Quantitative Measures of Crystalline Fenofibrate in Amorphous Solid Dispersion Formulations by X-Ray Microscopy.

Abstract In the pharmaceutical industry, amorphous solid dispersion can be utilized to enhance the solubility, hence bioavailability, of poorly solubility active pharmaceutical ingredients owing to the higher free energy of the amorphous state. Measuring the concentration, size and spatial distribution of crystalline API particles that may be present in amorphous solid dispersions (ASD) is critical to understanding product performance and developing improved formulations. In this study X-Ray Microscopy (XRM) was used to nondestructively measure these attributes in ASDs. Model tablets of amorphous fenofibrate in a copovidone matrix spiked with known concentrations of crystalline fenofibrate were examined by XRM to measure the concentration, size and distribution of crystalline particles in the tablets. Data collection and analysis conditions were evaluated and reported. XRM images showed contrast between the crystalline API and the amorphous matrix of the tablet. Image analysis using basic thresholding provided quantitative and distribution data of the crystallinity present. Crystals as small as 10 μm were detected and practical quantitation limits of 0.2% (w/w of total tablet) crystallinity were demonstrated. The aspects of manual data thresholding were tested for operator influence and threshold selection and found to be robust. This technique was demonstrated to provide quantitative measures of crystallinity below standard X-Ray Powder Diffraction (XRPD) techniques, provide three-dimensional information regarding size, shape and distribution of API crystals and can be performed nondestructively.