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In-Situ Molecular Vapor Composition Measurements During Lyophilization



Monitoring process conditions during lyophilization is essential to ensuring product quality for lyophilized pharmaceutical products. Residual gas analysis has been applied previously in lyophilization applications for leak detection, determination of endpoint in primary and secondary drying, monitoring sterilization processes, and measuring complex solvents. The purpose of this study is to investigate the temporal evolution of the process gas for various formulations during lyophilization to better understand the relative extraction rates of various molecular compounds over the course of primary drying.


In this study, residual gas analysis is used to monitor molecular composition of gases in the product chamber during lyophilization of aqueous formulations typical for pharmaceuticals. Residual gas analysis is also used in the determination of the primary drying endpoint and compared to the results obtained using the comparative pressure measurement technique.


The dynamics of solvent vapors, those species dissolved therein, and the ballast gas (the gas supplied to maintain a set-point pressure in the product chamber) are observed throughout the course of lyophilization. In addition to water vapor and nitrogen, the two most abundant gases for all considered aqueous formulations are oxygen and carbon dioxide. In particular, it is observed that the relative concentrations of carbon dioxide and oxygen vary depending on the formulation, an observation which stems from the varying solubility of these species. This result has implications on product shelf life and stability during the lyophilization process.


Chamber process gas composition during lyophilization is quantified for several representative formulations using residual gas analysis. The advantages of the technique lie in its ability to measure the relative concentration of various species during the lyophilization process. This feature gives residual gas analysis utility in a host of applications from endpoint determination to quality assurance. In contrast to other methods, residual gas analysis is able to determine oxygen and water vapor content in the process gas. These compounds have been shown to directly influence product shelf life. With these results, residual gas analysis technique presents a potential new method for real-time lyophilization process control and improved understanding of formulation and processing effects for lyophilized pharmaceutical products.

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The authors are grateful to Nate Graff and Steve Lakeman from INFICON and Qiming Wang and T.N. Thompson from Millrock for their work in implementing the RGA equipment into the REVO lyophilizer operation. We also would like to thank Dr. Steven Nail and Dr. Gregory Sacha from Baxter for allowing us to use the D-Mannitol in 2-Butanol/water RGA data and to Professor Michael Pikal for helpful suggestions. LyoHUB Consortium at Purdue University provided funding for RGA testing and summer internship for Evan Liechty. Additional funding was provided for in-situ RGA for lyophilization process research by the Center for Pharmaceutical Processing Research. 

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Correspondence to Alina A. Alexeenko.

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Guest Editors: Tony Zhou and Tonglei Li

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Liechty, E.T., Strongrich, A.D., Moussa, E.M. et al. In-Situ Molecular Vapor Composition Measurements During Lyophilization. Pharm Res 35, 115 (2018).

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