Microscale freeze-drying with Raman spectroscopy as a tool for process development

Ari Kauppinen (Corresponding Author), Maunu Toiviainen, Jaakko Aaltonen, Ossi Korhonen, Kristiina Järvinen, Mikko Juuti, Riikka Pellinen, Jarkko Ketolainen

Research output: Contribution to journalArticleScientificpeer-review

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Abstract

Until recently, the freeze-drying process and formulation development have suffered from a lack of microscale analytical tools. Using such an analytical tool should decrease the required sample volume and also shorten the duration of the experiment compared to a laboratory scale setup. This study evaluated the applicability of Raman spectroscopy for in-line monitoring of a microscale freeze-drying process. The effect of cooling rate and annealing step on the solid-state formation of mannitol was studied. Raman spectra were subjected to principal component analysis to gain a qualitative understanding of the process behavior. In addition, mannitol solid-state form ratios were semiquantitatively analyzed during the process with a classical least-squares regression. A standard cooling rate of 1 °C/min with or without an annealing step at −10 °C resulted in a mixture of α, β, δ, and amorphous forms of mannitol. However, a standard cooling rate induced the formation of mannitol hemihydrate, and a secondary drying temperature of +60 °C was required to transform the hemihydrate form to the more stable anhydrous polymorphs. A fast cooling rate of 10 °C/min mainly produced δ and amorphous forms of mannitol, regardless of annealing. These results are consistent with those from larger scale equipment. In-line monitoring the solid-state form of a sample is feasible with a Raman spectrometer coupled microscale freeze-drying stage. These results demonstrate the utility of a rapid, in-line, low sample volume method for the semiquantitative analysis of the process and formulation development of freeze-dried products on the microscale.
Original languageEnglish
Pages (from-to)2109-2116
JournalAnalytical Chemistry
Volume85
Issue number4
DOIs
Publication statusPublished - 2013
MoE publication typeA1 Journal article-refereed

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Mannitol
Raman spectroscopy
Drying
Cooling
Annealing
Monitoring
Polymorphism
Principal component analysis
Spectrometers
Raman scattering
Experiments
Temperature

Cite this

Kauppinen, A., Toiviainen, M., Aaltonen, J., Korhonen, O., Järvinen, K., Juuti, M., ... Ketolainen, J. (2013). Microscale freeze-drying with Raman spectroscopy as a tool for process development. Analytical Chemistry, 85(4), 2109-2116. https://doi.org/10.1021/ac3027349
Kauppinen, Ari ; Toiviainen, Maunu ; Aaltonen, Jaakko ; Korhonen, Ossi ; Järvinen, Kristiina ; Juuti, Mikko ; Pellinen, Riikka ; Ketolainen, Jarkko. / Microscale freeze-drying with Raman spectroscopy as a tool for process development. In: Analytical Chemistry. 2013 ; Vol. 85, No. 4. pp. 2109-2116.
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Kauppinen, A, Toiviainen, M, Aaltonen, J, Korhonen, O, Järvinen, K, Juuti, M, Pellinen, R & Ketolainen, J 2013, 'Microscale freeze-drying with Raman spectroscopy as a tool for process development', Analytical Chemistry, vol. 85, no. 4, pp. 2109-2116. https://doi.org/10.1021/ac3027349

Microscale freeze-drying with Raman spectroscopy as a tool for process development. / Kauppinen, Ari (Corresponding Author); Toiviainen, Maunu; Aaltonen, Jaakko; Korhonen, Ossi; Järvinen, Kristiina; Juuti, Mikko; Pellinen, Riikka; Ketolainen, Jarkko.

In: Analytical Chemistry, Vol. 85, No. 4, 2013, p. 2109-2116.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Microscale freeze-drying with Raman spectroscopy as a tool for process development

AU - Kauppinen, Ari

AU - Toiviainen, Maunu

AU - Aaltonen, Jaakko

AU - Korhonen, Ossi

AU - Järvinen, Kristiina

AU - Juuti, Mikko

AU - Pellinen, Riikka

AU - Ketolainen, Jarkko

PY - 2013

Y1 - 2013

N2 - Until recently, the freeze-drying process and formulation development have suffered from a lack of microscale analytical tools. Using such an analytical tool should decrease the required sample volume and also shorten the duration of the experiment compared to a laboratory scale setup. This study evaluated the applicability of Raman spectroscopy for in-line monitoring of a microscale freeze-drying process. The effect of cooling rate and annealing step on the solid-state formation of mannitol was studied. Raman spectra were subjected to principal component analysis to gain a qualitative understanding of the process behavior. In addition, mannitol solid-state form ratios were semiquantitatively analyzed during the process with a classical least-squares regression. A standard cooling rate of 1 °C/min with or without an annealing step at −10 °C resulted in a mixture of α, β, δ, and amorphous forms of mannitol. However, a standard cooling rate induced the formation of mannitol hemihydrate, and a secondary drying temperature of +60 °C was required to transform the hemihydrate form to the more stable anhydrous polymorphs. A fast cooling rate of 10 °C/min mainly produced δ and amorphous forms of mannitol, regardless of annealing. These results are consistent with those from larger scale equipment. In-line monitoring the solid-state form of a sample is feasible with a Raman spectrometer coupled microscale freeze-drying stage. These results demonstrate the utility of a rapid, in-line, low sample volume method for the semiquantitative analysis of the process and formulation development of freeze-dried products on the microscale.

AB - Until recently, the freeze-drying process and formulation development have suffered from a lack of microscale analytical tools. Using such an analytical tool should decrease the required sample volume and also shorten the duration of the experiment compared to a laboratory scale setup. This study evaluated the applicability of Raman spectroscopy for in-line monitoring of a microscale freeze-drying process. The effect of cooling rate and annealing step on the solid-state formation of mannitol was studied. Raman spectra were subjected to principal component analysis to gain a qualitative understanding of the process behavior. In addition, mannitol solid-state form ratios were semiquantitatively analyzed during the process with a classical least-squares regression. A standard cooling rate of 1 °C/min with or without an annealing step at −10 °C resulted in a mixture of α, β, δ, and amorphous forms of mannitol. However, a standard cooling rate induced the formation of mannitol hemihydrate, and a secondary drying temperature of +60 °C was required to transform the hemihydrate form to the more stable anhydrous polymorphs. A fast cooling rate of 10 °C/min mainly produced δ and amorphous forms of mannitol, regardless of annealing. These results are consistent with those from larger scale equipment. In-line monitoring the solid-state form of a sample is feasible with a Raman spectrometer coupled microscale freeze-drying stage. These results demonstrate the utility of a rapid, in-line, low sample volume method for the semiquantitative analysis of the process and formulation development of freeze-dried products on the microscale.

U2 - 10.1021/ac3027349

DO - 10.1021/ac3027349

M3 - Article

VL - 85

SP - 2109

EP - 2116

JO - Analytical Chemistry

JF - Analytical Chemistry

SN - 0003-2700

IS - 4

ER -

Kauppinen A, Toiviainen M, Aaltonen J, Korhonen O, Järvinen K, Juuti M et al. Microscale freeze-drying with Raman spectroscopy as a tool for process development. Analytical Chemistry. 2013;85(4):2109-2116. https://doi.org/10.1021/ac3027349