(586f) Using On-Line Mass Spectrometry to Predict the End Point During Drying of Pharmaceutical Products

Authors: 
Dodda, A. G., University of Massachusetts, Amherst
Henson, M. A., University of Massachusetts Amherst
Saranteas, K., Sunovion Pharmaceuticals Inc.



Downstream
processing of Active Pharmaceutical Ingredients (APIs) typically involves
extraction, crystallization, filtration and drying. In addition to being the
most energy intensive unit operation, drying is often a major manufacturing
bottleneck due to its relatively long processing times. Furthermore, drying
conditions must be carefully selected and maintained to avoid problems such as
API degradation. As a result, the optimization of dryer operation is needed to ensure product quality and
minimize operating time. A key requirement for any optimization strategy is the
ability to determine the drying end point, the time at which all solvent has
been evaporated from the solid cake. While a variety of mathematical models
have been developed to describe drying processes, available models are not
sufficiently accurate to predict the end point and/or are too complex to be
used for real-time applications in a pharmaceutical manufacturing environment.
An alternative approach is to develop Process Analytical Technology (PAT) tools
that take advantage of emerging on-line measurement capabilities. Near Infrared
(NIR) spectroscopy and Mid Infrared (MIR) spectroscopy
have been proposed as suitable methods for monitoring dryer performance and
detecting the end point. However, these approaches require the development of chemometric models to map the measured spectra to solvent
concentrations. Moreover, spectroscopic methods are only capable of measuring
gas phase solvent concentrations, which can be quite different than solvent
concentrations in the cake due to the gas residence time of the drying oven.

In this
presentation, we describe the development and testing of a novel method for
determining the end point for pharmaceutical dryers based on on-line mass spectroscopy. The proposed method offers several
advantages over existing spectroscopic methods, including the ability to detect
when the cake is dry from vapor phase measurements and very simple
implementation that does not require chemometric models. The drying end point
for each solvent is determined as the time at which the gas phase solvent
concentration measurement from the mass spectrometer converges to a predicted
value computed from a solvent mass balance on the oven assuming zero flow rate
from the cake. The method was tested on a laboratory scale vacuum dryer over a
range of temperatures and pressures using glass beads with three different
particle sizes. Drying end points were detected for acetone, methanol and methanol-MTBE solvents well
before the unprocessed gas phase solvent concentration measurements suggested that
drying was complete. We found that the drying rate increased and the end point
was reached more quickly as the mean bead size increased. The method was
validated by performing Loss On Drying (LOD) experiments for one combination of
pressure, temperature and bead size. Application of the method to an API with
methanol-MTBE solvents produced a substantially reduced drying rate compared to
the glass bead, most likely due to interactions between the API and solvents.
We concluded that the proposed method represents a powerful Quality by Design
(QbD) approach for pharmaceutical drying processes.