Lilly Compound X (LCX) is an oncology drug that was tested in a phase I clinical study using starch blend capsules. The drug was given to a small patient population (4 patients) and showed large inter- and intra-patient variability. In order to evaluate the possible effect of stomach pH on exposure and ways to mitigate the variability issue, artificial stomach-duodenum (ASD) experiments were conducted to investigate the hypothesis that carefully selected dosing fluids would have an impact in minimizing exposure variability caused by the formulation, which could lead to more consistent evaluation of drug absorption in patients. The ASD data corroborates the observed variability, and was a good tool to investigate the effect of stomach pH and potential dosing solutions on duodenal concentrations. Administering capsules co-formulated with Captisol (10% drug load) along with Sprite was shown by the ASD to be an effective way to increase duodenal concentrations as well as to reduce the difference between duodenal concentrations for different gastric pH. The reduction in variability of duodenum AUC (in ASD) is expected to correlate well with a reduction of variability in patient exposure. The dosing regimen of Sprite/Captisol is therefore suggested for future clinical trials involving LCX. Furthermore, for design of early phase clinical trials, ASD technology can be used to assist in choosing the proper dosing solution to mitigate absorption and exposure variability issues.

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Several factors influence the desolvation behavior of calcium salts. We believe the flexibility of the benzene rings in CaKTN, CaFEN, CaMEF and CaTOLF was important for these products to become mesomorphous when they loose their crystalline water; meanwhile, CaDIF where the two benzene rings are coplanar remained crystalline when heated. Additionally, the existence of water channels and the hydrogen bonding networks in the crystals is hypothesized to play an important role in the desolvation behavior of these materials.

In this study, the ability of different analytical techniques to detect and characterize trace crystallinity in amorphous saquinavir was compared and the same techniques were used to investigate differences in the amorphous material before and after removal of the trace crystallinity by milling or heating. Saquinavir samples were analyzed for trace crystallinity and differences in the amorphous state by X-ray powder diffraction in combination with pair distribution function transforms, differential scanning calorimetry, modulated temperature differential scanning calorimetry, polarizing light microscopy, scanning electron microscopy, as well as Raman, near-infrared, and mid-infrared spectroscopy combined with multivariate analysis. X-ray powder diffraction and polarizing light microscopy were best suited to detecting small amounts of residual crystallinity and showed that these can easily be removed by heating or milling. Thermal analysis confirmed structural differences between amorphous saquinavir containing trace crystallinity and the milled and heated samples. Pair distribution function transforms of the X-ray powder diffraction data and the spectroscopic techniques in combination with multivariate analysis revealed differences in short-range and long-range order of the different samples. Raman spectroscopy was the most sensitive spectroscopic technique to detect structural changes induced by milling and heating saquinavir. Overall, the results suggest that the amorphous forms differ in their degree of disorder and molecular bonding arrangements. The study shows that significant insight into trace crystallinity and short-range order in amorphous material can be obtained by using a variety of physical characterization methods and data analysis techniques.