WO1997002235A1 - A process for preparing iopamidol by using a c1-c5 monoalkylether of a c2-c10 alkylen-glycol - Google Patents

A process for preparing iopamidol by using a c1-c5 monoalkylether of a c2-c10 alkylen-glycol Download PDF

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Publication number
WO1997002235A1
WO1997002235A1 PCT/EP1996/002863 EP9602863W WO9702235A1 WO 1997002235 A1 WO1997002235 A1 WO 1997002235A1 EP 9602863 W EP9602863 W EP 9602863W WO 9702235 A1 WO9702235 A1 WO 9702235A1
Authority
WO
WIPO (PCT)
Prior art keywords
iopamidol
alkylen
glycol
propandiol
process according
Prior art date
Application number
PCT/EP1996/002863
Other languages
English (en)
French (fr)
Inventor
Antonio Tarquini
Maria Donnarumma
Original Assignee
Recordati S.A. Chemical And Pharmaceutical Company
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 ITMI951429 external-priority patent/IT1275473B/it
Priority claimed from ITMI952572 external-priority patent/IT1277049B1/it
Application filed by Recordati S.A. Chemical And Pharmaceutical Company filed Critical Recordati S.A. Chemical And Pharmaceutical Company
Priority to AU65161/96A priority Critical patent/AU6516196A/en
Priority to EP96924828A priority patent/EP0842141A1/en
Publication of WO1997002235A1 publication Critical patent/WO1997002235A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/38—Separation; Purification; Stabilisation; Use of additives
    • C07C227/40—Separation; Purification
    • C07C227/42—Crystallisation

Definitions

  • the present invention relates to a process of purification of iopamidol. by crystallization with a solvent which is a C ⁇ -Cc monoalkylether of a alkylen- glycol.
  • 5-lactamimido-isophtalimide commonly known as iopamidol
  • iopamidol is a highly soluble non ionic contrast medium, widely utilized in radiology for diagnostic purposes.
  • USP 4,001,323 describes the synthesis process, starting from 2,4,6- tri-iodo-5-amino-isophtalic acid chloride , which is successively treated with L-2 -acetoxy-propionyl chloride, and finally with 2- ami no- 1,3 propandiol.
  • Iopamidol is a white solid, decomposing, without melting at about
  • the product as such exhibits a low toxicity, (LD50 ranges from 19.4 in rabbit to 44,5 g/kg in mouse) [The Merck Index 11 th Ed. No. 943 Ed. -
  • the product is isolated by evaporation of the aqueous solution thereof and the obtained raw product is crystallized from ethanol.
  • iopamidol can be obtained in hydrated, mono- hydrated or pentahydrated form and in low yields also by slow crystallization from water.
  • the drawback of these crystallization processes resides in that a significant quantity of solvent, which is not easily removable either by heating at elevated temperatures or under vacuum, always remains in the crystalline product. Also the remotion of residual traces of water from the crystalline product, coming from the above mentioned crystallization processes, requires prolonged heating at temperatures higher than 100°C.
  • the most recent GB 2,280,436 describes a process for crystallizing iopamidol from butanol aqueous solution, allowing to obtain in high yield a crystalline product, having the above mentioned requirements established in US Pharmacopeia.
  • the Applicant has now unexpectedly found that by using as the crystallization solvent a alkylen- glycol, it is possible to obtain crystalline iopamidol having a purity degree ranging from 99.5 to 99.9 starting from a iopamidol having a HPLC purity degree of 99.1%.
  • the object of the present invention is a process for obtaining crystalline iopamidol in high yield and in an almost complete absence of residual solvents, comprising crystallizing iopamidol from a a C j _- Cc monoalkylether of a C2-C-J_Q. alkylen- glycol as the solvent , optionally in the presence of water.
  • C ⁇ -Cc monoalkylether of a C 2 -C ⁇ Q alkylen- glycol belongs to one of the following classes represented respectively by the following general formulas ( I ) and ( II ) :
  • a further object of the present invention is crystalline iopamidol having a purity degree higher than or equal to 99- •
  • the preferred C ⁇ -Cc monoalkylether of a C 2 ⁇ C 1 Q alkylen- glycol used in the process according to the present invention are those of formula
  • R is a C- ⁇ C/ j alkyl radical.
  • the C ⁇ -Cc monoalkylether of a C 2 ⁇ C 1 Q alkylen- glycol is selected from the group consisting of: 1,2 propandiol-monomethylether, 1,2 propandiol-monoethylether, 1,2 propandiol-monobutylether, 1,3 propandiol-monomethylether, 1,3 propandiol-monoethylether, 1,3 propandiol-monobutylether, 2- ethoxyethanol, 2-methoxyethanol.
  • the process according to the present invention can be carried out in the absence of water, by crystallization of iopamidol from a Ci-Ce monoalkylether of a C ⁇ -C- ⁇ Q alkylen- glycol. In this case for the dissolution of iopamidol in this solvent the amount of water still incorporated in iopamidol itself is used.
  • the process is preferably carried out in the presence of water.
  • the process when carried out in water it preferably comprises the following steps: a) dissolving iopamidol at a temperature ranging from 80 and 150 °C in a C ⁇ -Cc monoalkylether of a C 2 -C ⁇ Q alkylen- glycol and in the presence of the necessary amount of water for solubilizing iopamidol, partially or completely removing water by azeotropic distillation and optionally restoring the distilled solvent; b) cooling at a temperature comprised between 0 and 0 °C the solution coming from step (a) and recovering the crystallized product by filtration.
  • the volume of the C- ⁇ -Cc monoalkylether of ⁇ C ⁇ Q alkylen- glycol used in step (a) is comprised between 1 and 10 times, preferably between 3 and 5 times the theoretical ponderal quantity of iopamidol to be purified.
  • the following ratio volume of water / volume of solvent is generally comprised between 1/8 and 1/4.
  • the presence of humidity residues in the crystallization mixture does not adversely affect the quality and the yield of the final product, which is in any case obtained in an almost anhydrous form.
  • the crystallization directly from an aqueous solution of iopamidol, prepared for this specific purpose or an aqueous solution coming from the same synthesis process.
  • the C ⁇ -Cc monoalkylether of a C 2 -C ⁇ Q alkylen- glycol is preferably added in the above mentioned ratios to the aqueous solution containing iopamidol.
  • step (b) the mixture is then heated to carry out the azeotropic distillation of water, and this distillation is continued until the mixture reaches the boiling temperature of the pure solvent.
  • a third solvent such as toluene, suitable to form a ternary azeotrope with water, may be added to the mixture of iopamidol water and said C ⁇ -Cc monoalkylether of a C -C- ⁇ Q alkylen- glycol in order to make easier the complete remotion of water.
  • the cooling temperature of step (b) in the case the process is carried out in a solvent selected from the group consisting of: 2- ethoxyethanol, 2-methoxyethanol, is preferably comprised between 20 and 90 °C, in the case the process is carried out in the presence of a solvent selected from the group consisting of: 1,2 propandiol- monomethylether, 1,2 propandiol-monoethylether, 1,2 propandiol- monobutylether, 1,3 propandiol-monomethylether, 1,3 propandiol- monoethylether, 1,3 propandiol-monobutylether, ranges from 0 to 80° C. In both the above mentioned cases the cooling temperature is more preferably comprised between 50 and 70°C.
  • step (b) the crystallization of the product occurs, and the product is maintained at the cooling temperature for a period comprised between 30 minutes and 3 hours, the desired product is recovered by filtration and dried under vacuum for 3-4 hours at a temperature of 60° C.
  • the properties of the iopamidol thus obtained are determined by HPLC. For example for determining the HPLC degree of purity of iopamidol the standard operating conditions reported in Pharmeuropa 6, No. 4, page 343 , (1994) may be followed .
  • the crystallization yields of the process according to the present invention are very high and in any case are comprised between 80 and 95%-

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
PCT/EP1996/002863 1995-07-04 1996-07-01 A process for preparing iopamidol by using a c1-c5 monoalkylether of a c2-c10 alkylen-glycol WO1997002235A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU65161/96A AU6516196A (en) 1995-07-04 1996-07-01 A process for preparing iopamidol by using a c1-c5 monoalkylether of a c2-c10 alkylene-glycol
EP96924828A EP0842141A1 (en) 1995-07-04 1996-07-01 A process for preparing iopamidol by using a c1-c5 monoalkylether of a c2-c10 alkylen-glycol

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
ITMI95A001429 1995-07-04
ITMI951429 IT1275473B (it) 1995-07-04 1995-07-04 Procedimento per purificare lo iopamidolo
ITMI95A002572 1995-12-06
ITMI952572 IT1277049B1 (it) 1995-12-06 1995-12-06 Processo di purificazione di iopamidolo mediante l'impiego come solvente di un monoalchiletere c1-c5 di un glicole alchilenico

Publications (1)

Publication Number Publication Date
WO1997002235A1 true WO1997002235A1 (en) 1997-01-23

Family

ID=26331296

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1996/002863 WO1997002235A1 (en) 1995-07-04 1996-07-01 A process for preparing iopamidol by using a c1-c5 monoalkylether of a c2-c10 alkylen-glycol

Country Status (4)

Country Link
EP (1) EP0842141A1 (enrdf_load_stackoverflow)
AU (1) AU6516196A (enrdf_load_stackoverflow)
IN (1) IN181340B (enrdf_load_stackoverflow)
WO (1) WO1997002235A1 (enrdf_load_stackoverflow)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998034908A1 (en) * 1997-02-11 1998-08-13 Bracco International B.V. PROCESS FOR THE CRYSTALLIZATION FROM A LINEAR OR BRANCHED (C5-C6) ALCOHOL OR THEIR MIXTURES OF (S)-N,N'-bis[2-HYDROXY-1- (HYDROXYMETHYL)ETHYL]-5-[ (2-HYDROXY-1-OXOPROPYl)AMINO]-2,4,6- TRIIODO-1,3-BENZENDICARBOXAMIDE
EP0992245A1 (en) * 1998-09-16 2000-04-12 Goldham Bioglan Pharma GmbH Radio-contrast agents

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988009328A1 (en) * 1987-05-22 1988-12-01 Bracco Industria Chimica S.P.A. Preparation of 5-acylamino-2,4,6-triiodo- or tribromo-benzoic acid derivatives
GB2280436A (en) * 1993-07-30 1995-02-01 Zambon Spa Process for crystallization of iopamidol

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988009328A1 (en) * 1987-05-22 1988-12-01 Bracco Industria Chimica S.P.A. Preparation of 5-acylamino-2,4,6-triiodo- or tribromo-benzoic acid derivatives
GB2280436A (en) * 1993-07-30 1995-02-01 Zambon Spa Process for crystallization of iopamidol

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
FELDER, ERNST ET AL: "Iopamidol", ANAL. PROFILES DRUG SUBST. (1988), 17, 115-54 CODEN: APDSB7;ISSN: 0099-5428, XP002012662 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998034908A1 (en) * 1997-02-11 1998-08-13 Bracco International B.V. PROCESS FOR THE CRYSTALLIZATION FROM A LINEAR OR BRANCHED (C5-C6) ALCOHOL OR THEIR MIXTURES OF (S)-N,N'-bis[2-HYDROXY-1- (HYDROXYMETHYL)ETHYL]-5-[ (2-HYDROXY-1-OXOPROPYl)AMINO]-2,4,6- TRIIODO-1,3-BENZENDICARBOXAMIDE
CZ299420B6 (cs) * 1997-02-11 2008-07-23 Bracco International B. V. Zpusob krystalizace iopamidolu
EP0992245A1 (en) * 1998-09-16 2000-04-12 Goldham Bioglan Pharma GmbH Radio-contrast agents
WO2000015266A3 (en) * 1998-09-16 2000-05-25 Goldham Bioglan Pharma Gmbh Radio-contrast agents

Also Published As

Publication number Publication date
IN181340B (enrdf_load_stackoverflow) 1998-05-16
AU6516196A (en) 1997-02-05
EP0842141A1 (en) 1998-05-20

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