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 method comprising:
loading containers comprising a liquid solution onto a plurality of tray surfaces in a lyophilization chamber; the liquid solution comprising a solute and a solvent and characterized by a top surface and a bottom surface, and the tray surfaces being disposed between parallel upper and lower heat sinks, with a conductive thermal insulator being disposed between the tray surfaces and each respective lower heat sink; and
lowering the temperature of the heat sinks and thereby the ambient temperature in the lyophilization chamber comprising the containers, tray surfaces, and thermal insulators to a temperature sufficient to freeze the liquid solution from the top and the bottom surfaces at approximately the same rate in each container 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 containers comprise vials.
4. 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.
5. 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 .
6. The lyophilized cake of claim 5 , 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.
7. The method of claim 1 , wherein the solute comprises a sugar.