Abstract
Bulk solutions of therapeutic proteins are often frozen for long-term storage. During the freezing process, proteins in liquid solution redistribute and segregate in the interstitial space between ice crystals. This is due to solute exclusion from ice crystals, higher viscosity of the concentrated solution, and space confinement between crystals. Such segregation may have a negative impact on the native conformation of protein molecules. To better understand the mechanisms, we developed a phase-field model to describe the growth of ice crystals and the dynamics of freeze concentration at the mesoscale based on mean field approximation of solute concentration and the underlying heat, mass and momentum transport phenomena. The model focuses on evolution of the interfaces between liquid solution and ice crystals, and the degree of solute concentration due to partition, diffusive, and convective effects. The growth of crystals is driven by cooling of the bulk solution, but suppressed by a higher solute concentration due to increase of solution viscosity, decrease of freezing point, and the release of latent heat. The results demonstrate the interplay of solute exclusion, space confinement, heat transfer, coalescence of crystals, and the dynamic formation of narrow gaps between crystals and Plateau border areas along with correlations of thermophysical properties in the supercooled regime.
Highlights
Understanding the mechanisms and process impacts of freezing on protein solutions is critical in the pharmaceutical industry for the manufacturing of high quality biologics
Huang et al [22] revealed directional growth of anisotropic ice crystals in ceramic colloidal suspensions, with the resulting porous material having potential for biomedical applications such as functional materials for implants. These relevant studies have only focused on either thermal or composition with phase transition in the freezing process, at the mesoscale in particular, multiple physics are often convoluted in the phase transition dynamics, requiring the inclusion of the effects of thermal, fluid flow, thermal mechanical response, composition and changes of thermophysical properties into the analysis [23,24]
The solute volume fraction φc (Figure 2b) shows that solutes are pushed away by the interfaces as they grow into the liquid mixture. This is due to solute exclusion from the crystals, and the solute concentration is further enhanced between close-approached crystals as the space is confined
Summary
Understanding the mechanisms and process impacts of freezing on protein solutions is critical in the pharmaceutical industry for the manufacturing of high quality biologics. Huang et al [22] revealed directional growth of anisotropic ice crystals in ceramic colloidal suspensions, with the resulting porous material having potential for biomedical applications such as functional materials for implants These relevant studies have only focused on either thermal or composition with phase transition in the freezing process, at the mesoscale in particular, multiple physics are often convoluted in the phase transition dynamics, requiring the inclusion of the effects of thermal, fluid flow, thermal mechanical response, composition and changes of thermophysical properties into the analysis [23,24]. Instead of anisotropic interfacial energy, the focus here is to couple the evolving dynamics of crystals with fluid flow, heat transfer, protein diffusion, and the convective transport induced by gravity effect and density variation across the moving ice/freeze-concentrate interface. The cooling effect is simplified by using a representative bulk cooling rate, which reduces the computational cost and potentially can be extended and integrated with multiscale analysis including container configuration and experimental settings at a larger scale
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