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                          The Manufacture of Aspirin


1. Introduction

The history, synthesis, and industrial manufacture of aspirin (acetylsalicylic acid)  and related compounds will be covered. The differences between  three levels of chemistry -- student laboratory,bench-scale and industrial scale -- are used to help you  understand the intricate interplay between research chemistry and industrial manufacturing process development. Areas such as acid-base, solution, and equilibrium chemistry are discussed for background. Also, the idea of life-cycle analysis will be explained because of its importance to the various levels of decision-making involved in pollution prevention as it relates to the aspirin production process. Finally, the Batch Design Kit tool will be introduced at the end of the module to show different ways in which decision-making can affect the aspirin manufacturing process described in this  case study,  as well as many other processes.

2. History

2.1 Willow Bark: The Precursor to Aspirin

Today, aspirin is a common remedy. Less than one hundred years ago, however, it was considered a  wonder-drug, the newest thing to hit the stores. Many similar compounds had been produced before and many different means of producing aspirin have been devised since, but nothing has rivaled the success of this one synthetic compound. Before undertaking a discussion of exactly what aspirin is and how it is made, it is important to understand what it came from. More than 2500 years ago, in approximately 500 BC, Chinese healers used willow bark as a remedy for many ailments. About 400 BC, Hippocrates, a Greek often proclaimed as the Father of Medicine, suggested that chewing willow bark lowered fever and reduced pain. Other accounts such as these litter the history books. Five hundred years after Hippocrates, in 100 AD, Dioscorides, a Greek physician, prescribed willow bark to reduce inflammation in his patients. These are the traditional uses of the precursor to aspirin. Unfortunately, during the middle ages, the benefits of willow bark were lost to physicians. Though the use of willow bark for its medicinal properties continued in other parts of the globe. It was forgotten in  Europe was without its benefits for many years.

In the middle of the eighteenth century, Reverend Edward Stone of Oxford began experimenting with ways to reduce fever. Stone pulverized a pound of dried willow bark and gave it to fifty feverish people over several years time. He tried mixing the bark powder into tea, water, or even "small beer." With few exceptions, the fevers disappeared. This might have seemed evident but Stone knew nothing of the thousands of years of cases which preceeded his work. In 1763 The Royal Society of London published Stone's accounts of the success of willow bark in reducing fever. It would still be several years before medicine would be able to make wide use of the bark’s beneficial properties.

In 1828, German chemists isolated the active ingredient in willow bark. Since the Latin name for the willow tree was salix, the new compound was named salicin. When crystallized, salicin was appear yellow and  bitter-tasting. Ten years later, a French chemist synthesized a  purer compound named salicylic acid. Salicylic acid would eventually be used as a building block for many other pharmaceutical compounds including acetylsalicylic acid.

While willow bark was the main source of salicin, several other related plants were producing similar compounds with almost the same types of medicinal powers. Over time, scientists were able to isolate several different salicylic acid derivatives which could be found in nature or more importantly synthesized in the laboratory. One of the most important of these is sodium salicylate. Once ingested this compound is transformed to salicylic acid. Unfortunately for its users, sodium salicylate has the unfortunate side effect of causing upset stomach.

Sodium and methyl salicylate were some of the first salicylates isolated from natural sources. Today there are several salicylates which are used commercially. These include: sodium salicylate, magnesium salicylate, choline salicylate, and choline magnesium salicylate. The most widely used compound, which when ingested becomes salicylic acid is, of course, acetylsalicylic acid.

Before continuing on with the story of aspirin, it is important to take a moment and discuss some of the chemistry involved in the isolation process of salicin and the other salicylates. Earlier, the idea of solubility and crystallization was mentioned. Now, let us take a closer look at these ideas and how they are important to the research chemist trying to isolate a chemical like salicin.

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