Apri 25, 2004
By Narlin B. Beaty, Ph.D.
Chesapeake Biological Laboratories, Inc.
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Elementary lyophilization involves thinking about processes that occur in an environment foreign to
common human experience. The science of lyophilization is taught at the college level in two courses, over
three to four semesters. The courses are physical chemistry and mechanics, and they are often split over
departments, chemistry, physics and engineering. Obviously, the information from those courses is not
tailored to freeze drying and encompass greater depth than required for freeze drying alone. The purpose of
this document is to extract and introduce the relevant sections from those disciplines and to apply it only to
lyophilization. Lyophilization is composed of three events. The first two are freezing and sublimation ?
physical phase changes. The third event, desorption, comes from surface science, a relatively new field that
is still rapidly developing.
Why freeze dry? Usually, the reason is to preserve food or drugs. Freeze drying lowers moisture content
and consequently decreases hydrolysis reactions that ultimately degrade food and pharmaceutical products
despite sterile conditions. Other reasons to freeze dry drugs are to permit product reconstitution at a higher
concentration than it was at the time of freezing, or to permit storage of the product at ambient temperatures.
The later can be particularly useful for hospital products in areas that do not have ready access to freezers,
especially ultra-cold freezers. Although pharmaceutical regulatory authorities will not assign multi-decade
expiration dating to any products, it is well known that the US smallpox vaccine (Dryvax) manufactured by
Wyeth as a lyophilized live virus was found to be still active and still potent 30 years beyond its original date
of manufacture. Freeze drying works.
Technically, lyophilization is the vacuum sublimation of ice crystals that are formed when an aqueous
solution is frozen. Left behind are the solid non-volatile solutes which may have been excipients and
pharmaceutical ingredients of the liquid product. Within the box that is called a lyophilizer there is a large
amount of stainless steel in the way of shelves and tubing. In use, there is also a reasonable amount of glass
as vials. The remainder of the box volume is largely empty. How empty is it, and how does that exert
control over the rate of lyophilization?
Kinetic theory is that branch of physics for which the laws of mechanics (Newton?s Laws) are used to
calculate the properties of bulk matter. It is instructive to apply those laws at the molecular level to the
gasses (usually nitrogen and water) that compose the atmosphere during lyophilization. The first derivation
of kinetic theory was provided by Daniel Bernoulli in 1738. Through consideration of nothing more than
the elastic collision of rigid spheres, he successfully derived Boyle?s Law (At constant temperature, gas
volume varies inversely as the pressure). Since lyophilization is all about temperature and pressure, and
since pressure relationships can be obtained from idealized models of rigid spheres, then lyophilization, to
the extent that it involves gas molecules, may also be understood through kinetic theory.