Synthesis, isomerism and characterization of iopentol.

The synthesis of iopentol is described, and the IR, NMR and FAB MS data of the compound are discussed. Iopentol exists as a mixture of several diastereomers and conformers. This topic is discussed in some detail. The kinetics of the isomerization from pure exo-iopentol to an equilibrium mixture of exo- and endo-iopentol is measured by HPLC and 1H NMR spectroscopy. At 40 degrees C the endo:exo ratio is calculated from the HPLC experiments to be 0.26. The time it takes endo-iopentol to reach half of its equilibrium concentration, and the equilibration time are calculated to be 0.8 h and 5.0 h, respectively. Iopentol may exist as exo/endo pairs of four racemates. Neither GC, HPLC, IR nor high field NMR spectroscopy were suited to reveal the diastereomeric composition of the product.

Determination of iopentol and other non-ionic contrast agents in biologic fluids by high-performance liquid chromatography.

A simple, accurate and precise high-performance liquid chromatographic method for determination of iopentol in urine and serum is presented. The modifications of the method necessary for the determination of some other non-ionic contrast agents and in other biologic fluids are also presented.

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.

Formulation and stability of iopentol.

The autoclaving studies which were performed to develop a formulation of iopentol are presented. The same formulation as used for iohexol was found to be suitable for iopentol. It was shown that it is essential to use a buffer such as trometamol to lower the pH during autoclaving in order to achieve a low level of deiodination after autoclaving. Results from the on-going stability studies indicate a good stability of iopentol finished product.