Process characterisation, optimisation and validation of production of diacetylmorphine/caffeine sachets: a design of experiments approach.

摘要

Powder filled sachets containing a 3:1 (w/w) powder mixture of diacetylmorphine base and caffeine anhydrate were developed as a dosage form for smokable heroin used for the treatment of chronic, treatment-resistant heroin addicts. The powder mixture was filled into sachets using a micro dose auger filler machine. The goal of this study was to identify the most important process variables that influence precision of dosing. Five variables were tested: auger speed, agitator speed, hopper fill level, dose interval, and dose. An experimental design was used to study the effects of each of these variables, including possible non-linear and interaction effects. A 9-term regression model was constructed, explaining 94% of the observed variation in dose weight variation coefficient. Dose, agitator speed and hopper fill level were the most important variables. The regression model was used to identify optimal settings of the variables for four sachet doses intended for routine manufacture. The results of four test batches manufactured with these optimised settings showed that accurate (accuracy: 99.0-101.0%) and precise (CV: 3.2-5.3%) filling of diacetylmorphine/caffeine sachets is possible using the micro dose auger filler machine.