Through-vial impedance spectroscopy of critical events during the freezing stage of the lyophilization cycle: the example of the impact of sucrose on the crystallization of mannitol.
The aim of this work was to evaluate the application of through-vial impedance spectroscopy in the measurement of eutectic crystallization during the freezing stage of the lyophilisation cycle. Impedance measurements of various sugar solutions (mannitol 5%, 10% and 15% w/v, sucrose 5% w/v and mannitol 5% w/v, and sucrose 5% w/v solutions) were taken during a freeze-thaw cycle, over a frequency range 10-10(6) Hz with a scan interval of 1.5 min, using measurement vials with externally attached electrodes connected to a high resolution impedance analyzer. Estimates for the electrical resistance of the mannitol solutions record the exothermic crystallization of mannitol at a temperature of -24 °C during the temperature ramp down stage of the freezing cycle, which is in close agreement with the off-line DSC measurement of -22 °C. The freezing profile of a 5% mannitol solution with 5% sucrose (a component that does not crystallize in the frozen solution) demonstrated the inhibition of mannitol crystallization (with the implication that the product will then require sub-Tg' freezing and drying). The work suggests a role for through-vial impedance spectroscopy in the concurrent development of the product formulation and freeze drying cycle without the uncertainty introduced when using off-line date to define the critical process parameters.
Leicester School of Pharmacy, De Montfort University, Leicester, United Kingdom.
Muhammad Sohail
MS
Arshad
Leicester School of Pharmacy, De Montfort University, Leicester, United Kingdom. Electronic address: GSmith02@dmu.ac.uk.
Geoff
G
Smith
Leicester School of Pharmacy, De Montfort University, Leicester, United Kingdom.
Eugene
E
Polygalov
Leicester School of Pharmacy, De Montfort University, Leicester, United Kingdom.
Irina
I
Ermolina
D002152:Calorimetry, Differential Scanning / Q000379:methods; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization / Q000379:methods; D058266:Dielectric Spectroscopy / Q000379:methods; D005612:Freeze Drying / Q000379:methods; D005615:Freezing; D008353:Mannitol / Q000737:chemistry*; D012996:Solutions / Q000737:chemistry; D013395:Sucrose / Q000737:chemistry*; D013696:Temperature
D012996:Solutions; D008353:Mannitol; D013395:Sucrose
Eutectic crystallization; Freeze drying; Impedance measurements; Mannitol; Process analytical technology (PAT); Sucrose