Development of a stable single-vial formulation for a new technetium complex using bilayer lyophilization.

The interaction between different components used in the preparation of a new radiodiagnostic agent, BMS-181321, was overcome by its lyophilization as a bilayered product. BMS-181321 is composed of a nitroimidazole ligand BMS-181032, that is complexed with technetium-99m just before it is used in radionuclide imaging studies. Stannous chloride is required to reduce technetium from the +7 to the +5 oxidation state before it can be complexed by the ligand. Because BMS-181032 is unstable in the presence of stannous chloride (when mixed in the liquid or solid state), the two components must be contained in separate vials. A bilayered lyophile was manufactured, containing the ligand and stannous chloride in separate layers in a single vial. The bilayered product was manufactured by first filling a solution of the ligand into a vial and freezing the solution. A solution containing stannous chloride was then filled into the same vial on top of the frozen layer of ligand, and this second layer was also frozen. The two frozen layers were then lyophilized to a dry solid cake. The resulting bilayered product showed stability comparable to that seen when the ligand and the reducing agent were contained in separate vials. The separation provided by the layering was sufficient to prevent any significant interaction between the reducing agent and the ligand.