LONG-TERM STORAGE STABILITY AND OXIDATION PRODUCTS OF THE CYANIDE ANTIDOTE DIMETHYL TRISULFIDE

Exposure to cyanide (CN) leads to the malfunction of mitochondrial activity by inhibiting the terminal oxidase, cytochrome c oxidase. The brain and heart are the highest oxygen consumers and are the critical target organs harmed by CN. Dimethyl trisulfide (DMTS) is a well-studied CN antidote with the major mechanism of sulfur donation for CN conversion to SCN. However, recent investigations revealed a minor mechanism of methemoglobin formation from DMTS that is a CN scavenger type antidote. Formulation efforts of DMTS focus on optimizing pharmacokinetic and storage stability parameters. This study reports the storage stability of a formulation for DMTS (F3-formulation) developed by Southwest Research Institute, San Antonio, Texas. The F3-formulated DMTS was stored in glass ampules at 4, 22 and 37 ºC. At regular time intervals over the period of one year, nine ampules (three stored at each temperature) were opened and analyzed by HPLC-UV to determine their DMTS content. The results showed that there was no measurable loss of DMTS over the one-year period of the study for the samples stored at 4 and 22 ºC. The samples stored at 37 ºC showed good stability for five months. However, in the sixth month of storage, these samples showed a 10% (M/M) decrease in DMTS content. Discoloration and the appearance of a new peak in the HPLC chromatogram accompanied this loss of DMTS. Continued growth of these new peaks and deepening discoloration was observed over the final 5 months of the study. To identify the degradation products formed during storage at 37 ºC, separate oxidation studies were performed with DMTS using strong oxidizing agents, such as mCPBA or H2O2. The products of the oxidation studies were compared to those of the stability study samples. Dimethyl tetrasulfide and dimethyl pentasulfide were observed as products of both studies. Dimethyl disulfide was observed as a product of degradation and S-methyl methanethiosulfonate was revealed as a product of oxidation. The HPLC and GC-MS SPME analysis revealed a good agreement between the degradation products of the stability study and the direct oxidation reactions. Because the 22 and 4 ºC samples remained stable for a year, we can conclude that the F3-formulated DMTS fulfills the criteria for storage stability.