Mn(II) chelates are particularly useful as MRI contrast agents because manganese is less toxic than many paramagnetic metal ions, manganese being normally present in the body in low concentrations, and because Mn(II) has optimum properties for enhancing MRI contrast. A number of Mn(II) chelates have been investigated for use as MRI contrast agents and reported in the literature.
Chelates of paramagnetic metal ions are normally formed by reacting an aqueous solution of a paramagnetic metal salt with the chelating agent in approximate molar proportions, yielding an acidic solution of the chelate and salt anion. An alkaline agent such as sodium hydroxide is added to neutralize the solution to a physiologically acceptable pH, introducing further ions (cation). The process yields a hyperosmotic injection solution, increasing the LD.sub.50 of the drug product. Substantial efforts are then required to separate the chelate from the soluble ions, and lower the toxicity of the final product formulation.
It is an object of this invention to provide an improved process which directly yields either a low osmolarity solution useful as a MRI contrast agent without further purification, or a novel protonated Mn(II) chelate solid which can be easily separated from the reaction mixture and used to prepare a low osmolarity injection solution.