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

Abstract

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 methanol−methyl 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 methanol−MtBE 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.

Robust Process Scale-Up Leveraging Design of Experiments to Map Active Pharmaceutical Ingredient Humid Drying Parameter Space

“…Values of all drying parameters were recorded continuously throughout each experiment. Process analytical technology (PAT) tools were used to monitor the volatile components in the exiting gas stream by mass spectrometry, while the crystalline form of the drying solids was tracked by Raman spectroscopy. , Alternatively, the Raman probe could be replaced with a thermocouple to monitor the temperature of the cake during drying.…”

New Bench-Scale Method To Elucidate Active Pharmaceutical Ingredient Drying Mechanisms

“…Drying is an important unit operation in the pharmaceutical industry and because of the complex nature of the compounds under development, the variety of drying behaviors encountered, and the specific critical attributes targeted, researchers in the field have developed many different tools to study the aspects of interest. − For drying kinetics, these include experimental methods ranging from small scale dynamic vapor sorption chambers and flow cells to larger scale pilot plant agitated dryers and, in some cases, mechanistic models are provided. − Often, to minimize system disturbances and material requirements, in-line process analytical technology is used to supplement or in lieu of off-line testing of in process samples. Common examples include near infrared (NIR) or RAMAN probes, in contact with the solids, to determine the solvent content or physical form of the solids as well as mass spectroscopy to monitor components leaving in off gas streams. − The current work introduces another experimental tool for inclusion in the drying process development toolbox.…”

Monitoring Drug Substance Drying with Online GC

“…Mass spectrometry provides an orthogonal approach to spectroscopic tools for monitoring drying via analyzing the headspace stream from a filter-dryer. , We wanted to expand upon this headspace sampling approach by instead using gas chromatography (GC) as an analytical technique. We selected GC as our analytical instrument of choice because it is the gold standard for residual solvent analysis due to its ability to quantify multiple solvents simultaneously with a high linear range. , GC methods that can separate 25 or more common solvents are routinely used providing unparalleled quantitative ability compared to mass spectrometry. , Additionally, because this technique only analyzes the headspace of the filter-dryer, it should provide a nearly universal technique for monitoring the drying of materials in agitated filter-dryers of differing sizes.…”

“…Mass spectrometry provides an orthogonal approach to spectroscopic tools for monitoring drying via analyzing the headspace stream from a filter-dryer. 21,22 We wanted to expand upon this headspace sampling approach by instead using gas chromatography (GC) as an analytical technique. We selected GC as our analytical instrument of choice because it is the gold standard for residual solvent analysis due to its ability to quantify multiple solvents simultaneously with a high linear range.…”