Title of Invention

PROCESS FOR THE CRYSTALLIZATION FROM WATER OF IOPAMIDOL IN A CRYSTALLINE ANHYDROUS FORM

Abstract

Abstract PROCESS FOB THR CRYSTALLIZATION FROM WATER OF tSl-H.M'-BIS r 2-HVDROXY-l-(HYDROXYMBTHYL)RTHYL1-5-[(2-BYDBOXY-l-OXOPROPYL)AMINO]-2.4.6-TRIIODO-l 3-BEHZBKDICARBOXAMIDE. This invention refers to a process for the crystallization from water of S-N,N'-bis[2-hydroxy-l-(hydroxymethyl)ethyl]-5-[(2-hydroxy-l-oxopropyl)amino]-2,4,6-triiodo-l,3-benzendicarboxamide known as Iopamidol. According to the process of this invention, a crystalline anhydrous Iopamidol in accordance with pharmacopeia standards can be obtained.

Full Text

This invention refers to a process for the crystallization from water of S-N,N'-bisE2-hydroxy-l-(hydroxymethy1)ethyl]-5-[(2-hydroxy-l-oxopropyl)amino]-2,4,6-triiodo-l,3-benzendicarboxamide, best known as Iopamidol, which is one of the world top compounds in the field of non-ionic X-ray contrast media. The syntheses of Iopamidol known in literature, for instance the one described in GB 1472050, foresee a final purification at the end of the process, by using ion-exchange resins and successive recrystallization from EtOH, which produces a water-soluble product {2.3 g of product crystallize from a solution of 10 g of Iopamidol in 10 mL of water during some days in a fridge at 4*C). This good solubility is reported in articles successively published, such as Felder E. et al, Boll. Chim. Farm., 1981, 120, 639, or Pelder E., Invest. Radiol., 1984, 19, S164 and the monography on Iopamidol in Analytical Profiles of Drug Substances, vol. 17, 115, together with the scarce solubility in MeOH and the insolubility in Et2O, benzene, chloroform and EtOH. Said articles describe the different crystalline forms of Iopamidol, i. e. anhydrous, monohydrated and pentahydrated, each form having a different IR spectrum. X-ray powder diffraction patterns and distinct enthalpimetric and gravimetric thermograms. Said crystals have been obtained with a very slow kinetics from aqueous solutions. the best experimental conditions in order to carry out the process of this invention. EXAMPLE 1 Crystallization from water of Iopamidol A solution of 500 kg of Iopamidol in 600 kg of deionized water is decolorised using 5 kg of Carbopuron-B'. The suspension is filtered and washed with 100 kg of water. The solution is concentrated at approx. 60*C and at 150 mm Hg up to a volume of 370 L (625 kg) and germinated with 1 kg of anhydrous crystalline germs. The solution crystallizes during 8 h while the temperature is carefully kept at 60'c. Then it is filtered at 60*C without washing and the aqueous liquors are collected (210 kg). After concentration to dryness (5-30 mmHg) at 60'C, 350 kg of the desired product are obtained. Yield: 69.9% The product physico-chemical characteristics are in accordance with pharmacopeia standards. EXAMPLE 2 Recovery of Iopamidol from mother liquors obtained according to EXAMPLE 1 The mother liquors deriving from three crystallization on batches of 500 kg of Iopamidol are collected together and diluted with 285 L of deionized water. At 80'C, the solution is decolorised with 5 kg of CarbopuroifS' and filtered. The filter is washed with 100 kg of water. At 60*C and 150 mm Hg the solution is concentrated to give a residue of 333 L, then it is germinated with 1 kg of the product of the previous preparations. The product crystallizes during 8 h and at 60'C. Then it is filtered without washing, 355 leg of wet product are concentrated under vacuum at 60"c, thus giving 316 kg of Iopamidol. Yield {on dried product): 63% Yield of crystallization starting from EXAMPLE 1: 90.9% The product physico-chemical characteristics are in accordance with pharmacopeia standards. EXAMPLE 3 Purification of crystals obtained according to EXAMPLE 1, when a residue of dimethylacetamide is present. The crystalline solid obtained after filtration according to the procedure of EXAMPLE 1, having a dimethylacetamide content equal to 50 ppm, is washed with absolute ethyl alcohol 5 times (ratio equal to 12.5% weight of EtOH w/w of Iopamidol) and the resulting solid is dried at 50*C under vacuum. The analysis of the resulting product shows a content of dimethylacetamide equal to 16 ppm. WE, CLAIM : A process for the crystalization from water of froamidof in a crystalline anhydrous form and in accordance to the pharmacopeias standards comprising the following steps: -dissolution of lopamidol in deionizer water by heating: -dissolorisation of the solution with active carbon; -vacuum-connectration of the aqueous solution at 60c; addition of crystaline germs of anhydrous iopamidol for seeding the crystallization; -crystallization at 60c; -filtration of the resulting precipitate: - vacuum-drying of the wet product. 2. The process according to claim 1, wherein the iopamidol concentration in the aqeous solution is more than 78.6 (g/ml. of solution). 3. The process accoriding to claim 1, wherein the crystaline germs of the anydrous form of iopamidol are added in amounts from 1 to 10% of the starting iopamidol. 4. The process according to claim 1, wherein the filtered crystalline solid is further washed with a linear or4 branched (c1-C4) Stenholm. 5. The process according to cliam4, wherein said alcohol is ethyl

Documents:

1552-mas-1996 abstract.pdf

1552-mas-1996 assignment.pdf

1552-mas-1996 claims.pdf

1552-mas-1996 correspondence others.pdf

1552-mas-1996 correspondence po.pdf

1552-mas-1996 description(complete).pdf

1552-mas-1996 form 10.pdf

1552-mas-1996 form 2.pdf

1552-mas-1996 form 4.pdf

1552-mas-1996 form 6.pdf

1552-mas-1996 others.pdf