Optimization of Nucleation and Crystallization for Lyophilization Using Gap Freezing

• US 20120077971A1
• Filed: 09/27/2011
• Published: 03/29/2012
• Est. Priority Date: 09/28/2010
• Status: Active Grant

• Current Assignee: Baxter Healthcare SA (Baxter International Inc.), Baxter International Inc.
• Original Assignee: Baxter Healthcare SA (Baxter International Inc.), Baxter International Inc.
• Inventors: Kuu, Wei Y.
• Granted Patent: US 8,689,460 B2
• Time in Patent Office: Days
• US Class Current: 536/123
• CPC Class Codes: F26B 5/06 the process involving freezing

Abstract

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.

Claims

1. A method comprising:

loading a container comprising a liquid solution into a lyophilization chamber comprising a heat sink;

the liquid solution comprising a solute and a solvent and characterized by a top surface and a bottom surface;

providing a thermal insulator between the container and the heat sink; and

lowering the temperature of the heat sink and thereby the ambient temperature in the lyophilization chamber comprising the container and thermal insulator to a temperature sufficient to freeze the liquid solution from the top and the bottom surfaces at approximately the same rate and form a frozen solution.

2. The method of claim 1 further comprising reducing the ambient pressure in the chamber to lyophilize the frozen solution.

3. The method of claim 1, wherein the container comprises a vial.

4. The method of claim 1, wherein the lyophilization chamber comprises a plurality of heat sinks.

5. The method of claim 4, comprising loading the container comprising the liquid solution into the lyophilization chamber between two parallel heat sinks.

6. The method of claim 1, wherein the heat sink comprises a heat sink surface, the container comprises a bottom, and the thermal insulator comprises a gap between the heat sink surface and the container bottom.

7. The method of claim 1 further comprising loading the container comprising the liquid solution onto a tray surface;

wherein the thermal insulator is disposed between the tray surface and the heat sink.

9. A lyophilized cake comprising:

a lyophilized material; and

a plurality of pores in the lyophilized material having substantially the same pore size;

wherein the lyophilized cake is made by the method of claim 2.

10. The lyophilized cake of claim 9, wherein the pore size is substantially larger than the pore size of a reference lyophilized cake;

the reference lyophilized cake comprising the same material as the lyophilized cake but made by a method comprising loading a container comprising a liquid solution into a lyophilization chamber comprising a heat sink;

the liquid solution comprising the material and a solvent;

excluding a thermal insulator between the container and the heat sink;

lowering the temperature of the heat sink and thereby the ambient temperature in the lyophilization chamber comprising the container comprising the liquid solution to a temperature sufficient to freeze the liquid solution;

freezing the liquid solution; and

lyophilizing the frozen solution.

8. In a method of freezing a liquid solution for subsequent lyophilization, the liquid comprising top and bottom surfaces and disposed in a container, and the container disposed in a lyophilization chamber comprising a heat sink, the improvement comprising separating the container from direct contact with the heat sink to thereby freeze the solution from the top and bottom surfaces at approximately the same rate.

11. An article adapted for use in a lyophilization chamber comprising:

a heat sink comprising a heat sink surface in thermal communication with a refrigerant;

a tray surface; and

a thermal insulator disposed between the heat sink surface and the tray surface.

12. The article of claim 11, wherein the heat sink comprises a refrigerant conduit in thermal communication with the heat sink surface.

13. The article of claim 12, wherein the heat sink further comprises a heat sink medium disposed between the refrigerant conduit and the heat sink surface.

14. The article of claim 11, wherein the heat sink surface and tray surface are separated by a fixed distance of greater than about 0.5 mm.

15. The article of claim 11 further comprising a spacer disposed between the heat sink surface and the tray surface.

16. The article of claim 15, wherein the spacer has a thickness of greater than about 0.5 mm.

17. The article of claim 15, wherein the spacer supports a tray carrying the tray surface.

18. The article of claim 11, wherein the thermal insulator carries the tray surface.

19. 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 surface disposed between the upper heat sink and a lower heat sink surface; and

a thermal insulator disposed between the tray surface and the lower heat sink.

20. The article of claim 19, wherein the heat sink comprises a refrigerant conduit in thermal communication with the heat sink surface.

21. The article of claim 20, wherein the heat sink further comprises a heat sink medium disposed between the refrigerant conduit and the heat sink surface.

22. The article of claim 19, wherein the heat sink surface and tray surface are separated by a fixed distance of greater than about 0.5 mm.

23. The article of claim 19 further comprising a spacer disposed between the heat sink surface and the tray surface.

24. The article of claim 23, wherein the spacer has a thickness of greater than about 0.5 mm.

25. The article of claim 23, wherein the spacer supports a tray carrying the tray surface.

26. The article of claim 19, wherein the thermal insulator carries the tray surface.

27. The article of claim 19, wherein a tray carrying the tray surface is supported by a brace affixed to an internal wall of the lyophilization device.

28. A sample container comprising

a vial comprising top and a bottom;

and

a thermally insulating support affixed to the bottom of the vial, the thermally insulating support having a thermal conductivity less than about 0.2 W/m·

K at 25°

C.

29. The vial of claim 28, wherein the vial and the insulating support comprise different materials from each other.