A preformulation study on the kinetics of HI-6 in concentrated solution

The degradation kinetics of HI-6 have been investigated at various temperatures and at different pHs at a concentration of 200 mg/ml. Both aqueous and other hydrophilic solvents (glycols and glycerol-water mixtures) have been used. The degradation of HI-6 follows pseudo-first-order kinetics with respect to HI-6. The observed rate seems to depend on a hydroxyl ion-catalyzed reaction (k_OH) and an un/water catalyzed reaction (k₀) which show influence at pH below 3. The pH profile shows a positive slope less than one, which seems to depend on an error in the determination of the rate constants at higher pH. k_OH was determined to be 1 · 10⁹ andk₀ to be 0 · 011 h^?1 at 60° C. The observed rate seems to be independent of the dielectric constant of the solvent. The activation energy k₀ has been determined to be 82.0 kJ mol^?1. Based upon these data the predicted shelf life (t_90%) at pH 0 will not be long than 13 days at 25 ° C and 9 months at 0°C. Thus, the systems studied seem to be unsuitable to formulate a stable intramuscular formulation of HI-6.