Synthesis, analysis and toxicity of three compounds formed during the synthesis of iodixanol.

The origin of 4-acetyl-2-[N-acetyl-3,5-bis(2,3-dihydroxypropylcarbamoyl)- 2,4,6-triiodoanilinomethyl]-5,7-diiodo-3,4-dihydro-2H-benzo[1,4]ox azine- 6,8-dicarboxylic acid bis(2,3-dihydroxypropylamide) = N-acetyl cyclized iodixanol, 2-[N-acetyl-3,5-bis-(2,3-dihydroxypropylcarbamoyl)-2,4,6- triiodoanilinomethyl]-5,7-diiodo-3,4-dihydro-2H-benzo[1,4]oxazine- 6,8-dicarboxylic acid bis(2,3-dihydroxypropylamide) = cyclized iodixanol and 5,5'-(N-acetyl-2-hydroxypropane-1,3-diyldiamino)bis[N,N'-bis(2,3- dihydroxypropyl)-2,4,6-triiodoisophthalamide] = deacetyl iodixanol in the manufacturing process of the X-ray contrast agent 3,3',5,5'-tetrakis(2,3-dihydroxypropylcarbamoyl)-2,2',4,4',6,6'-++ +hexaiodo- N,N'-(2-hydroxypropane-1,3-diyl)diacetanilide = iodixanol is discussed and their synthesis and purification are described. Their physical and toxicological properties, and analytical and spectroscopic data are summarized.

Synthesis and characterization of iodixanol.

Iodixanol (Visipaque) is a new nonionic roentgen contrast medium intended for general use. Visipaque is a pharmaceutical formulation of iodixanol which is isotonic and iso-osmotic with blood. Two synthetic routes from 5-nitro-isophthalic acid to iodixanol are described. The chemical structure is confirmed spectroscopical data ((1)H-NMR, (13)C-NMR, FAB-MS, UV, IR and Raman). Chromotographic characteristics are related to the isomerism of iodixanol.

Structure-stability relationships of Gd(III) ion complexes for magnetic resonance imaging.

Molecular mechanical calculations and molecular dynamics simulations, based on the AMBER force field, were used to examine the molecular structures and stabilities of nine multidentate ligands and their Gd(III) ion complexes. The magnitude of various factors determining the stability of multidentate Gd(III) complexes, including the energy loss due to change of ligand conformation by complexation, the energy gain from cation-ligand attraction, and effects of intramolecular hydrogen bonding, were calculated by molecular mechanics. The fit between the Gd cation and the binding cavity in the ligands was examined by molecular graphics techniques. Intramolecular hydrogen bonds in free ligands with amide or hydroxyl as H-bond donors usually disfavor complex formation, due to disruption of hydrogen bonds during complex formation. Intramolecular hydrogen bonds may contribute to enhance complex stability if they make the desolvation energy of the free ligands smaller. The calculated complex stabilities were in reasonable agreement with experimental log K values which were available for five of the compounds. The calculated complex stabilities of two hitherto unsynthesized covalently constrained DTPA-derivatives and a DOTA-derivative bearing phenoxy groups as pendant arms indicate that these may form Gd(III) complexes with sufficient stability for use in magnetic resonance imaging techniques.

Synthesis, analysis and toxicity of some compounds which may be formed during the synthesis of iopentol.

The process developed for the synthesis of iopentol consists of several steps. Nine possible impurities from the synthesis of iopentol have been synthesized and one has been isolated from iopentol mother liquor. These substances have been analysed by HPLC methods developed for routine control of iopentol bulk substance. Capacity factors have been calculated for each compound which relate its position in the chromatogram to iopentol. Some of the synthesized compounds have never been found in iopentol and their toxicities have therefore not been determined. Approximate intravenous LD50 values in mice have been determined for the remaining compounds. Taking into consideration these results and the small quantities in which the impurities are present, it is unlikely that they will affect the safety of the final product.