title: Microscale freeze-drying with Raman spectroscopy as a tool for process development.
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.
authors: School of Pharmacy, Promis Centre, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland. ari.kauppinen@uef.fi
authors: Ari
authors: A
authors: Kauppinen
authors: Maunu
authors: M
authors: Toiviainen
authors: Jaakko
authors: J
authors: Aaltonen
authors: Ossi
authors: O
authors: Korhonen
authors: Kristiina
authors: K
authors: Järvinen
authors: Mikko
authors: M
authors: Juuti
authors: Riikka
authors: R
authors: Pellinen
authors: Jarkko
authors: J
authors: Ketolainen
mesh_terms: D002152:Calorimetry, Differential Scanning; D005612:Freeze Drying; D016018:Least-Squares Analysis; D008353:Mannitol / Q000737:chemistry*; D025341:Principal Component Analysis; D013059:Spectrum Analysis, Raman; D013696:Temperature
chemical_list: D008353:Mannitol