By Dr. Dimitrios Zarkadas, Ph.D.
Director, Merck & Co

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 presentation, the efforts to develop a robust isolation process for Boceprevir, which delivers specific surface areas between 3.0 and 9.4 m2/g, will be reported. This surface area range was critical to ensure acceptable dissolution performance for the finished product.  Our team 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 the glass transition temperature of the amorphous API solids. Processing time and thermal history also influence API surface area evolution, rendering a dynamic nature to it. A control strategy was developed consisting of two elements: a continuous tee mixer precipitation process, which delivers API in the 40-60 m2/g range and one of two annealing step variants to control the surface area to its final desired range. In the first annealing process, surface area was controlled in four 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 vs. time. The findings of this work, especially the method to determine the glass transition temperature of amorphous API suspensions and the connection between the API glass transition temperature and the processing conditions are expected to be widely applicable in process development and physical attribute control for amorphous APIs.