Drug agglomeration and dissolution - What is the influence of powder mixing?

This study determined the influence of mixing speed and time on the dissolution and deagglomeration of a micronised, poorly water-soluble drug, indomethacin, in lactose interactive mixtures. Mixing occurred in a Tubular mixer; dissolution studies were performed using the USP paddle method, and the extent of deagglomeration was determined using modelling strategies and laser diffraction partcile sizing of the powder mixtures. During low energy mixing at low rates and short mixing times, dissolution profiles showed an unusual flat asymmptote indicating incomplete extents of dissolution caused by agglomerates that did not readily disperse in the dissolution and deagglomeration of the indomethacin powder. Nonlinear least squares modelling of the dissolution data using a sigmoidal equation provided estimates of the extent and rate dissolution. Mixing speed and time had a much greater influence on the extent of dissolution which was controlled by deagglomeration than on the initial dissolution rate which was related to dispersed indomethacin. While some deagglomeration did occur at higher mixing energies, the deagglomeration of the indomethacin was not complete with only 58-80 of indomethacin particles overlapping with the primary indomethacin particle size distribution. The significant outcome of this study was that mixing conditions have a major influence on the mixing quality, especially in areas where agglomerate charactersitics influence performance.