A1 (fr) 2005-12-22 2007-06-27 KRKA, tovarna zdravil, d.d., Novo mesto Sel d'arginine d'ésoméprazole
WO2007142580A1 (fr) 2006-06-07 2007-12-13 Astrazeneca Ab Nouveau procédé pour préparer des sels d'ammonium d'ésoméprazole
WO2007148213A2 (fr) 2006-06-21 2007-12-27 Glenmark Pharmaceuticals Limited Nouveau polymorphe de potassium d'ésoméprazole
EP1885711A1 (fr) 2005-05-06 2008-02-13 Glenmark Pharmaceuticals Limited Sel de strontium d'esomeprazole, procede de preparation de ce sel et compositions pharmaceutiques le contenant
EP1919897A1 (fr) 2005-07-28 2008-05-14 Hanmi Pharm. Co., Ltd. Procede de preparation d'esomeprazole et de ses sels
WO2008102145A2 (fr) 2007-02-21 2008-08-28 Cipla Limited Procédé pour la préparation de ésoméprazole magnésium dihydraté
EP2000468A1 (fr) 2007-05-09 2008-12-10 Dr. Reddy's Laboratories Ltd. Sels d'ésoméprazole et procédés pour leur préparation
WO2009027614A2 (fr) * 2007-08-29 2009-03-05 Universite De Rouen Procede de dedoublement de sels de l'omeprazole

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5693818A (en) 1993-05-28 1997-12-02 Astra Aktiebolag Process for preparing pure salts of pyridinylmethyl-sulfinyl-1H-benzimidazole
US5948789A (en) 1994-07-15 1999-09-07 Astra Aktiebolag Process for synthesis of substituted sulphoxides
EP0897386A1 (fr) 1996-04-26 1999-02-24 Astra Aktiebolag Procede de preparation d'un sel de magnesium d'un heterocycle sulfinyl substitue
WO1998054171A1 (fr) 1997-05-30 1998-12-03 Astra Aktiebolag Nouvelle forme de s-omeprazole
WO2000044744A1 (fr) 1999-01-28 2000-08-03 Astrazeneca Ab Sel de potassium, de ($i(s))-omeprazole
WO2002098423A1 (fr) * 2001-06-06 2002-12-12 Cipla Limited Compose d'inclusion de s-omeprazole (esomeprazole) avec des cyclodextrines
WO2004037253A1 (fr) * 2002-10-22 2004-05-06 Ranbaxy Laboratories Limited Forme amorphe de sels d'esomeprazole
WO2005023797A1 (fr) 2003-09-04 2005-03-17 Astrazeneca Ab Nouveaux sels d'omeprazole et d'esomeprazole ii
WO2005082888A1 (fr) 2004-03-01 2005-09-09 Milen Merkez Ilac Endustrisi A.S. Procede de preparation d'un sel magnesique d'omeprazole
EP1885711A1 (fr) 2005-05-06 2008-02-13 Glenmark Pharmaceuticals Limited Sel de strontium d'esomeprazole, procede de preparation de ce sel et compositions pharmaceutiques le contenant
EP1919897A1 (fr) 2005-07-28 2008-05-14 Hanmi Pharm. Co., Ltd. Procede de preparation d'esomeprazole et de ses sels
EP1801110A1 (fr) 2005-12-22 2007-06-27 KRKA, tovarna zdravil, d.d., Novo mesto Sel d'arginine d'ésoméprazole
WO2007142580A1 (fr) 2006-06-07 2007-12-13 Astrazeneca Ab Nouveau procédé pour préparer des sels d'ammonium d'ésoméprazole
WO2007148213A2 (fr) 2006-06-21 2007-12-27 Glenmark Pharmaceuticals Limited Nouveau polymorphe de potassium d'ésoméprazole
WO2008102145A2 (fr) 2007-02-21 2008-08-28 Cipla Limited Procédé pour la préparation de ésoméprazole magnésium dihydraté
EP2000468A1 (fr) 2007-05-09 2008-12-10 Dr. Reddy's Laboratories Ltd. Sels d'ésoméprazole et procédés pour leur préparation
WO2009027614A2 (fr) * 2007-08-29 2009-03-05 Universite De Rouen Procede de dedoublement de sels de l'omeprazole

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111072633A (zh) * 2019-12-19 2020-04-28 山东达因海洋生物制药股份有限公司 一种埃索美拉唑镁三水合物的制备方法

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