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EP1773778A1 - Procede pour isoler des formes cristallines de la torasemide - Google Patents

Procede pour isoler des formes cristallines de la torasemide

Info

Publication number
EP1773778A1
EP1773778A1 EP05763057A EP05763057A EP1773778A1 EP 1773778 A1 EP1773778 A1 EP 1773778A1 EP 05763057 A EP05763057 A EP 05763057A EP 05763057 A EP05763057 A EP 05763057A EP 1773778 A1 EP1773778 A1 EP 1773778A1
Authority
EP
European Patent Office
Prior art keywords
crystal form
crystals
torsemide
preparation
ethanol
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Withdrawn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
EP05763057A
Other languages
German (de)
English (en)
Inventor
Stefan Welzig
Anton Gerdenitsch
Peter KÜHNHACKL
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.)
Sanochemia Pharmazeutika AG
Original Assignee
Sanochemia Pharmazeutika AG
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 Sanochemia Pharmazeutika AG filed Critical Sanochemia Pharmazeutika AG
Publication of EP1773778A1 publication Critical patent/EP1773778A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus

Definitions

  • the invention relates to a process for Reindar ⁇ position of the crystal form 1 of polymorphic crystalline Torsemid, in which Torsemid is dissolved in an ethanol-water mixture with heating, whereupon subsequently cooled and dried after separation of the crystals.
  • Torsemide (1-isopropyl-3- [(4-m-toluidino-3-pyridyl) sulfonyl] urea, also described in the literature as torasemide, is a known compound with interesting pharmacological properties Therefore, the active ingredient is advantageously used in the production of pharmaceutical preparations which are to be administered as diuretics.
  • torasemide exists in various crystal forms. Dupont, L., Campestone, H., Lamotte, J. & Vermeire, M. (1978) Structure of a seconde variete de Ia torasemide, Acta Cryst. B34, pages 2659 to 2662 it can be seen that torasemide can be present in at least two crystal forms, which differ from one another by X-ray crystallography. The two crystal forms arise according to this reference next to each other, if a solution of torasemide in petroleum ether ethanol is evaporated. In the crystallographic distinction, a crystal form 1 was described which crystallizes monoclinically in the space group P2 ⁇ / c.
  • crystal form 2 Another crystal form, which was designated as crystal form 2, crystallizes monoclinically in the space group P2 / n.
  • the crystallographic data for elementary cells in both cases gave measured values of ⁇ and ⁇ of 90 °.
  • the crystal form 1 was determined to have an angle ⁇ of 107 °, whereas the crystal form 2 gave an angle ⁇ of the unit cells of almost 109 °.
  • the edge lengths of the unit cells could be clearly differentiated from each other. The two forms of crystallization are thus clearly distinguishable from each other, as has also been described in the literature.
  • crystal form 1 or 2 and modification 1 or 2 are not necessarily synonymous, as described in Rollinger, Judith Maria et al., "Crystal forms of torasemide: new insights” Europ. of Phrmaceutics and Biopharmaceutics 53 (2002) 75-85.
  • the invention now aims to provide a Ver ⁇ drive, with which it It is possible, under particularly mild conditions, to produce torsemide of the crystal form 1 in high purity, avoiding impurities such as, for example, the carbamates or decomposition products resulting from prolonged thermal stress.
  • the process according to the invention consists essentially in the fact that the drying is carried out under simultaneous mechanical loading of the crystals, for example in a paddle dryer, wherein crystals of the crystal form 2 are transferred to the crystal form 1.
  • the separated crystals which are mostly crystals of the crystal form 2 or represent mixtures of the crystals 2 and 1, are now dried under simultaneous mechanical loading of the crystals.
  • This mechanical stress on the crystals during drying now leads to a rearrangement of the crystals of the crystal form 2 in crystals of the crystal form 1 and overall to a final product with substantially greater purity than by direct production of the crystal form I without the detour via the preparation of the crystal form 2 would be possible.
  • This is substantially further improved if, as proposed according to a preferred procedure, before the formation of the pure crystal form 2, ie before the crystallization, a mechanical solids separation, in particular filtration vor ⁇ is taken.
  • the inventively proposed pure production of the crystal form 2 leads to the corresponding mechanical stress in the further drying to a rearrangement in the crystal form 1, with regard to the previously shown purely pure crystal form 2 in this rearrangement directly not otherwise achievable purity of the recrystallized or rearranged to the pure crystal form 1 crystals of torasemide is achieved.
  • the process according to the invention advantageously becomes so is carried out such that the heating is carried out at temperatures up to the reflux temperature over a period of less than 30 minutes, preferably 10 to 20 minutes. It is thus achieved a total solution by the choice of an ethanol-water mixture with the appropriate suitability torsemide at much shorter times and thus set the thermal load herab ⁇ significantly.
  • mixtures in which ethanol and water have a mass ratio of 55:45 (volume ratio about 60:40) with a maximum deviation of the respective proportions from one to the other have proven to be particularly advantageous as ethanol-water mixture 15% by mass.
  • Such ethanol-water mixtures presumably lead to the formation of Chlatraten and allow crystallization of exceedingly pure crystals of the crystal form 2 of Torsemids.
  • the limitation of the solution process carried out at elevated temperature to 10 to 20 minutes represents a particularly gentle treatment, where appropriate, insoluble decomposition products or even torsemide of the crystal form 1, which dissolves relatively poorly, can be separated before seeding with seed crystals of pure crystal form 2.
  • the process according to the invention is carried out in such a way that, for the preparation of the pure crystal form 2, cooling takes place with a temperature gradient of 0.2 to 1 ° C./min, preferably 0.4 ° / min to 0.6 ° / min Temperatures below 40 ° C, preferably about 20 ° C, made, whereby the thermal load can be further reduced.
  • the preparation of the pure crystal form 2 of the torsemide is preferably proceeded so that immediately before or when reaching the saturation temperature, in particular between 70 ° and 60 ° C, on cooling the solution seed crystals of the crystal form 2 are added, wherein, as already mentioned, with Advantage before the addition of the seed crystals, a mechanical solids separation, in particular filtration, is made. After separation of the crystals from the liquid phase, drying under subatmospheric pressure can be carried out, thereby avoiding further thermal stresses.
  • the drying was carried out in a paddle dryer.
  • the mechanical stress in the drying at 40 0 C to 80 ° C resulted in complete conversion to the crystal form 1, wherein crystallographically the amount of crystal form 2 was below the detection limit.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Hematology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Obesity (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

L'invention concerne un procédé pour isoler la forme cristalline 1 de la torasémide cristalline polymorphe. Ce procédé consiste : à dissoudre la torasémide dans un mélange éthanol-eau, ce qui génère de la chaleur, puis ; à refroidir la solution et à la sécher après la séparation des cristaux. Cette invention est caractérisée en ce que le séchage est effectué dans un séchoir à aubes, par exemple, tandis que les cristaux sont soumis à des contraintes mécaniques, les cristaux de la forme cristalline 2 étant transformés en cristaux de la forme cristalline 1.
EP05763057A 2004-07-28 2005-07-28 Procede pour isoler des formes cristallines de la torasemide Withdrawn EP1773778A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AT0129304A AT500576B1 (de) 2004-07-28 2004-07-28 Verfahren zur reindarstellung von kristallformen von torsemid
PCT/AT2005/000299 WO2006010189A1 (fr) 2004-07-28 2005-07-28 Procede pour isoler des formes cristallines de la torasemide

Publications (1)

Publication Number Publication Date
EP1773778A1 true EP1773778A1 (fr) 2007-04-18

Family

ID=35106999

Family Applications (1)

Application Number Title Priority Date Filing Date
EP05763057A Withdrawn EP1773778A1 (fr) 2004-07-28 2005-07-28 Procede pour isoler des formes cristallines de la torasemide

Country Status (12)

Country Link
US (1) US20070260068A1 (fr)
EP (1) EP1773778A1 (fr)
JP (1) JP2008507568A (fr)
CN (1) CN101056856A (fr)
AT (1) AT500576B1 (fr)
AU (1) AU2005266828A1 (fr)
CA (1) CA2575283A1 (fr)
MX (1) MX2007001074A (fr)
NO (1) NO20070856L (fr)
RU (1) RU2007103177A (fr)
WO (1) WO2006010189A1 (fr)
ZA (1) ZA200701438B (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102432532B (zh) * 2011-11-10 2014-06-18 天津市汉康医药生物技术有限公司 高纯度托拉塞米化合物
CN104370805B (zh) * 2013-08-13 2016-09-07 天津汉瑞药业有限公司 托拉塞米化合物
CN115417810B (zh) * 2022-09-22 2023-10-10 南京正科医药股份有限公司 一种托拉塞米晶型ⅰ的精制方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3529529A1 (de) * 1985-08-17 1987-02-19 Boehringer Mannheim Gmbh Verfahren zur herstellung einer stabilen modifikation von torasemid
US6166045A (en) * 1998-06-02 2000-12-26 Roche Diagnostics Gmbh Torasemide of modification III
KR20020025217A (ko) * 1999-08-11 2002-04-03 추후보정 토르세미드 동질이상

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006010189A1 *

Also Published As

Publication number Publication date
AT500576B1 (de) 2006-11-15
AU2005266828A1 (en) 2006-02-02
NO20070856L (no) 2006-04-19
AT500576A1 (de) 2006-02-15
RU2007103177A (ru) 2008-08-10
US20070260068A1 (en) 2007-11-08
MX2007001074A (es) 2007-04-19
CN101056856A (zh) 2007-10-17
CA2575283A1 (fr) 2006-02-02
JP2008507568A (ja) 2008-03-13
ZA200701438B (en) 2008-06-25
WO2006010189A1 (fr) 2006-02-02

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