EP2240496A2 - Préparation de magnésium d ésoméprazole et de ses hydrates - Google Patents

Préparation de magnésium d ésoméprazole et de ses hydrates

Info

Publication number
EP2240496A2
EP2240496A2 EP09709236A EP09709236A EP2240496A2 EP 2240496 A2 EP2240496 A2 EP 2240496A2 EP 09709236 A EP09709236 A EP 09709236A EP 09709236 A EP09709236 A EP 09709236A EP 2240496 A2 EP2240496 A2 EP 2240496A2
Authority
EP
European Patent Office
Prior art keywords
esomeprazole magnesium
esomeprazole
solvent
magnesium
trihydrate
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.)
Withdrawn
Application number
EP09709236A
Other languages
German (de)
English (en)
Other versions
EP2240496A4 (fr
Inventor
Vijaya Bhaskar Bolugoddu
Venkata Annapurna Sasikala Cheemalapati
Siva Prasad Reddy Seerapu
Ravi Ram Chandrasekhar Elati
Surya Narayana Devarakonda
Sesha Reddy Yerraguntla
Ujjwal Kedia
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.)
Dr Reddys Laboratories Ltd
Dr Reddys Laboratories Inc
Original Assignee
Dr Reddys Laboratories Ltd
Dr Reddys Laboratories Inc
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 Dr Reddys Laboratories Ltd, Dr Reddys Laboratories Inc filed Critical Dr Reddys Laboratories Ltd
Publication of EP2240496A2 publication Critical patent/EP2240496A2/fr
Publication of EP2240496A4 publication Critical patent/EP2240496A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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

Definitions

  • the present application relates to processes for the preparation of crystalline esomeprazole magnesium hydrates.
  • Esomeprazole magnesium is bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2- pyridinyl)methyl]sulfinyl]-1 H-benzimidazole-1-yl)magnesium trihydrate, and has the structure of Formula (I).
  • Esomeprazole magnesium and its hydrates are useful in inhibiting gastric acid secretion.
  • U.S. Patent No. 6,262,085 discloses a process for the preparation of the magnesium salt of S-omeprazole using magnesium metal, methanol, and a catalytic amount of methylene dichloride.
  • U.S. Patent No. 6,369,085 discloses a form of the magnesium salt of the S- enantiomer of omeprazole trihydrate. This patent also discloses processes for preparing that form of the S-omeprazole magnesium salt.
  • U.S. Patent No. 6,747,155 discloses a process for the preparation of the magnesium salt of esomeprazole trihydrate. The '155 patent also discloses a process for the preparation of esomeprazole magnesium dihydrate Form A and Form B.
  • U.S. 6,894,066 discloses a process for producing the magnesium salt of S- omeprazole with varying percents of crystallinity and varying amounts of residual solvents in the solid.
  • U.S. Patent Application Publication No. 2007/0259921 discloses processes for the preparation of different crystalline forms of esomeprazole sodium and a crystalline form of esomeprazole magnesium. There still exists a need of a commercially viable processes for making crystalline esomeprazole magnesium hydrates, more particularly the dihydrate and trihydrate forms.
  • the present invention includes processes for the preparation of crystalline esomeprazole magnesium trihydrate, which processes comprise at least one of the steps of:
  • the present invention includes processes for the preparation of esomeprazole magnesium dehydrate and, in particular, Form B thereof, which processes comprise at least one of the steps of:
  • the present invention includes esomeprazole magnesium dihydrate Form B having a degree of crystallinity of about 70% or less, or in the range of from about 20% to about 70%, or in the range of from about 45% to about 70%.
  • the present invention includes micronized esomeprazole magnesium dihydrate
  • the micronized esomeprazole magnesium dihydrate Form B may be produced in an air-jet miller.
  • the present invention includes a process for analysing the particle size of esomeprazole magnesium dihydrate Form B.
  • the present invention includes pharmaceutical compositions comprising esomeprazole magnesium dihydrate Form B and at least one pharmaceutically acceptable excipient.
  • Fig. 1 is an X-ray powder diffraction (XRPD) pattern of crystalline esomeprazole magnesium trihydrate.
  • Fig. 2 is an X-ray powder diffraction (XRPD) pattern of crystalline esomeprazole magnesium dihydrate Form B.
  • This document may refer to a material, such as in this instance, esomeprazole and its salts, crystalline forms, solvates, or optical isomers by reference to patterns, spectra, or other graphical data "substantially” as shown in a Figure, or by one or more data points.
  • patterns, spectra, and other graphical data can be shifted in their positions, relative intensities, and/or values due to a number of factors known to those of skill in the art.
  • such shifts in peak positions or the relative intensities of one or more peaks can occur because of, without limitation: the equipment used, the sample preparation protocol, preferred packing and orientations, the radiation source, operator error, method and length of data collection, and the like.
  • those of ordinary skill in the art should be able to compare the figures herein with a pattern generated of an unknown form of, in this case, esomeprazole, and confirm its identity as one of the forms disclosed and claimed herein. The same holds true for other techniques that may be reported herein.
  • Crystalline forms may be characterized by such analytical methods as X-ray powder diffraction ("XRPD”) pattern, differential scanning calorimetry (“DSC”) curves, and thermogravimetric analysis (“TGA”) curves.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • the present invention includes processes for the preparation of crystalline esomeprazole magnesium trihydrate, which processes comprise at least one of the steps of:
  • Step (a) involves providing a solution comprising esomeprazole and a solvent comprising at least about 80% water.
  • the solvent system may comprise 100% water.
  • the solution may be prepared at a temperature ranging from about 15°C to about 45°C.
  • Step (b) involves adding a magnesium salt to the solution to precipitate esomeprazole magnesium.
  • magnesium salt leads to precipitation of esomeprazole magnesium that is less soluble in water than esomeprazole sodium.
  • Suitable magnesium salts include and are not limited to magnesium sulphate.
  • the magnesium salt may be added as solid crystals or a solution in a solvent such as, for example, water, methanol, and the like.
  • the mode of addition may be by dumping, slow addition, lot wise addition, or fast addition.
  • the temperature for addition and reaction may range from between 15°C to 45°C.
  • the mass may be maintained at a temperature from about 15°C to about 45°C for a time period from about 30 minutes to about 5 hours, preferably with concurrent stirring, to facilitate complete precipitation of esomeprazole magnesium.
  • Step (c) involves isolating the precipitated esomeprazole magnesium.
  • the precipitated solid may be collected by various methods, such as, for example, gravity filtration suction, centrifugation, and the like.
  • the crystals so isolated may carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired, the crystals may be washed on the filter with a solvent to wash out the mother liquor.
  • Step (d) involves drying the isolated, precipitated esomeprazole magnesium.
  • the wet cake obtained in Step (c) may be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, and the like.
  • Drying may be carried out at a temperature from about 25 0 C to about 60 0 C under atmospheric pressure or reduced pressure, e.g., about 200 mmHg to about 300 mmHg. Drying may be carried out for any desired time ranging from about 30 minutes to about
  • the present invention includes processes for the preparation of Form B of esomeprazole magnesium dihydrate, which processes comprise at least one of the steps of:
  • Step (a) involves providing a solution comprising esomeprazole magnesium trihydrate and an alcoholic solvent.
  • the esomeprazole magnesium trihydrate may be prepared according to the processes of the present invention described hereinabove.
  • a solution of esomeprazole magnesium trihydrate may be prepared by dissolution thereof in any alcoholic solvent, such as, for example, methanol, ethanol, isopropanol, n-propanol, n-butanol, and tertiary-butyl alcohol; or mixtures thereof.
  • the solution may comprise esomeprazole magnesium trihydrate and methanol.
  • a suitable temperature for dissolution of esomeprazole magnesium trihydrate may range from about 15°C to about 45 0 C. Stirring may be carried out for a desired time periods ranging from 30 minutes to about 5 hours to achieve complete dissolution.
  • Step (b) involves adding an anti-solvent to the solution to precipitate esomeprazole magnesium dihydrate.
  • the anti-solvent may be any suitable organic solvent. Suitable anti-solvents include and are not limited to: ketones, such as, for example, acetone, ethyl methyl ketone, methyl isobutyl ketone, and tert-butyl ketone; esters, such as, for example, ethyl acetate and propyl acetate; or mixtures thereof.
  • the anti-solvent may be acetone or ethylacetate.
  • Fast addition means charging the anti-solvent to the reaction mass over a period of time that is less than about 30 minutes, or less than about 20 minutes, or less than about 15 minutes.
  • Form B of esomeprazole magnesium dihydrate may be obtained by removing the solvent of Step (a) and adding an anti-solvent.
  • the removal of the solvent may be accomplished by techniques, such as distillation either under vacuum or without vacuum.
  • a suitable temperature for evaporation of the solvent may be from about 2O 0 C to about 65 0 C.
  • a suitable time for evaporation of the solvent may be any desired time periods for about 30 minutes to about 10 hours or longer to achieve the desired product yield and purity.
  • Step (c) involves isolating the precipitated esomeprazole magnesium dihydrate.
  • the method by which the solid material is isolated from the final mixture, with or without cooling below the operating temperature may be any of techniques such as filtration by gravity, or by suction, centrifugation, and the like.
  • the crystals so isolated will carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired the crystals may be washed on the filter with a solvent to wash out the mother liquor.
  • Step (d) involves drying the isolated, precipitated esomeprazole magnesium dihydrate.
  • the wet cake obtained in step (d) may be dried. Drying may be suitably carried out in an air tray drier, vacuum oven, air oven, fluidized bed drier, spin flash drier, flash dryer and the like. Drying may be carried out at temperatures of from about 25°C to about 60 0 C under the reduced pressure of 200 mmHg to 300 mmHg. Drying may be carried out for any desired time until the required product purity is achieved, time periods from about 1 to about 30 hours. Preferably in an air tray drier at about 50 0 C for about 10 hours.
  • a process for the conversion of amorphous esomeprazole magnesium to crystalline esomeprazole magnesium dihydrate which process includes the steps of; (a) stirring amorphous esomeprazole magnesium in acetone for an optimum time; (b) collecting the solid; (c) drying the solid; (d) stirring the dried solid in mixture of methanol and ethyl acetate; (e) collecting the solid and; (f) drying the solid.
  • An embodiment of the present application provides esomeprazole magnesium dihydrate Form B with particle size distribution D 90 equal to or less than about 10 ⁇ m, 7.5 ⁇ m, or 5.0 ⁇ m.
  • a pharmaceutical composition may include one or more excipients that may, for example, enhance the stability, bioavailability, and the ease of use of the pharmaceutical composition.
  • the excipients may be solid, semisolid, or liquid and may be formulated with the compound in bulk form.
  • Esomeprazole magnesium of the present invention may be used in pharmaceutical compositions that may be contemplated in various formulations suitable for various modes of administration, including and not limited to inhalation, oral, rectal, parental, and intravenous.
  • the process of the present invention is cost effective, eco-friendly, and commercially suitable, to get a stable crystalline form of esomeprazole magnesium which is free flowing and directly compressible into stable pharmaceutical formulations.
  • Demineralized water (300 ml) and esomeprazole sodium (50 g) are charged into a round-bottom flask and the contents are stirred for a clear solution.
  • magnesium sulphate (26.9 g) (dissolved in demineralised water (200 ml)) is added at about 25°C to 35°C. Solid separation may be observed during addition.
  • the reaction mass is stirred for about 2 hours at 25°C to 30 0 C.
  • the solid is filtered and washed with demineralized water (300 ml).
  • the wet cake obtained is dried at about 50°C under vacuum for about 20 hours to afford 45 g of esomeprazole magnesium trihydrate.
  • Amorphous esomeprazole magnesium (10 g) and acetone (100 ml) are charged into a round-bottom flask and stirred for about 2 hours at about 25°C to about 35 0 C.
  • the solid is filtered, washed with acetone (200 ml), and dried for about 5 hours at about 5O 0 C.
  • the dried solid is charged in a round-bottom flask containing methanol (10 ml) and ethyl acetate (90 ml) and stirred for about 2 hours.
  • the separated solid is filtered and washed with ethyl acetate (20 ml).
  • the wet cake is dried in a rotary evaporator at about 5O 0 C under vacuum for about 8 hours to afford 7 g of esomeprazole magnesium dihydrate form B.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Cette invention concerne des procédés de préparation de magnésium d’ésoméprazole cristallisé dihydraté et/ou trihydraté. L’invention concerne la forme B d’ésoméprazole de magnésium dihydraté ayant un degré de cristallinité d’environ 70 % ou moins. L’invention concerne la forme B du magnésium d’ésoméprazole dihydraté micronisé d’une répartition granulométrique D90 égale ou inférieure à environ 10 µm.
EP09709236A 2008-02-01 2009-01-30 Préparation de magnésium d ésoméprazole et de ses hydrates Withdrawn EP2240496A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IN285CH2008 2008-02-01
US5993708P 2008-06-09 2008-06-09
PCT/US2009/032600 WO2009099933A2 (fr) 2008-02-01 2009-01-30 Préparation de magnésium d’ésoméprazole et de ses hydrates

Publications (2)

Publication Number Publication Date
EP2240496A2 true EP2240496A2 (fr) 2010-10-20
EP2240496A4 EP2240496A4 (fr) 2011-05-11

Family

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Family Applications (1)

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EP09709236A Withdrawn EP2240496A4 (fr) 2008-02-01 2009-01-30 Préparation de magnésium d ésoméprazole et de ses hydrates

Country Status (2)

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EP (1) EP2240496A4 (fr)
WO (1) WO2009099933A2 (fr)

Families Citing this family (4)

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Publication number Priority date Publication date Assignee Title
CN102285970B (zh) * 2011-09-21 2014-07-23 石药集团欧意药业有限公司 一种埃索美拉唑化合物、制备方法及其药物组合物
CN103214458B (zh) * 2012-01-19 2015-04-22 上海汇伦生命科技有限公司 一种埃索美拉唑镁二水合物的制备方法
US9011882B2 (en) * 2012-02-14 2015-04-21 The Board Of Trustees Of The Leland Stanford Junior University Dimethylarginine dimethylaminohydrolase inhibitors and methods of use thereof
CN104610227A (zh) * 2015-01-08 2015-05-13 浙江亚太药业股份有限公司 一种埃索美拉唑镁多晶型化合物的高压水热制备法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007031845A2 (fr) * 2005-09-14 2007-03-22 Glenmark Pharmaceuticals Limited Formes polymorphiques de sels de magnesium de (s)-omeprazole et procedes de preparation desdites formes
WO2009047775A2 (fr) * 2007-10-08 2009-04-16 Hetero Drugs Limited Polymorphes de sels de l'ésoméprazole

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE510650C2 (sv) * 1997-05-30 1999-06-14 Astra Ab Ny förening
WO2004046134A2 (fr) * 2002-11-18 2004-06-03 Dr. Reddy's Laboratories Limited Composes d'esomeprazole cristallins et procede permettant de preparer ces composes
US20050267159A1 (en) * 2004-05-28 2005-12-01 Aaipharma, Inc. Magnesium complexes of S-omeprazole
US20080249134A1 (en) * 2004-06-24 2008-10-09 Ursula Hohlneicher New Esomeprazole Sodium Salt Crystal Modification

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007031845A2 (fr) * 2005-09-14 2007-03-22 Glenmark Pharmaceuticals Limited Formes polymorphiques de sels de magnesium de (s)-omeprazole et procedes de preparation desdites formes
WO2009047775A2 (fr) * 2007-10-08 2009-04-16 Hetero Drugs Limited Polymorphes de sels de l'ésoméprazole

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO2009099933A2 *

Also Published As

Publication number Publication date
WO2009099933A2 (fr) 2009-08-13
EP2240496A4 (fr) 2011-05-11
WO2009099933A3 (fr) 2009-10-15

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