Formulating a heat- and shear-labile drug in an amorphous solid dispersion: Balancing drug degradation and crystallinity.

We seek to further addresss the questions posed by Moseson et al. regarding whether any residual crystal level, size, or characteristic is acceptable in an amorphous solid dispersion (ASD) such that its stability, enhanced dissolution, and increased bioavailability are not compromised. To address this highly relevant question, we study an interesting heat- and shear-labile drug in development, LY3009120. To study the effects of residual crystallinity and degradation in ASDs, we prepared three compositionally identical formulations (57-1, 59-4, and 59-5) using the KinetiSol process under various processing conditions to obtain samples with various levels of crystallinity (2.3%, 0.9%, and 0.1%, respectively) and degradation products (0.74%, 1.97%, and 3.12%, respectively). Samples with less than 1% crystallinity were placed on stability, and we observed no measurable change in the drug's crystallinity, dissolution profile or purity in the 59-4 and 59-5 formulations over four months of storage under closed conditions at 25 °C and 60% humidity. For formulations 57-1, 59-4, and 59-5, bioavailability studies in rats reveal a 44-fold, 55-fold, and 62-fold increase in mean AUC, respectively, compared to the physical mixture. This suggests that the presence of some residual crystals after processing can be acceptable and will not change the properties of the ASD over time.