ABSTRACT
Freezing and freeze-drying processes are commonly used to extend the shelf life of drug products and to ensure their safety and efficacy upon use. When designing a freezing process, it is beneficial to characterize multiple physicochemical properties of the formulation, such as nucleation rate, crystal growth rate, temperature and concentration of the maximally freeze-concentrated solution, and melting point. Differential scanning calorimetry has predominantly been used in this context but does have practical limitations and is unable to quantify the kinetics of crystal growth and nucleation. In this work, we introduce a microfluidic technique capable of quantifying the properties of interest and use it to investigate aqueous sucrose solutions of varying concentration. Three freeze-thaw cycles were performed on droplets with 75-µm diameters at cooling and warming rates of 1 °C/min. During each cycle, the visual appearance of the droplets was optically monitored as they experienced nucleation, crystal growth, formation of the maximally freeze-concentrated solution, and melting. Nucleation and crystal growth manifested as increases in droplet brightness during the cooling phase. Heating was associated with a further increase as the temperature associated with the maximally freeze-concentrated solution was approached. Heating beyond the melting point corresponded to a decrease in brightness. Comparison with the literature confirmed the accuracy of the new technique while offering new visual data on the maximally freeze-concentrated solution. Thus, the microfluidic technique presented here may serve as a complement to differential scanning calorimetry in the context of freezing and freeze-drying. In the future, it could be applied to a plethora of mixtures that undergo such processing, whether in pharmaceutics, food production, or beyond.
ABSTRACT
To understand the crystallization of aqueous solutions in the atmosphere, biological specimens, or pharmaceutical formulations, the rate at which ice nucleates from pure liquid water must be quantified. There is still an orders-of-magnitude spread in the homogeneous nucleation rate of water measured using different instruments, with the most important source of uncertainty being that of the measured temperature. Microfluidic platforms can generate hundreds to thousands of monodisperse water-in-oil droplets, unachievable by most other techniques. However, most microfluidic devices previously used to quantify homogeneous ice nucleation rates have reported high temperature uncertainties, between ±0.3 and ±0.7 K. We use the recently developed Microfluidic Ice Nuclei Counter Zurich (MINCZ) to observe the freezing of spherical water droplets with two diameters (75 and 100 µm) at two cooling rates (1 and 0.1 K min-1). By varying both droplet volume and cooling rate, we were able to probe a temperature range of 236.5-239.3 K with an accuracy of ±0.2 K, providing reliable data where previously determined nucleation rates suffered from large uncertainties and inconsistencies, especially at temperatures above 238 K. From these data and from Monte Carlo simulations, we demonstrate the importance of obtaining a sufficiently large dataset so that underlying nucleation rates are not overestimated at higher temperatures. Finally, we obtain new parameters for a previous parameterisation by fitting to our newly measured nucleation rates, enabling its use in applications where ice formation needs to be predicted.
