WO2007065534A1 - Procede de recuperation d'iopromide a usage pharmaceutique a partir d'eaux meres - Google Patents

Procede de recuperation d'iopromide a usage pharmaceutique a partir d'eaux meres Download PDF

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Publication number
WO2007065534A1
WO2007065534A1 PCT/EP2006/010943 EP2006010943W WO2007065534A1 WO 2007065534 A1 WO2007065534 A1 WO 2007065534A1 EP 2006010943 W EP2006010943 W EP 2006010943W WO 2007065534 A1 WO2007065534 A1 WO 2007065534A1
Authority
WO
WIPO (PCT)
Prior art keywords
lopromide
pharmaceutical purposes
flow tube
mother liquors
crystallization
Prior art date
Application number
PCT/EP2006/010943
Other languages
German (de)
English (en)
Inventor
Hartmut Kagerer
Meike Dembeck
Hartmut Seba
Ingo Ortmann
Original Assignee
Bayer Schering Pharma Aktiengesellschaft
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
Priority claimed from DE200510059191 external-priority patent/DE102005059191B4/de
Application filed by Bayer Schering Pharma Aktiengesellschaft filed Critical Bayer Schering Pharma Aktiengesellschaft
Priority to EP06818545A priority Critical patent/EP1960348A1/fr
Priority to JP2008543678A priority patent/JP2009518325A/ja
Priority to CA2630413A priority patent/CA2630413C/fr
Publication of WO2007065534A1 publication Critical patent/WO2007065534A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B63/00—Purification; Separation; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and at least three atoms of bromine or iodine, bound to carbon atoms of the same non-condensed six-membered aromatic ring

Definitions

  • the invention relates to a process for the recovery of lopromide suitable for pharmaceutical purposes by thermal treatment of the mother liquors or the dissolved second crystallizate in a reactor and subsequent crystallization.
  • the two atropisomeric compounds differ in their physical properties, especially in their solubilities in water and organic solvents.
  • Only lopromide of a certain composition with regard to these atropisomers is approved as an X-ray contrast medium (40-51% isomer 1 and 49-60% isomer 2).
  • Cleaning processes for iodinated X-ray contrast media, such as lopamidol, are known from the prior art, see EP 1 025 067 B1 and GB 2 280 436. Crystallizations at elevated temperatures are described therein.
  • the document WO 2004 031 110 A2 discloses the isomerization of chiral compounds by thermal treatment. However, these procedures do not involve the treatment of lopromide mother liquors.
  • Iopromide for pharmaceutical purposes is obtained by crystallization from ethanol. This regularly results in a mixture consisting of approx. 48% isomer 1 and approx. 52% isomer 2.
  • the mother liquor contains about 60% of isomer 1 and only about 40% of isomer 2. For this reason, only a second crystallizate with the wrong composition regarding the atropisomers can be obtained from the mother liquor (contains too much isomer 1).
  • the disadvantages described above could surprisingly be solved by first obtaining a K2 from the lopromide, pure mother liquors by means of a suitable second crystallization, which then a suitable thermal treatment is isomerized in a continuous flow tube reactor according to the specification without significant decomposition of the substance.
  • the invention thus includes a method for recovering suitable for pharmaceutical purposes iopromide aud lopromidmutterlaugen or solutions of the second and Vietnamesekristallisats by thermal treatment of the solution, preferably in a flow tube reactor at 100-300 0 C, advantageously at 200-220 0 C, and then rapid cooling to room temperature and crystallization.
  • the thermal treatment in a flow reactor is advantageously carried out in aqueous solution with hydrodynamic residence times of 1 to 60 minutes.
  • the particular embodiments are listed in the claims.
  • the total yield of lopromide can be increased purely significantly by this method according to the invention, so that the economy increases. In addition, there is less halogen-containing waste.
  • a second crystallizate is first applied from the lopromide, pure mother liquors, by concentrating the ethanolic mother liquors by a factor of 2-16 and dissolving them in an alcohol at elevated temperature.
  • suitable alcohols are alkanols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol.
  • Ethanol, 1-propanol and 2-propanol are preferably used, particularly preferably 1-propanol, since the crystallization takes place particularly quickly and completely from this solvent and thus saves costs.
  • To initiate the crystallization can be inoculated with lopromid, pure. The K2 crystals are then isolated, washed and dried by known methods.
  • the second crystallizate obtained from the mother liquor has the following
  • the applied second crystallizate is then brought into solution, ie dissolved in water and thermally isomerized in a pressure-resistant, suitably designed, continuously operated tubular reactor.
  • hydrodynamic residence times of 1 to 60 minutes, preferably 1-30 minutes, more preferably 1 to 10 minutes at temperatures between 100 to 300 0 C, preferably from 150 0 C to 250 ° C, preferably from 180 0 C to 230 0 C, particularly preferably set from 200 ° C. to 220 ° C.
  • the thermally treated lopromid K2 solution is then rapidly cooled to room temperature in a downstream heat exchanger.
  • Iopromid-K2 from Example 1 280 g of Iopromid-K2 from Example 1 are dissolved in 520 g of water. The solution is then at a flow rate of 3 ml / min, by using a pressure retaining valve 20 bar provided flow tube at 208 - 209 0 C pumped.
  • the flow tube used has an inner diameter of 1.7526 mm and a heated length of 5.5 m (see Fig. 1).
  • a solution of the isomerized lopromide second crystallizate is then purified over ion exchange columns and crystallized from ethanol.
  • the yield of the lopromide crystallized from ethanol, based on the second crystallizate used in the isomerization, is 80% of.
  • the crystals show a content according to HPLC (standard method) of greater than 97.5% compared to external standards and have the following atropisomer ratio:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne un procédé de récupération d'iopromide à usage pharmaceutique par traitement thermique des eaux mères ou du produit de cristallisation secondaire dans un réacteur puis par cristallisation.
PCT/EP2006/010943 2005-12-05 2006-11-10 Procede de recuperation d'iopromide a usage pharmaceutique a partir d'eaux meres WO2007065534A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP06818545A EP1960348A1 (fr) 2005-12-05 2006-11-10 Procede de recuperation d'iopromide a usage pharmaceutique a partir d'eaux meres
JP2008543678A JP2009518325A (ja) 2005-12-05 2006-11-10 医薬目的のために適切なイオプロミドの母液からの回収方法
CA2630413A CA2630413C (fr) 2005-12-05 2006-11-10 Procede de recuperation d'iopromide, a partir de solution-mere, convenant a des fins pharmaceutiques

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE200510059191 DE102005059191B4 (de) 2005-12-05 2005-12-05 Verfahren zur Rückgewinnung von für pharmazeutische Zwecke geeignetem Iopromid aus Mutterlaugen
DE102005059191.4 2005-12-05
US74817505P 2005-12-08 2005-12-08
US60/748,175 2005-12-08

Publications (1)

Publication Number Publication Date
WO2007065534A1 true WO2007065534A1 (fr) 2007-06-14

Family

ID=37773154

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2006/010943 WO2007065534A1 (fr) 2005-12-05 2006-11-10 Procede de recuperation d'iopromide a usage pharmaceutique a partir d'eaux meres

Country Status (5)

Country Link
EP (1) EP1960348A1 (fr)
JP (1) JP2009518325A (fr)
KR (1) KR20080073369A (fr)
CA (1) CA2630413C (fr)
WO (1) WO2007065534A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110245347A1 (en) * 2008-12-05 2011-10-06 Daewoong Pharmaceutical Co., Ltd. Method for selectively crystallizing a z isomer of iopromide

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0015867A1 (fr) * 1979-03-08 1980-09-17 Schering Aktiengesellschaft Diamides d'acides triiodo-isophtaliques, leur préparation et agents de contraste radiographiques les contenant
WO1999018054A1 (fr) * 1997-10-02 1999-04-15 Nycomed Imaging As Procede de cristallisation de composes steriquement encombres

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0015867A1 (fr) * 1979-03-08 1980-09-17 Schering Aktiengesellschaft Diamides d'acides triiodo-isophtaliques, leur préparation et agents de contraste radiographiques les contenant
WO1999018054A1 (fr) * 1997-10-02 1999-04-15 Nycomed Imaging As Procede de cristallisation de composes steriquement encombres

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110245347A1 (en) * 2008-12-05 2011-10-06 Daewoong Pharmaceutical Co., Ltd. Method for selectively crystallizing a z isomer of iopromide
CN102239135A (zh) * 2008-12-05 2011-11-09 大熊制药株式会社 选择性地结晶碘普罗胺的z异构体的方法
JP2012510510A (ja) * 2008-12-05 2012-05-10 ダエウン ファーマシューティカル カンパニー リミテッド イオプロミドのｚ異性体を選択的に結晶化する方法
RU2481325C2 (ru) * 2008-12-05 2013-05-10 Даевунг Фармасьютикал Ко., Лтд. Способ селективной кристаллизации z-изомера иопромида
US8541620B2 (en) * 2008-12-05 2013-09-24 Daewoong Pharmaceutical Co., Ltd. Method for selectively crystallizing a Z isomer of iopromide

Also Published As

Publication number Publication date
KR20080073369A (ko) 2008-08-08
JP2009518325A (ja) 2009-05-07
CA2630413A1 (fr) 2007-06-14
EP1960348A1 (fr) 2008-08-27
CA2630413C (fr) 2013-06-25

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