Evaluation of Time Consolidation Effect of Pharmaceutical Powders

We aim to perform a systematic study of the time consolidation effect, i.e. the reduction of powder flowability resulting from at-rest storage, on a diverse array of pharmaceutical powders under different stress, humidity, and length of time.

A ring shear cell-based methodology was employed. An instantaneous flow function was obtained, followed immediately by at-rest consolidation at precisely controlled humidity, stress, and duration. The consolidated powder was then subjected to shear-cell measurement. The difference in flowability between the immediate and consolidated specimens were attributed to the time consolidation effect.

Among the six excipients tested, three exhibited time consolidation at varying extents. Citric acid and starch underwent time consolidation only at high relative humidity (RH = 75%), promoted by vapor condensation and liquid bridge formation. For both materials, the flowability decreased with time, and the extent of time consolidation was not sensitive to the stress applied (0.4-2 kPa). Importantly, mannitol was found to time consolidate under both 50% and 75% RH. Given time, mannitol formed cake, giving rise to flow function below unity. Inverse gas chromatography analysis indicated that mannitol possesses high total surface energy among known pharmaceutical powders.

While time consolidation is prevalent among pharmaceutical powders, most can be mitigated by controlling the RH to below 75%. Notably, for materials possessing high surface energy, such as mannitol, time consolidation could occur at ambient humidity. Therefore, it is desirable to consider in-depth time consolidation evaluation for high surface energy powders, e.g. those subjected to milling or of amorphous nature.