Thiermann_1996_Int.J.Pharm_137_167

To oppose the rapid onset of cholinergic crisis after poisoning with highly toxic organophosphorus compounds, atropine in combination with a cholinesterase reactivator should be administered as early as possible. Due to its broader antidotal spectrum against nerve agents, the second-generation oxime HI 6 appears suitable to replace the marketed oximes, pralidoxime and obidoxime. To meet the requirement of prompt availability, even in the absence of a physician, autoinjectors for intramuscular injection are of advantage. Five hundred micrograms HI 6 dichloride has been considered an appropriate dose for human adults which has to be dissolved in a volume not exceeding 3 ml. Such a concentrated HI 6 solution (appr. 0.5 M) is too unstable for storage. Therefore, dry/wet autoinjectors have been developed in which the HI 6 powder is dissolved in an atropine solution by activating and shaking the device for 5 s immediately before use. However, absolute solubility of HI 6 dichloride is lower than the considered 0.5 M when the temperature is below 10C. Moreover, the dissolution rate is markedly reduced when the absolute solubility is approached. In case of low ambient temperature, malfunctions of autoinjectors containing HI 6 dichloride may occur with plugging the cannula by undissolved HI 6 and failure in delivery of both antidotal components. Such an event would be particularly tragic if the life-saving atropine dose will not been administered. In contrast to HI 6 dichloride, HI 6 dimethanesulfonate, prepared from the dichloride by ion exchange, is much better soluble and its absolute water-solubility is two and five times higher at 20 and 5C, respectively. To follow the dissolution kinetics on-line in the short time scale of interest, a method was developed for conductivity measurement of high salinities in a miniaturized assembly in order to be sparing with the valuable oximes. As a result, HI 6 dimethanesulfonate dissolves about 4 and 6 times faster than HI 6 dichloride at 20C and 5C, respectively. Thus, HI 6 dimethanesulfonate appears to meet the required specification of quick dissolution much better than the dichloride salt.