Solid state NMR and DSC methods for quantifying the amorphous content in solid dosage forms:: an application to ball-milling of trehalose

The purpose of this study was to determine quantitatively the amorphous fraction in crystalline-amorphous powder mixtures of trehalose, in order to assess the ability of the C-13 NMR technique for quantitative amorphous characterization. The NMR method is described in detail and its accuracy is compared to that of the DSC technique. Amorphous trehalose was prepared by mechanical milling. Samples with different amorphous fractions were prepared by physical mixing of purely amorphous and purely crystalline powders. The results reveal a close correlation between the imposed compositions of the physical mixtures and those determined by NMR and DSC, indicating that both are useful and accurate methods for compositional characterization of powders. The NMR method is then used to determine the evolution of the amorphous fraction in a trehalose powder, during a milling procedure which ultimately leads to a fully amorphous state. (C) 2004 Elsevier B.V. All rights reserved.