Optimization of nucleation and crystallization for lyophilization using gap freezing
View Patent ↗This application discloses devices, articles, and methods useful for producing lyophilized cakes of solutes. The devices and articles provide for a method of freezing liquid solutions of the solute by the top and the bottom of the solution simultaneously. The as frozen solution then provides a lyophilized cake of the solutes with large and uniform pores.
1. A lyophilization device comprising:
a plurality of heat sinks that individually have a heat sink surface in thermal communication with a refrigerant, at least one of said heat sinks being disposed above another to thereby form upper and lower heat sinks; wherein the lower heat sink surface is disposed between the upper and lower heat sinks;
a tray carrying a tray surface disposed between the upper heat sink and a lower heat sink surface; and
a thermal insulator formed extending between the container on the tray and the lower heat sink, wherein the thermal insulator is a gas having a thermal conductivity of less than about 0.2 W/mK at 25° C.
2. The article of claim 1 , wherein the heat sink comprises a refrigerant conduit in thermal communication with the heat sink surface.
3. The article of claim 2 , wherein the heat sink further comprises a heat sink medium disposed between the refrigerant conduit and the heat sink surface.
4. The article of claim 1 , wherein the heat sink surface and tray surface—are separated by a fixed distance of greater than about 0.5 mm.
5. The article of claim 1 further comprising a spacer disposed between the heat sink surface and the tray surface.
6. The article of claim 5 , wherein the spacer has a thickness of greater than about 0.5 mm.
7. The article of claim 1 , wherein the tray carrying the tray surface is supported by a brace affixed to an internal wall of the lyophilization device.
8. The article of claim 1 , wherein the thermal insulator is air having a pressure below atmospheric pressure.
9. The article of claim 1 , comprising a plurality of said upper and lower heat sink pairs with interdisposed trays.
10. The article of claim 1 , further comprising a container disposed on the tray.
11. The article of claim 10 , wherein the container comprises a vial.
12. The article of claim 10 , wherein the container holds a liquid solution.
13. The article of claim 12 , wherein the liquid solution comprises a sugar.
14. The article of claim 1 , wherein the thermal insulator has a thermal conductivity of less than about 0.1 W/mK at 25° C.
15. The article of claim 14 , wherein the thermal insulator has a thermal conductivity of less than about 0.05 W/mK at 25° C.
16. The article of claim 1 , wherein the heat sink surface and tray surface are separated by a fixed distance in a range of about 0.5 mm to about 50 mm.
17. The article of claim 1 , wherein the heat sink surface and tray surface are separated by a fixed distance in a range of about 0.5 mm to about 10 mm.