(330b) Case Study: Modifying API Crystal Habit to Improve Flowability

Daniel A. Green, Jennifer L. Tansey, & Yan T. Sun – GlaxoSmithKline, Upper Merion, PA, USA.

Abstract

An Active Pharmaceutical Ingredient (API) precipitates as acicular crystals from the original crystallization solvent mixture: water and isopropyl alcohol (IPA). Extremely poor flowability of the solid API was noted after shipping a sample from the US to the UK. Our hypothesis was that the crystal habit exacerbates the observed poor flowability upon shipping. To test this hypothesis, we investigated altering the crystal habit by crystallizing from different solutions. We varied the ratio of water and IPA in the original water/IPA solvent system, and investigated the acetone/water system. We compared bulk density and powder flow properties for several cases. We find both crystal habit change, density, and flowability improvement. Specifically, the average aspect ratio of the crystals is significantly less in acetone/H₂O compared to IPA/H₂O. The aspect ratio depends on the acetone/H₂O ratio as well: increasing as the fraction of acetone increases over the range studied (50 - 90% acetone), while the dependence on the IPA/H₂O ratio is much weaker.