Detecting Crystallization in Spray-dried Amorphous Solid Dispersion Tablets Administered in Apple Sauce: Feasibility, Challenges and Considerations.

GENE-A, a small molecule classified as a BCS Class IV compound, was formulated as a spray dried amorphous solid dispersion (SDD) using HPMC-AS polymer for oral delivery and compressed with additional excipients to yield tablets. Owing to a high clinical daily dose projection, the possibility of administering multiple tablets in applesauce was explored for patient compliance. Since GENE-A crystallized to a hydrate in aqueous media in previously conducted solubility studies, dispersion of SDD tablets in applesauce (aqueous medium) necessitated the development of an analytical method to detect low levels of crystallinity in these mixtures. Using transmission PXRD and multistep sample preparation procedure, a calibration curve was obtained by employing powder blends with matching composition as SDD tablets, spiked with different amounts of crystalline hydrate, dispersed in applesauce. From this curve, the limits of detection and quantitation of crystalline active in these samples were determined to be 1.8 and 4.9% respectively. A 8.5-12% error of prediction for % crystallinity was obtained for validation samples which may be attributed primarily to sample preparation challenges such as retention of water in the centrifuged samples. Using this method, % crystallinity was determined to be < LOD in the test samples, i.e. film coated SDD tablets (for clinical use) dispersed in applesauce at T = 0 and 2 h. Our study is the first to demonstrate the development of a PXRD based method for detecting low levels of crystallinity in a semi-solid matrix to monitor physical stability of an active in drug-vehicle mixtures.