Avagacestat, BMS-708163, is a ?-secretase inhibitor that was intended for the treatment of Alzheimer's Disease.  BMS-708163 is a non-ionizable molecule with low aqueous solubility (< 1 �g/mL) with a BCS classification of II.  In addition, API particle size reduction did not show any appreciable improvement in bioavailability.  As a result, several formulation strategies to enhance solubility and bio-performance were explored during pharmaceutical development.Four solid oral formulations were developed which included a solubilized hard gelatin capsule, a soft gelatin capsule, a hot melt extrusion (HME) and a spray dried dispersion (SDD).  A brief overview of each of the formulations will be presented as a means of setting the stage for the analytical challenges which were encountered.The hard gelatin capsule and soft gelatin capsule utilized a significant amount of Vitamin E TPGS as a solubilizing vehicle.  Vitamin E TPGS is composed of a PEG chain (MW �1000) and the hydrophobic moiety of Vitamin E, when used at high amount (>10%) in formulation, poses significant challenges to the development of an HPLC impurity/degradant method.  Since BMS-708163 is non-ionizable, it was thought that the pH would not impact the dissolution profile.  However, during method development it was noted that the dissolution rate was highly variable for the soft gelatin capsules at different pHs.  The experimental design and the results from the dissolution method development will be presented, along with data demonstrating that the dissolution method was able to discriminate the potential for crystalline API in the soft gelatin capsule.

Analytical challenges of developing a poorly soluble drug:  The untold Avagacestat story

248th National Meeting (2014)

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