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In-Line and Real-Time Process Monitoring of a Freeze Drying Process Using Raman and NIR Spectroscopy as Complementary Process Analytical Technology (PAT) Tools

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Abstract
The aim of the present study was to examine the complementary properties of Raman and near infrared (NIR) spectroscopy as PAT tools for the fast, noninvasive, non-destructive and in-line process monitoring of a freeze drying process. Therefore, Raman and NIR probes were built in the freeze dryer chamber, allowing simultaneous process monitoring. A 5% (w/v) mannitol solution was used as model for freeze drying. Raman and NIR spectra were continuously collected during freeze drying (one Raman and NIR spectrum/min) and the spectra were analyzed using principal component analysis (PCA) and multivariate curve resolution (MCR). Raman spectroscopy was able to supply information about (i) the mannitol solid state throughout the entire process, (ii) the endpoint of freezing (endpoint of mannitol crystallization), and (iii) several physical and chemical phenomena occurring during the process (onset of ice nucleation, onset of mannitol crystallization). NIR spectroscopy proved to be a more sensitive tool to monitor the critical aspects during drying: (i) endpoint of ice sublimation and (ii) monitoring the release of hydrate water during storage. Furthermore, via NIR spectroscopy some Raman observations were confirmed: start of ice nucleation, end of mannitol crystallization and solid state characteristics of the end product. When Raman and NIR monitoring were performed on the same vial, the Raman signal was saturated during the freezing step caused by reflected NIR light reaching the Raman detector. Therefore, NIR and Raman measurements were done on a different vial. Also the importance of the position of the probes (Raman probe above the vial and NIR probe at the bottom of the sidewall of the vial) in order to obtain all required critical information is outlined. Combining Raman and NIR spectroscopy for the simultaneous monitoring of freeze drying allows monitoring almost all critical freeze drying process aspects. Both techniques do not only complement each other, they also provided mutual confirmation of specific conclusions.
Keywords
CRYSTALLIZATION, LYOPHILIZATION, D-MANNITOL, CURVE RESOLUTION, MANOMETRIC TEMPERATURE-MEASUREMENT, NEAR-INFRARED SPECTROSCOPY, multivariate curve resolution (MCR), principal component analysis (PCA), process monitoring, freeze drying, NIR spectroscopy, process analytical technology (PAT), Raman spectroscopy, DIFFERENTIATION, CHEMOMETRICS, MIXTURES, MOISTURE

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MLA
De Beer, Thomas, et al. “In-Line and Real-Time Process Monitoring of a Freeze Drying Process Using Raman and NIR Spectroscopy as Complementary Process Analytical Technology (PAT) Tools.” Journal of Pharmaceutical Sciences, vol. 98, no. 9, John Wiley & Sons, 2009, pp. 3430–46, doi:10.1002/jps.21633.
APA
De Beer, T., Vercruysse, P., Burggraeve, A., Quinten, T., Ouyang, J., Zhang, X., … Baeyens, W. (2009). In-Line and Real-Time Process Monitoring of a Freeze Drying Process Using Raman and NIR Spectroscopy as Complementary Process Analytical Technology (PAT) Tools. Journal of Pharmaceutical Sciences, 98(9), 3430–3446. https://doi.org/10.1002/jps.21633
Chicago author-date
De Beer, Thomas, Pieter Vercruysse, Anneleen Burggraeve, Thomas Quinten, J. Ouyang, X. Zhang, Chris Vervaet, Jean Paul Remon, and Willy Baeyens. 2009. “In-Line and Real-Time Process Monitoring of a Freeze Drying Process Using Raman and NIR Spectroscopy as Complementary Process Analytical Technology (PAT) Tools.” Journal of Pharmaceutical Sciences 98 (9): 3430–46. https://doi.org/10.1002/jps.21633.
Chicago author-date (all authors)
De Beer, Thomas, Pieter Vercruysse, Anneleen Burggraeve, Thomas Quinten, J. Ouyang, X. Zhang, Chris Vervaet, Jean Paul Remon, and Willy Baeyens. 2009. “In-Line and Real-Time Process Monitoring of a Freeze Drying Process Using Raman and NIR Spectroscopy as Complementary Process Analytical Technology (PAT) Tools.” Journal of Pharmaceutical Sciences 98 (9): 3430–3446. doi:10.1002/jps.21633.
Vancouver
1.
De Beer T, Vercruysse P, Burggraeve A, Quinten T, Ouyang J, Zhang X, et al. In-Line and Real-Time Process Monitoring of a Freeze Drying Process Using Raman and NIR Spectroscopy as Complementary Process Analytical Technology (PAT) Tools. Journal of Pharmaceutical Sciences. 2009;98(9):3430–46.
IEEE
[1]
T. De Beer et al., “In-Line and Real-Time Process Monitoring of a Freeze Drying Process Using Raman and NIR Spectroscopy as Complementary Process Analytical Technology (PAT) Tools,” Journal of Pharmaceutical Sciences, vol. 98, no. 9, pp. 3430–3446, 2009.
@article{761512,
  abstract     = {{The aim of the present study was to examine the complementary properties of Raman and near infrared (NIR) spectroscopy as PAT tools for the fast, noninvasive, non-destructive and in-line process monitoring of a freeze drying process. Therefore, Raman and NIR probes were built in the freeze dryer chamber, allowing simultaneous process monitoring. A 5% (w/v) mannitol solution was used as model for freeze drying. Raman and NIR spectra were continuously collected during freeze drying (one Raman and NIR spectrum/min) and the spectra were analyzed using principal component analysis (PCA) and multivariate curve resolution (MCR). Raman spectroscopy was able to supply information about (i) the mannitol solid state throughout the entire process, (ii) the endpoint of freezing (endpoint of mannitol crystallization), and (iii) several physical and chemical phenomena occurring during the process (onset of ice nucleation, onset of mannitol crystallization). NIR spectroscopy proved to be a more sensitive tool to monitor the critical aspects during drying: (i) endpoint of ice sublimation and (ii) monitoring the release of hydrate water during storage. Furthermore, via NIR spectroscopy some Raman observations were confirmed: start of ice nucleation, end of mannitol crystallization and solid state characteristics of the end product. When Raman and NIR monitoring were performed on the same vial, the Raman signal was saturated during the freezing step caused by reflected NIR light reaching the Raman detector. Therefore, NIR and Raman measurements were done on a different vial. Also the importance of the position of the probes (Raman probe above the vial and NIR probe at the bottom of the sidewall of the vial) in order to obtain all required critical information is outlined. Combining Raman and NIR spectroscopy for the simultaneous monitoring of freeze drying allows monitoring almost all critical freeze drying process aspects. Both techniques do not only complement each other, they also provided mutual confirmation of specific conclusions.}},
  author       = {{De Beer, Thomas and Vercruysse, Pieter and Burggraeve, Anneleen and Quinten, Thomas and Ouyang, J. and Zhang, X. and Vervaet, Chris and Remon, Jean Paul and Baeyens, Willy}},
  issn         = {{0022-3549}},
  journal      = {{Journal of Pharmaceutical Sciences}},
  keywords     = {{CRYSTALLIZATION,LYOPHILIZATION,D-MANNITOL,CURVE RESOLUTION,MANOMETRIC TEMPERATURE-MEASUREMENT,NEAR-INFRARED SPECTROSCOPY,multivariate curve resolution (MCR),principal component analysis (PCA),process monitoring,freeze drying,NIR spectroscopy,process analytical technology (PAT),Raman spectroscopy,DIFFERENTIATION,CHEMOMETRICS,MIXTURES,MOISTURE}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{3430--3446}},
  publisher    = {{John Wiley & Sons}},
  title        = {{In-Line and Real-Time Process Monitoring of a Freeze Drying Process Using Raman and NIR Spectroscopy as Complementary Process Analytical Technology (PAT) Tools}},
  url          = {{http://doi.org/10.1002/jps.21633}},
  volume       = {{98}},
  year         = {{2009}},
}

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