Purpose Conventional shelf-freezing in pharmaceutical lyophilization suffers from batch variation and is potentially incompatible with emerging continuous lyophilization systems. This work presents a forced gas convective freezing chamber for suspended vials in cross-flow to improve the quality of the freezing process and meet the continuous lyophilization needs. Methods First, computational fluid dynamics simulations were performed to determine key process parameters. Then, physical chambers were built to meet these requirements. Sets of twenty 10R vials containing 3 mL of aqueous solution were frozen to characterize the per-vial heat transfer. Additionally, a novel nucleation technique was investigated where conditioned vials were exposed to an impulse of <InlineEquation ID="IEq1"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="12247_2025_10037_Article_IEq1.gif" Format="GIF" Height="11" Rendition="HTML" Resolution="72" Type="Linedraw" Width="17" /> </InlineMediaObject> <EquationSource Format="TEX">$<$</EquationSource> <EquationSource Format="MATHML"><math> <mo><</mo> </math></EquationSource> </InlineEquation> <InlineEquation ID="IEq2"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="12247_2025_10037_Article_IEq2.gif" Format="GIF" Height="13" Rendition="HTML" Resolution="72" Type="Linedraw" Width="19" /> </InlineMediaObject> <EquationSource Format="TEX">$-$</EquationSource> <EquationSource Format="MATHML"><math> <mo>-</mo> </math></EquationSource> </InlineEquation>30<InlineEquation ID="IEq3"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="12247_2025_10037_Article_IEq3.gif" Format="GIF" Height="7" Rendition="HTML" Resolution="72" Type="Linedraw" Width="9" /> </InlineMediaObject> <EquationSource Format="TEX">$^\circ $</EquationSource> <EquationSource Format="MATHML"><math> <mmultiscripts> <mrow /> <mrow /> <mo>∘</mo> </mmultiscripts> </math></EquationSource> </InlineEquation>C gas. Finally, frozen vials were completely dried in 12 h in an attached vacuum chamber. Results The chambers conditioned vials from 25<InlineEquation ID="IEq4"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="12247_2025_10037_Article_IEq3.gif" Format="GIF" Height="7" Rendition="HTML" Resolution="72" Type="Linedraw" Width="9" /> </InlineMediaObject> <EquationSource Format="TEX">$^\circ $</EquationSource> <EquationSource Format="MATHML"><math> <mmultiscripts> <mrow /> <mrow /> <mo>∘</mo> </mmultiscripts> </math></EquationSource> </InlineEquation>C to −1<InlineEquation ID="IEq5"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="12247_2025_10037_Article_IEq3.gif" Format="GIF" Height="7" Rendition="HTML" Resolution="72" Type="Linedraw" Width="9" /> </InlineMediaObject> <EquationSource Format="TEX">$^\circ $</EquationSource> <EquationSource Format="MATHML"><math> <mmultiscripts> <mrow /> <mrow /> <mo>∘</mo> </mmultiscripts> </math></EquationSource> </InlineEquation>C in under 20 min, with final vial temperatures varying by less than 0.5<InlineEquation ID="IEq6"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="12247_2025_10037_Article_IEq3.gif" Format="GIF" Height="7" Rendition="HTML" Resolution="72" Type="Linedraw" Width="9" /> </InlineMediaObject> <EquationSource Format="TEX">$^\circ $</EquationSource> <EquationSource Format="MATHML"><math> <mmultiscripts> <mrow /> <mrow /> <mo>∘</mo> </mmultiscripts> </math></EquationSource> </InlineEquation>C. The impulse technique induced nucleation in all vials within 30 s without significantly cooling them. After nucleation, the system accessed slow (0.05 g/min) and rapid (1.0 g/min) solidification rates, as well as post-solidification procedures including typical ramp and hold protocols. Dried vials had residual moisture below 2.5 wt% and showed no signs of collapse. Conclusions This freezing chamber was demonstrated to track gas temperature setpoints as low as −50<InlineEquation ID="IEq7"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="12247_2025_10037_Article_IEq3.gif" Format="GIF" Height="7" Rendition="HTML" Resolution="72" Type="Linedraw" Width="9" /> </InlineMediaObject> <EquationSource Format="TEX">$^\circ $</EquationSource> <EquationSource Format="MATHML"><math> <mmultiscripts> <mrow /> <mrow /> <mo>∘</mo> </mmultiscripts> </math></EquationSource> </InlineEquation>C within ±1<InlineEquation ID="IEq8"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="12247_2025_10037_Article_IEq3.gif" Format="GIF" Height="7" Rendition="HTML" Resolution="72" Type="Linedraw" Width="9" /> </InlineMediaObject> <EquationSource Format="TEX">$^\circ $</EquationSource> <EquationSource Format="MATHML"><math> <mmultiscripts> <mrow /> <mrow /> <mo>∘</mo> </mmultiscripts> </math></EquationSource> </InlineEquation>C and induce nucleation in all vials virtually simultaneously, enabling excellent control of the freezing process. The chamber’s cooling via forced convection and its available front and back faces make it compatible with integration into a continuous lyophilization system.

Forced Gas Convection for Uniform Freezing of Lyophilization Vials

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2025年7月29日

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Steven J. Burcat,
Rohan P. Kadambi,
Lorenzo Stratta,
Richard D. Braatz,
Roberto Pisano,
Alexander H. Slocum,
Bernhardt L. Trout

摘要

Purpose

Conventional shelf-freezing in pharmaceutical lyophilization suffers from batch variation and is potentially incompatible with emerging continuous lyophilization systems. This work presents a forced gas convective freezing chamber for suspended vials in cross-flow to improve the quality of the freezing process and meet the continuous lyophilization needs.

Methods

First, computational fluid dynamics simulations were performed to determine key process parameters. Then, physical chambers were built to meet these requirements. Sets of twenty 10R vials containing 3 mL of aqueous solution were frozen to characterize the per-vial heat transfer. Additionally, a novel nucleation technique was investigated where conditioned vials were exposed to an impulse of $<$ $<$ $-$ $-$ 30 $^\circ $ $^{\circ}$ C gas. Finally, frozen vials were completely dried in 12 h in an attached vacuum chamber.

Results

The chambers conditioned vials from 25 $^\circ $ $^{\circ}$ C to −1 $^\circ $ $^{\circ}$ C in under 20 min, with final vial temperatures varying by less than 0.5 $^\circ $ $^{\circ}$ C. The impulse technique induced nucleation in all vials within 30 s without significantly cooling them. After nucleation, the system accessed slow (0.05 g/min) and rapid (1.0 g/min) solidification rates, as well as post-solidification procedures including typical ramp and hold protocols. Dried vials had residual moisture below 2.5 wt% and showed no signs of collapse.

Conclusions

This freezing chamber was demonstrated to track gas temperature setpoints as low as −50 $^\circ $ $^{\circ}$ C within ±1 $^\circ $ $^{\circ}$ C and induce nucleation in all vials virtually simultaneously, enabling excellent control of the freezing process. The chamber’s cooling via forced convection and its available front and back faces make it compatible with integration into a continuous lyophilization system.