Business Considerations - Fundamentals of Industrial Chemistry: Pharmaceuticals, Polymers, and Business - page 78

of one of the starting materials was slightly different. Surprisingly, the purer
product used in the U.S. gave poorer results because a minor impurity in that
ingredient was critical for success.
Many chemicals are relatively easy to use in the laboratory but because of
reactivity, flammability, or toxicity can present problems on scale-up. They
can require special procedures or equipment and can increase the cost of
the process. It is sometimes appropriate to completely change a synthetic
sequence in order to avoid the use of certain chemicals.
Laboratory reactions are often done in a glass flask with plenty of surface
area. The reaction can be heated or cooled by placing the flask in a container
containing a hot or cold liquid. To cool, ice baths are commonly used. Baths
containing an organic solvent and dry ice such as dry ice/acetone baths are
also routinely used if further cooling is warranted. Flasks can be heated with
hot water, steam, or by immersing them in hot oil. There is a multitude of
options in the laboratory.
There are fewer practical heat-transfer options on scale-up, especially if
required to use existing equipment. Reactions are often done in large volume
reactors which have much less surface area per reactor volume than the
laboratory flask. Because of this, heat transfer is often much less efficient.
The heating or cooling is often done by use of a jacketed reactor. A liquid is
pumped through a jacket which surrounds the reactor and provides heating
or cooling. Often there are limitations as to the heat transfer fluid to be used.
For example, a reactor equipped with cooling water is not typically also used
with hot oil circulating in the jacket.
It is a lot easier and faster to cool from 70 ∘ Cto10 ∘ C if you have 50 mL
in the laboratory setting than if you have 3,000 gallons in a plant reactor. The
time factor can be important if there are stability issues with your reaction
mixture. It is important to recognize that operations can take much longer and
to plan for this. One scale-up I experienced involved a chemical that would
degrade in the liquid state. In the laboratory, it was purified, cooled to solidify
and stored in a refrigerator. When needed, it was melted just prior to use. This
was trivial in the laboratory but disastrous upon scale-up. After larger scale
purification, it took many hours to cool it to solidify and there was some loss
of purity. Then after storage, melting was a very long process and the purity
suffered more. The lesson is that heat transfer limitations need to be given
serious consideration prior to scale-up.
Heat transfer is even more serious for an exothermic reaction. Minor
exotherms in the laboratory may not even be apparent or if they are noticed
can be easily controlled with cooling. However, the same exotherm on a large
scale can be difficult to control and even present a safety hazard. Therefore it
is important to thoroughly understand the thermodynamics before increasing
reaction scale. This is often done by calorimetry experiments.