Relative bioavailability of three different solid forms of PNU-141659 as determined with the artificial...

The artificial stomach-duodenum (ASD) apparatus was designed and constructed to assess the in vitro performance of bulk drugs and their formulations in a device which is able to simulate different species and physiological conditions. As a continued demonstration of its application to a pharmaceutical problem, screening experiments were performed on three different solid forms of a drug candidate, PNU-141659. This compound exhibited poor solubility and permeability, and presented a significant problem in the development of a successful dosage form. Simple formulations of an anhydrous form, a hydrated form and an amorphous form of the drug were all assessed with the ASD set up to simulate dog physiology. The solubility ordering of these three forms was anhydrate < hemihydrate < amorphous and this is the first ASD study to directly compare amorphous and crystalline solid forms. However, the results of the ASD studies showed that the hydrated form, with the intermediate solubility should provide the highest bioavailability, not the more soluble amorphous form. This occurred because the more soluble amorphous form underwent a phase conversion to Form I during the ASD experiment. The results from the ASD compared favorably with those later obtained from in vivo dog studies.