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The Manufacture of Aspirin
The procedure used today to synthesize acetylsalicylic acid differs
from the ones first theorized and eventually developed by the pharmaceutical
chemists of the late nineteenth century. The most glaring difference is
the scale of the reaction. Bench chemists who work in laboratories are
interested in creating a few grams of material. Industrial processes generally
require kilograms of reactants in mixing tanks and storage containers which
are several hundred gallons each. Less clearly identified but equally important
is the temperature concerns of the reaction, the purity of the end product,
the economic cost of different reactants and catalysts, as well as many
other factors. Today, there are a large number of companies from various
countries which manufacture aspirin under more than a hundred trade names.
Not all of these manufacturers use the same synthesis process or even start
at the same level of production. Since the formation of aspirin can be
accomplished through the reaction of two well established chemicals, it
is difficult to show the entire industrial process in this case study.
One of those processes is described below. The information is taken from
the Pharmaceutical Manufacturing Encyclopedia and U.S. patent 2,731,492.
4.2.1 Synthesizing Aspirin
The main reactor for the process is a glass-lined 1500 gallon tank fitted
with a water-cooled reflux condenser, thermometers with automatic temperature
registers, and an efficient agitator.
The reactor is charged with a mother liquor. The mother liquor is prepared
by dissolving 1532 kilograms of acetic anhydride (15 mols) in 1200 kilograms
of toluene. The toluene is a solvent which does not participate in the
reaction and so can be recovered later and reused.
1382 kilograms of salicylic acid (10 mols) is added to the mother liquor
in the reactor.
The reaction mixture is heated to between 88 and 92 degrees Celsius.
It is kept at this temperature for twenty hours. Next, the reaction mixture
is transferred to aluminum cooling tanks and is allowed to cool for 3 to
4 days. By the end of cooling the mixture has reached room temperature,
approximately 15 to 25 degrees celsius.
At this point, the acetylsalicylic acid has precipitated as large regular
crystals. The mother liquor is now removed through filtration or centrifuging
to separate out as much liquid as possible. The filtrate will be a solution
of 180 to 270 kilograms of unprecipitated acetylsalicylic acid (1.0 to
1.5 mols), 510 kilograms of acetic anhydride (5.0 mols), 600 kilograms
of acetic acid (10.0 mols) and 1200 kilograms of toluene. The acetic acid
is obtained as a by-product of the acetylation step of the process.
Next, ketene gas is passed through the recycled filtrate at a temperature
of 15 to 25 degrees celsius. The gas is introduced into a well agitated
reactor using a diffusion plate or sparger. This continues until there
is a weight increase of 420.5 kilograms of ketene (10 mols) is observed.
At this point, the mother liquor contains 180 to 270 kilograms of unprecipitated
acetylsalicylic acid (1.0 to 1.5 mols) and 1532 kg of acetic anhydride
(15 mols) in 1200 kilograms of toluene.
The mother liquor is recycled and 1382 kilograms of salicylic acid (10
mols) is added to continue the reaction cycle.
The acetylsalicylic acid which was extracted after the initial reaction
is washed with distilled water until all the acetic acid is removed. It
is then pressed or centrifuged as dry as possible and then dried more by
a current of warm air at 60 to 70 degrees celsius.
The yield of pure acetylsalicylic acid is between 1780 to 1795 kilograms
per batch for this reaction process.
4.2.3 What's Next
It was only a matter of time before aspirin became so widely known that
itís name was used interchangeably with acetylsalicylic acid. Toady, over
one hundred companies hold patents for processes which generate aspirin.
Each is slightly different but all end with the same molecule. This, however,
does not mean that all work has stopped. In the age of economic and environmental
pressures, every process is being examined for its efficiency and safety
of the company and the environment. The remainder of this case study will
look at issues related to these topics.