The impact of low levels of amorphous material (<5%) on the blending characteristics of a direct compression formulation

During the manufacture of tablets for registration stability studies, it was observed that blends manufactured using milled active frequently failed the blend content uniformity criteria (actual relative standard deviation (RSD) of 4-15%) at the prelubrication stage, whereas unmilled active batches were consistently giving very good blend uniformity results (RSD <3.5%). The addition of magnesium stearate dramatically improved the blending characteristics of the milled batches, suggesting that milling had altered the surface properties. A hypothesis was presented that amorphous material was created during the milling of the active batches, which subsequently recrystallised over a short period of time e.g. days/hours. Following recrystallisation the batches did not exhibit the same physical properties as the unmilled actives, and this resulted in the drug product batches failing to meet their pre-lubrication acceptance criteria for blend content uniformity. This paper describes the results of a laboratory scale study to investigate this hypothesis and therefore explain the processing issues that were observed during the manufacture of the registration stability batches with milled active batches. (C) 2002 Elsevier science B.V. All rights reserved.