Process Development and Robust Control of Physical Attributes of an Amorphous Drug Substance

Abstract

Control of physical attributes of amorphous active pharmaceutical ingredients (APIs) can be challenging due to processability issues, their wide variation during processing and the requirement to control them to specific ranges. In this article, we report our efforts to develop a robust isolation process for boceprevir, which delivers specific surface areas between 3.0 and 9.4 m2/g. We developed mechanistic process understanding by utilizing a new method to measure glass transition temperature of API suspensions. Boceprevir processability and surface area are determined by the interplay between the suspension operating conditions and glass transition temperature. Processing time and thermal history also influence API surface area evolution, rendering a dynamic nature to it. A control strategy was developed consisting of 2 elements: a continuous tee mixer precipitation process, which delivers API in the 40-60 m2/g range and 1 of 2 annealing step variants. In the first, surface area was controlled in 4 batches to 6.7-7.5 m2/g by equilibrating the API suspension above its glass transition temperature and a subsequent vacuum distillation. The second annealing variant controlled surface area to 4.5-6.5 m2/g for over 70 commercial batches through a dynamic vacuum distillation step with prescribed temperature and % batch volume distilled profiles versus time.