Using Online Mass Spectrometry to Predict the End Point during Drying of Pharmaceutical Products

Drying of active pharmaceutical ingredients (APIs) is an energy-intensive process that is often a manufacturing bottleneck due to the relatively long processing times. A key objective is the ability to determine the drying end point, the time at which all solvent has been evaporated from the solid cake. In this contribution, we describe the development and testing of a novel method for determining the end point of pharmaceutical dryers on the basis of online mass spectrometry. The proposed method offers several advantages over existing spectrometric methods, including the ability to detect when the cake is dry from vapor phase measurements and a 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 in the oven, assuming zero flow rate from the cake. The method is 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 are automatically detected for acetone, methanol, and methanolmethyl tert-butyl ether (MtBE) solvents well before the unprocessed gas phase solvent concentration measurements suggest that drying is complete. We find that the drying rate increases and the end point is reached more quickly as the mean bead size increases. The method is validated by performing loss on drying experiments for one combination of pressure, temperature, and bead size. Application of the method to an API with methanolMtBE solvents produced a substantially reduced drying rate compared to that for the glass beads, most likely due to interactions between the API and solvents. We conclude that the proposed method represents a powerful Quality by Design (QbD) approach for pharmaceutical drying processes.