Analytical method development for cyanide antidotes and characterization of a new formulation of dimethyl trisulfide.
Hewa Rahinduwage, Chathuranga Chinthana
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Cyanide (CN) is one of the most highlighted toxic compounds. It inhibits the cytochrome c oxidase enzyme, which catalyzes oxygen utilization in cells. As the brain and the heart are the main oxygen consumers, the effects of CN are more prominent on these organs. CN is converted into the less toxic thiocyanate in the presence of a sulfur donor, such as DMTS or thiosulfate (TS). In-house analytical methods were developed to determine CN, TS and nitrite (NT) concentrations by ion chromatograph (IC). Two different formulations for DMTS have been prepared for intramuscular (IM) administration. Formulation 1 (DMTS-F1) is a dispersion of DMTS in 15% aqueous polyoxyethylenesorbitan monooleate (poly80) solution. Formulation 2 (DMTS-F2) is a dispersion of DMTS in a mixture of poly80 and sorbitan monooleate (span80) (1:3 w/w). The concentrations of DMTS in F1 is 50 mg/mL and in F2 is 400 mg/mL. The Blood Brain Barrier (BBB) penetration by the two formulated DMTS structures were studied in a BBB model, Parallel Artificial Membrane Permeability Assay (PAMPA). The PAMPA system has two compartments to model the brain side and the blood vessel side of the BBB. Those compartments are separated with a porcine brain lipid-impregnated membrane. The antidote concentrations in the PAMPA samples were determined by HPLC with UV detection. In the first 30 minutes DMTS-F1 showed much higher speed in traveling from the blood to the brain side of the PAMPA. However, after 30 minutes DMTS-F2 showed much higher travel speed to the brain side. The size distribution stability of the two formulations were measured using a dynamic light scattering (DLS) instrument (Zetasizer). For quality measurements, this technique requires an estimate of the viscosity of the liquid. The viscosity of 2.32 cP for DMTS-F1 and 511.00 cP for DMTS-F2 were measured by a dropping ball viscometer. Size distribution studies suggest that the DMTS-F1 stored at 4 ̊C provides much more stable droplet size.