Despite the ubiquitous use of multi-phase drug formulations, detailed investigations on the dispersion kinetics upon shaking are apparently lacking. We were faced with these problems when analysing the operational function of newly developed autoinjectors containing a pharmaceutically unstable nerve agent antidote formulation. For the immediate treatment of organophosphate poisoning, dry/wet autoinjectors have been developed, containing the broad-spectrum cholinesterase reactivator HI 6 dichloride as a powder and atropine in solution. After breaking a separating membrane, HI 6 has to be dissolved by shaking for 5 s prior to injection. Although being crucial for quick dissolution, the mode of shaking has been poorly specified by the two manufacturers. After recording the individual shaking behaviour of 50 volunteers, we constructed a shaking apparatus allowing the imitation of the spontaneous human shaking motion. Mockups of both autoinjector chambers with pneumatic activation, programmed shaking and ejection of the suspension through a filter allowed us to analyse the dissolution progress within seconds. The results with HI 6 dichloride at 5°C showed that complete dissolution was not achieved within 5 s. The dissolution rate was dependent on shaking frequency, height of stroke, inclination of the shaking axis, and the dimensions of the mockups. Upon vertical shaking, a threshold frequency was observed above which the dissolution rate increased abruptly. Horizontal shaking accelerated the dissolution rate and the threshold frequency could be lowered considerably. While HI 6 dichloride did not allow complete dissolution at 5°C, HI 6 dimethanesulphonate was completely dissolved in less than 5 s under shaking conditions as observed with more than 75% of the untrained volunteers. Copyright (C) 1998 Elsevier Science B.V.
Thiermann, H., Schreiner, R., & Eyer, P. (1998). Dissolution kinetics of unstable drugs in two-compartment autoinjectors: Analysis of the individual shaking behaviour and influence of various shaking parameters on the dissolution rate of HI 6 in an automated system. International Journal of Pharmaceutics, 170(1), 23–32. https://doi.org/10.1016/S0378-5173(98)00094-5