Comparison of Differential Scanning Calorimetry, Powder X-ray Diffraction, and Solid-state Nuclear Magnetic Resonance Spectroscopy for Measuring Crystallinity in Amorphous Solid Dispersions - Application to Drug-in-polymer Solubility

Abstract

The widespread use of amorphous solid dispersions (ASDs) dictates that analytical methods are required to accurately quantify crystallinity and characterize crystals formed in order to help design a stable ASD. Current crystallinity quantitation methods are limited to ASDs of moderate drug loadings, single polymorphs, and fast crystallization kinetics. The ability of multiple differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and solid-state nuclear magnetic resonance (SSNMR) techniques were compared for quantifying crystallinity in ASDs in varying conditions. Determining crystallinity by DSC is limited by its ability to measure Tg or heat of fusion. PXRD was relatively robust in determining crystalline and amorphous ratios for drug-polymer systems in the absence of other excipients. SSNMR provides both quantitative information and reveal how crystal quality changes with crystallization conditions and helps to explain the failure of DSC methods. The results of five different methods using three techniques were directly applied to measure drug-in-polymer solubility with four agreeing well with the literature. PXRD and SSNMR are therefore proposed as alternative methods to quantify crystallinity and predict drug-in-polymer solubility when DSC methods do not work. In-situ and ex-situ annealing was also compared, and equivalent crystallinity data was acquired.