Monitoring Drug Substance Drying with Online GC

Abstract

We report a technique for monitoring the drying of drug substances in agitated filter-dryers. Online gas chromatography (GC) was leveraged to perform unattended sampling of the headspace of the filter-dryer throughout drying. To validate the technique, we monitored the drying of sodium naproxen in an agitated filter-dryer using a ternary solvent system consisting of methyl tert-butyl ether, acetonitrile, and isopropyl acetate. A drying curve for each solvent was generated with a sampling frequency of <6 min per injection. Physical disturbances to the cake that occurred throughout drying were observed as spikes in headspace solvent concentration. The effects of vacuum pressure, cake agitation, and heating on drying were also explored. Offline headspace GC measurements were completed in parallel to measure the residual solvent content and corroborate the observations regarding cake heterogeneity throughout the drying process. The alignment between the offline and online GC measurements as well as the unique insights offered by online sampling demonstrates that this online technique can be used as an easily implementable approach to monitor drug substance drying in agitated filter-dryers.