Drying and gas or vapor contact with solids – Process – Freeze-drying
Reexamination Certificate
2001-03-12
2003-05-20
Lu, Jiping (Department: 3749)
Drying and gas or vapor contact with solids
Process
Freeze-drying
C034S287000, C034S289000, C034S297000, C034S092000
Reexamination Certificate
active
06564471
ABSTRACT:
TECHNICAL FIELD
This invention relates generally to apparatus and methods used for freeze-drying products or specimens. That is, the present invention relates to apparatus and methods for removing a solvent, typically water, from a specimen containing a solvent by first reducing the temperature of the specimen so that the solvent solidifies and then exposing the sample to subatmospheric pressures so that the frozen solvent sublimates with little or no generation of liquid solvent. Specifically, the present invention provides improved methods and apparatus for freeze-drying in which the process can be performed more quickly and more efficiently than conventional processes.
BACKGROUND OF THE INVENTION
Freeze-drying, which is also known as lyophilization, is the process of removing a solvent, typically water, from a product by sublimation and desorbtion. Though the laymen may associate the freeze-drying process with instant coffee, the process is typically applied to a broad range of medical, biological, and pharmaceutical products, typically for preservation of the product being treated. For example, some pharmaceutical compounds decompose in the presence of water and freeze-drying these compounds improves their stability and shelf life. Many parentereal medications, such as vaccines, proteins, peptides, and antibiotics, have been successfully freeze-dried. Many products in the burgeoning field of biotechnology are also amenable to freeze-drying and new developments in this field will increase the demand for freeze-drying methods and apparatus.
Freeze-drying typically is performed in a three-phase process: freezing, primary drying, and secondary drying. During the freezing phase, the goal is to freeze the solvent, typically water, of the product being treated. Significant supercooling of the liquid solvent may be encountered during the freezing step, so the temperature of the freezing step is typically much lower than the actual freezing temperature of the solvent to ensure that freezing (that is, solidification) of all the solvent present occurs. Cooling to temperatures below the freezing point of the solvent, for example, to temperatures of minus 40 degrees or below, better ensures that the specimen is “fully frozen”. That is, cooling to these low temperatures minimizes the presence of any liquid in the specimen, for example, liquid eutectics interstitially located between other solidified components of the specimen, the presence of which can produce inferior freeze-dried products. The rate of cooling will influence the structure of the frozen matrix. The method of cooling will also affect the structure and appearance of the matrix and final product. Thus, in the freeze-drying process the regulation and control of the freezing process is very important to the quality of the resulting freeze-dried substance. According to one aspect of the present invention, the freezing phase of the freeze-drying process can be more efficiently regulated.
In the primary drying phase, the pressure to which the frozen sample is exposed is reduced, and then heat is applied to the product to cause the frozen solvent to sublime, or pass from a solid phase directly to a gaseous phase. The solvent vapor is collected, for example, on the surface of a condenser. The condenser must have sufficient surface area and cooling capacity to hold all of the solvent sublimated from the product sample. In addition, it is preferred that the surface temperature of the condensed solvent be lower than the product temperature. If the temperature of the condensed solvent on the condenser (for example, the ice formed on the condenser coils) is warmer than the product, solvent vapor will tend to flow toward the product and not the condenser and drying will stop. Of course, this is undesirable. According to another aspect of this invention, the location of the condensing surface provides enhanced condensation compared to the prior art.
It is important to control the drying rate and the heating rate during the primary drying phase. If the drying proceeds too rapidly, sublimation can occur too rapidly and the rapid release of gaseous solvent from within the product can violently eject some of the product out the container holding the product and result in unusable product. If the product is heated too rapidly, the product will melt or collapse. This may cause degradation of the product, and will certainly change the physical characteristics of the dried material, making it visually unappealing and harder to reconstitute. While frozen solvent is present, the product must be held below the eutectic temperature or glass transition temperature of the solvent.
After completion of the primary drying phase, there is typically no “mobile” liquid solvent remaining in the product. Thus, after the primary drying phase, the temperature of the freeze-dryer, for example, the shelf temperature, may be increased without causing melting. However, there may be immobile, trapped, or “bound” liquid solvent still present in the product. Therefore, to remove this bound solvent, the temperature can be increased to desorb the bound liquid solvent, such as the water of crystallization, until the residual liquid solvent content falls to the range required for optimum product stability. This phase of the freeze-drying process is referred to as “secondary drying”. Secondary drying is usually performed at the maximum vacuum that the dryer can achieve, although there are products that benefit from increased pressures also.
Freeze-drying equipment has improved over the years, and, with the advent of automated, sophisticated control mechanisms, freeze-drying equipment has become much easier to use. However, there is still a need to improve the operation and maintainability of prior art freeze-dryers.
One prior art freeze-dryer over which the present invention is an improvement, is the ALPHA 1-2 freeze-dryer manufactured by Martin Christ of Osterode, Germany, for example, the freeze-dryer disclosed in the undated Martin Christ brochure entitled “ALPHA, The Freeze Dryer”. For example,
FIG. 1
of this brochure illustrates a shallow-pan freeze dryer having exposed cooling coils about its internal surface. Not only can the location and configuration of these coils interfere with the handling of specimens and the cleaning of the device shown, but exposed coils such as these are limited to cooling the specimens shown only by means of radiation and convection. This cooling at-a-distance is not as efficient or as effective as cooling by direct thermal contact with the specimen being cooled. In addition, the treatment chambers shown in this brochure typically include a plurality of ports or orifices, for example, for vacuum source access, coolant ingress and egress, and drains, that also require machining during fabrication and maintenance during use.
Regardless of the improvements made, existing methods and equipment for effecting freeze-drying still have limited cooling capacity, require multiple ports in the treatment chamber, and are cumbersome to use due to the presence of exposed cooling coils, among other disadvantages. The present invention provides enhanced methods and apparatus for freeze-drying which overcome these and other limitations of the prior art.
SUMMARY OF THE INVENTION
The present invention provides methods and apparatus which address many of the limitations of prior art methods and apparatus. Though the present invention can be adapted for large commercial processing, the present invention is typically applicable to “bench-top” applications, for example, for research or academic laboratories. The present invention can be designed to have an “ice capacity” of up to about 100 kg or more, but, typically the present invention has a capacity of less than 50 kg, for example, between about 1 and 10 kg. One embodiment of the present invention is a freeze-dryer comprising: a chamber having a cover, side walls and a thermally-conductive base, the base having an interior surface and a conduit therein; a specimen holder disposed in the chamber for holdin
Blednick Miriam
Sutherland David T.
Heslin Rothenberg Farley & & Mesiti P.C.
Lu Jiping
Pietrangelo John
S. P. Industries, Inc., The Virtis Division
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