De-agglomeration of micronized benzodiazepines in dissolution media measured by laser diffraction particle sizing

The objective of this research was to develop a method to characterize the degree of particle agglomeration using laser diffraction particle sizing, following the addition of benzodiazepine interactive mixtures to water. Interactive mixtures of diazepam, nitrazepam and oxazepam (up to 20% w/w) were prepared by mixing micronized benzodiazepines with lactose granules (250-355 microm). Micronized sodium lauryl sulfate and cetrimide (up to 5% w/w) were added to the benzodiazepine-lactose interactive mixes to produce ternary mixtures. Particle size distributions of benzodiazepines, after addition of the interactive mixtures to water, were determined using laser diffraction particle sizing. Bimodal distributions representing dispersed particles and agglomerates were observed initially after lactose carrier dissolution. Partial agglomerate to dispersed particle transition occurred during a 60-min observation period for all mixtures, reaching a constant level of agglomeration after this time. Interactive mixtures with higher benzodiazepine concentrations displayed transition profiles with higher levels of agglomeration. The presence of surfactant in interactive mixtures dramatically decreased agglomeration. Sodium lauryl sulfate was more effective than cetrimide in dispersing agglomerates. The shape of the transition curves during de-agglomeration demonstrated the presence of stable agglomerates that remained after the initial transition; these may be important in explaining dissolution and absorption rates.