Development, chemistry, and physical properties of iopamidol and its analogues

A series of 5-hydroxyacylamino-2,4,6-triiodo-N,N'-hydroxy-alkyl-isophtalamides was prepared in order to study the structural requirements for high water solubility and low toxicity. Among the amides substituted by 2-hydroxyethyl; 2,3-dihydroxypropyl; 1,3-dihydroxypropyl-; and 1,1-dihydroxy-methyl-2-oxyethyl- groups, the highest water solubility was obtained with the 1,3-dihydroxypropyl- group. Neither optical resolution of the 2,3-dihydroxypropyl moiety nor amide formation with two different amines improved the water solubility. The optimal solubility was obtained with S-5-alpha-hydroxypropionylamino-2,4,6-triiodoisophtalic acid di-(1,3-dihydroxy-2-propylamide), iopamidol. Iopamidol forms anhydrous and monohydrate crystals, characterized by differential thermal analyses, x-ray diffraction patterns, and solubility patterns. A method for enzymatic assay of the optical purity of iopamidol with lactodehydrogenase is described as well as partition coefficient, ionization constant of the oxyacylamido-group, critical micelle formation, surface tension, and osmolarity.