(622a) The Challenge to Determine Particle Size and Specific Surface Area of an Agglomerated Drug Substance in the Late-Stage Development

Solid-state powder properties of a drug substance, alternatively called active pharmaceutical ingredient (API), such as particle size and specific surface area, play a critical role in late-stage pharmaceutical development.  Specifically, surface area and particle size of APIs can impact bioavailability and dissolution of the solid oral dosage form.  Further, these parameters are used to establish process robustness.  Naturally, there is a need to determine particle size and specific surface area during API manufacturing.  This presentation focuses on the particle size and surface area method development for an API that is agglomerated to enhance the flow of the material.  Furthermore, this material is a non-stoichiometric hydrate that is particularly challenging in terms of method development.  In particular, surface area measurements require an initial degassing of the material, which could alter the hydration state of this API.  The difficulties and challenges to measure the primary particle size, agglomerate size, and specific surface area of this agglomerated drug substance will be presented.  The effect of the agglomerated API and its hydration state on the particle size and surface area as well as their implications for dissolution and bioavailability will be discussed.