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                           The Manufacture of Aspirin



4.2 The Industrial Procedure For Synthesizing 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 (acetylsalicylic acid)

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.

4.2.2 Purification's

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.


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