Phase-Field Modeling of Freeze Concentration of Protein Solutions

Fan, Tai‐Hsi; Li, Ji-Qin; Minatovicz, Bruna; Soha, Elizabeth; Sun, Lanxiang; Patel, Sajal M.; Chaudhuri, Bodhisattwa; Bogner, Robin H.

doi:10.3390/polym11010010

Cited by 21 publications

(6 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Among the excipients used to stabilize frozen and freeze-dried materials, sucrose is perhaps the most widely used. 12 In prior analyses of freezing dynamics of sucrose solution, 13,14 we have not addressed the subtle details of interfacial instability and the anisotropic effect during ice crystal formation. The interfacial stability primarily depends on the interplay of solutal and thermal effects.…”

Section: Introductionmentioning

confidence: 99%

Dendritic Morphology and Growth Inhibition of Ice Crystals in Sucrose Solutions

Rahman

Patel

et al. 2022

Crystal Growth & Design

Self Cite

View full text Add to dashboard Cite

The impact of freeze-concentrated solutes on ice crystal growth is not well understood in pharmaceutical processes. We present a quantitative analysis of the inhibition of anisotropic growth of ice crystals in sucrose solutions by combining the phase-field method and the Flory–Huggins solution theory. To better understand the driving mechanisms underlying the dendritic morphology and the freeze-concentration effect, the diffusion–partition coupling and the anisotropic interfacial energy are integrated using the thermodynamic approach. The computational results indicate that the sucrose in an aqueous solution inhibits or slows down the growth of ice crystals while enhancing the degree of branching due to the interfacial instability promoted by segregated solutes. Meanwhile, a self-similar dendritic pattern is found by covarying the initial solute concentration and the degree of supercool. The analysis and computational results are consistent with the experimental observations.

show abstract

Section: Introductionmentioning

confidence: 99%

Dendritic Morphology and Growth Inhibition of Ice Crystals in Sucrose Solutions

Rahman

Patel

et al. 2022

Crystal Growth & Design

Self Cite

View full text Add to dashboard Cite

show abstract

“…Freeze concentration was shown to be dependent on the freezing process rather than storage temperature (Hauptmann et al, 2019). However, investigations of freeze-thaw characterizations with a focus on heat transfer and phase change are missing (Fan et al, 2018), but necessary to ensure process scalability and to allow process optimization with regards to ideal freezing temperature. A key parameter often used for characterization of freezing processes is the ice front velocity, which impacts the maximum freeze concentration (Webb et al, 2002;Rodrigues et al, 2011;Hauptmann et al, 2019) and the total freezing time.…”

Section: Introductionmentioning

confidence: 99%

Temperature Based Process Characterization of Pharmaceutical Freeze-Thaw Operations

Weber

Hubbuch

2021

Front. Bioeng. Biotechnol.

View full text Add to dashboard Cite

In biopharmaceutical production processes, freeze-thaw operations are used to ensure product integrity during long hold times, but they also introduce additional stresses such as freeze concentration gradients that might lead to a loss of protein activity. Process characterization of freeze-thaw operations at different scales should be conducted with attention to freezing time and boundary effects to ensure the product stability throughout the process and process development. Currently, process characterization often relies on one or very few temperature probes that detect freezing times based on raw temperature, which is largely influenced by freezing-point depression in case of concentrated solutions. A method to detect freezing based on the second derivative of temperature measurements from Fiber-Bragg-Grating sensors is presented to overcome this issue. The applicability of the method is demonstrated by process characterization of a novel small-scale freeze-thaw device with minimized boundary effects using freezing times of purified water and concentrated formulations. Freezing times varied from 35 to 81 min for temperatures between −60 and −20°C and impacted freeze concentration profiles. Furthermore, freezing time estimations based on the Plank equation revealed model limitations due to start-up temperature gradients, that can be corrected by an empirically extended Plank model. As a hypothesis, we conclude that freezing temperature, from a freeze concentration view, is less important in containers with small characteristic freezing distances such as freeze bags. Using a 2D-resolved temperature profile, a shift of the last point to freeze position from top to bottom of a container was observed when freezing above −30°C.

show abstract

“…For example, denaturation of proteins at the ice-liquid interface has been reported for many proteins (33,34). Another consequence of the ice formation is the freeze concentration of all solutes remaining in the unfrozen solution, including proteins (35,36). Apart from the up-concentration of solutes, which may accelerate bimolecular reactions leading to protein aggregation, phase separation may also occur as a consequence of freeze concentration (37).…”

Section: Effect Of Processing Conditions On Protein Stabilitymentioning

confidence: 99%

Use of a Design of Experiments (DoE) Approach to Optimize Large-Scale Freeze-Thaw Process of Biologics

2021

Self Cite

View full text Add to dashboard Cite

Large volumes of protein solutions are commonly stored in a frozen state before further drug product fill and finish. This study aimed to establish a design space to perform large-scale freeze-thaw (F/T) processes of biotherapeutics without inducing protein destabilization. A response surface model was designed to evaluate the following main factors and interactions: fill volume of the protein solution in 1-L containers, distance among nine containers during both F/T, freezer set temperature, and a novel forced air flow methodology during thawing. The analysis from 46 experimental runs indicated over 4-fold increase in the freezing rate by lowering the freezing temperature from −20 to −80°C, and the forced air flow at 98 fpm doubled the thawing rate. Furthermore, multivariate linear regression modeling revealed the significant impact of all main factors investigated on lactate dehydrogenase (LDH) quality attributes. The factor that most strongly affected the retention of LDH activity was the loading distance: ≥ 5 cm among containers positively affected the LDH activity response in 50.6%. The factor that most strongly retained the LDH tetramers was the set freezer temperature towards the lower range of −80°C (2.2% higher tetramer retention compared to −20°C freezing, due to faster freezing rate). In summary, this DoEbased systematic analysis increased F/T process understanding at large scale, identified critical F/T process parameters, and confirmed the feasibility of applying faster freezing and forced air thawing procedures to maintain the stability of LDH solutions subject to largescale F/T.

show abstract

Phase-Field Modeling of Freeze Concentration of Protein Solutions

Cited by 21 publications

References 41 publications

Dendritic Morphology and Growth Inhibition of Ice Crystals in Sucrose Solutions

Dendritic Morphology and Growth Inhibition of Ice Crystals in Sucrose Solutions

Temperature Based Process Characterization of Pharmaceutical Freeze-Thaw Operations

Use of a Design of Experiments (DoE) Approach to Optimize Large-Scale Freeze-Thaw Process of Biologics

Contact Info

Product

Resources

About