True density and thermal expansivity of pharmaceutical solids: comparison of methods and assessment of crystallinity

Abstract

Three methods for determining the density of solids, namely displacement of a liquid, displacement of a gas and flotation in a liquid, have been compared using adipic acid doped with various concentrations of oleic acid. The liquid displacement method is tedious and tends to underestimate the true density. Gas pycnometry is rapid, non-destructive and relatively simple to use, but requires expensive instrumentation andalarge sample size, while its accuracy is limited by the relatively low precision of the volume measurements. The flotation method is much simpler in operation, is inexpensive and demonstrates the probabilistic nature of density distribution within a powder sample. Although it is more time consuming than gas pycnometry, the final density values can be accurate to four significant figures using the simplest apparatus. More elaborate set-ups increase the accuracy. The use of two or more suspending liquids in the flotation method enables the density of a given crystal to be determined at two or more temperatures and therefore provides the thermal expansivity. The crystal density at ambient temperature may be interpolated from a plot of density against temperature. The presence of traces of oleic acid in adipic acid crystals marginally lowers the density. Application of the flotation method to acetaminophen crystals shows that the presence of traces of p-acetoxyacetanilide increases the mean density by shifting the density distribution closer to its upper limit. Trace additives in the crystals of both adipic acid and acetaminophen change the thermal expansivity of the most dense crystals in each sample. The use of a single liquid in the flotation method, together with the assumption that the densities of crystals are independent of temperature, may hide significant effects. The results suggest that the thermal expansivity is a more reliable indicator of crystaliinity than density measurements at a fixed temperature.