ASSESSMENT OF DISORDER IN CRYSTALLINE SOLIDS

In the processing of pharmaceutical solids, disruption or activation of the crystalline structure often leads to varying degrees of disorder through the formation of defects and amorphous regions. Since percent disorder of processed samples must be assessed quantitatively using premixed standard samples of highly crystalline and amorphous solids, in the past, a number of questions about the validity of such an approach have been raised. Using sucrose as a model solid, a comprehensive assessment of such disorder has been carried out on predetermined mixtures of crystalline and amorphous samples, as well as on crystalline samples mechanically milled for various periods of time. Particular emphasis was placed on determining low levels of disorder in highly crystalline samples, since most techniques can detect no less than about 10% disorder. With predetermined mixtures, measurements of X-ray powder diffraction, density and heats of crystallization revealed good linearity with the percent disorder and acceptable detectability down to about 10%, as expected. However, using water vapor sorption measurements under very carefully controlled conditions proved effective in being able to detect disorder as low as 1%. A comparison of these four methods for estimating the percent disorder of milled samples of sucrose gave very consistent results, once the underlying factors that make these techniques sensitive to the concentration of amorphous structure present were recognized and taken into account.