Pharmaceutical Research

, 35:115 | Cite as

In-Situ Molecular Vapor Composition Measurements During Lyophilization

  • Evan T. Liechty
  • Andrew D. Strongrich
  • Ehab M. Moussa
  • Elizabeth Topp
  • Alina A. Alexeenko
Research Paper Theme: Formulation and Manufacturing of Solid Dosage Forms
Part of the following topical collections:
  1. Formulation and Manufacturing of Solid Dosage Forms

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

Key words

freeze-drying lyophilization mass spectroscopy process monitoring residual gas analysis (RGA) 

Notes

ACKNOWLEDGMENTS AND DISCLOSURES

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. 

References

  1. 1.
    Centerwatch.com [Internet]. Boston: FDA Approved Drugs; c2017 [cited 2017 Oct 29]. Available from: http://centerwatch.com/drug-information/fda-approved-drugs/
  2. 2.
    Nail S, Tchessalov S, Shalaev E, Ganguly A, Renzi E, Dimarco F, et al. Recommended Best Practices for Process Monitoring Instrumentation in Pharmaceutical Freeze Drying—2017. AAPS Pharm Sci Tech. 2017;15:1–5.Google Scholar
  3. 3.
    Patel SM, Doen T, Pikal MJ. Determination of end point of primary drying in freeze-drying process control. AAPS PharmSciTech. 2010;11(1):73–84.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Inficon.com [Internet]. Switzerland: Transpector MPH Residual Gas Analyzer; c2017 [cited 2017 Oct 29]. Available from: http://products.inficon.com/getattachment.axd/?attaname=c9829f02-36db-455e-972b-1d673a944eb9
  5. 5.
    Jennings TA. Residual gas analysis and vacuum freeze drying. PDA J Pharm Sci Technol. 1980;34(1):62–9.Google Scholar
  6. 6.
    Leebron KS, Jennings TA. Determination of the vacuum outgassing properties of elastic closures by mass spectrometry. PDA J Pharm Sci Technol. 1981;35(3):100–5.Google Scholar
  7. 7.
    Nail SL, Johnson W. Methodology for in-process determination of residual water in freeze-dried products. Dev Biol Stand. 1991;74:137–50.Google Scholar
  8. 8.
    Connelly JP, Welch JV. Monitor lyophilization with mass spectrometer gas analysis. PDA J Pharm Sci Technol. 1993;47(2):70–5.Google Scholar
  9. 9.
    Meissner U, Stahl H, Steinkellner D. Detection of Silicone Oil Leakages in Freeze Dryers. PDA J Pharm Sci Technol. 2011;65(5):481–5.CrossRefPubMedGoogle Scholar
  10. 10.
    Teagarden DL, Baker DS. Practical aspects of lyophilization using non-aqueous co-solvent systems. Eur J Pharm Sci. 2002;15(2):115–33.CrossRefPubMedGoogle Scholar
  11. 11.
    Pikal MJ, Dellerman K, Roy ML. Formulation and stability of freeze-dried proteins: effects of moisture and oxygen on the stability of freeze-dried formulations of human growth hormone. Dev Biol Stand. 1992;74:21–37.PubMedGoogle Scholar
  12. 12.
    Paul W. Electromagnetic traps for charged and neutral particles. Rev Mod Phys. 1990;62(3):531.CrossRefGoogle Scholar
  13. 13.
    Millrock.com [Internet]. New York: REVO Research and Development Freeze Dryer c2017 [cited 2017 Oct 29]. Available from: https://www.millrocktech.com/freeze-dryers/revo-research-development-freeze-dryer/
  14. 14.
    Nist.gov [Internet]. Maryland: NIST Chemistry Webbook; [cited 2017 Oct 29]. Available from: http://webbook.nist.gov/chemistry/
  15. 15.
    Green DW, Perry RH. (2008) Perry's chemical engineers' handbook, 8th Edition. McGraw-Hill.Google Scholar
  16. 16.
    Pardo J, Lopez MC, Mayoral JA, Royo FM, Urieta JS. Solubility of gases in butanols. III. Solubilities of non-polar gases in 2-butanol from 263.15 to 303.15 K at 101.33 kPa partial pressure of gas. Fluid Phase Equilib. 1997;134(1):133–40.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Davidson School of Chemical EngineeringPurdue UniversityWest LafayetteUSA
  2. 2.School of Aeronautics and AstronauticsPurdue UniversityWest LafayetteUSA
  3. 3.Birck Nanotechnology CenterPurdue UniversityWest LafayetteUSA
  4. 4.Department of Industrial and Physical PharmacyPurdue UniversityWest LafayetteUSA
  5. 5.Drug Product DevelopmentAbbVie Inc.North ChicagoUSA

Personalised recommendations