Being a naturally-occurring non-protein nervous toxins, tetrodotoxin binds with the SS1/SS2 subunit of sodium channels with high specificity and high affinity, and has been widely used as a tool drug in pharmacological research, particularly neuropharmacology and muscular physiology for decades. On the market, Sigma-Aldrich supplies a typical product of tetrodotoxin, a freeze-dried solid powder containing 1 mg of tetrodotoxin (product number T5881). In addition to its use in scientific research, therapeutic applications were discovered; among them a tetrodotoxin composition for injection (aqueous solution), intended for treatment of drug addiction and pain has been described (US Patent Pan, et al. U.S. Pat. No. 5,846,975; Dong, et al. U.S. Pat. No. 6,407,088). However, tetrodotoxin injection (aqueous solution) is so sensitive to temperature that it degrades under temperature's influence; the higher temperature, the faster it degrades. Once the content of tetrodotoxin, the active pharmaceutical ingredient, is reduced to less than 90% of the labeled amount, or the relative content of related substances exceeds the specified limit by clinical standards (greater than the main peak area of a control solution), the drug will not be suitable for clinical use any more.
The chemical name of tetrodotoxin is octahydro-12-(hydroxymethyl)-2-imino-5,9:7,10a-dimethano-10aH-(1,3) dioxocino (6,5-d)-pyrimidine-4,7,10,11, 12-pentol, with molecular formula C11H17N3O8 and molecular weight 319.28, which has the following structure:

Tetrodotoxin darkens above 220° C. without decomposition. [α]D25−8.64 (C=8.55 in diluted acetic acid), pKa 8.76 (aqueous); 9.4 (50% alcohol). Soluble in diluted acetic acid, insoluble in water, dry alcohol, ether, insoluble in other organic solvents. Toxin destroyed in strong acids and in alkaline solvents (The Merck Index. 13th Ed. 2001, 9318).
Tetrodotoxin in the solid state is relatively stable to heat, but not so when in aqueous solution, particularly in diluted acid aqueous solution with a low concentration (Kang, et al. U.S. Pat. No. 6,559,154).
USPTO Backgrounds
USPTO Backgrounds