Terminology and processes used in drug manufacture

The terms and nomenclature used in chemistry might seem over-complicated at first, but they have been internationally accepted. In this book we use the scientific names for chemicals, not their trivial or common names, e.g. ethanoic acid is used for acetic acid (a constituent of vinegar).
As disease agents, such as MRSA, become more and more resistant to drugs, the search is on for new drugs to combat disease and attack viruses. Where should we look for new sources of combatants against disease? We should look where people have always looked – the natural drugs present in the plant world. There have always been ‘witch doctors’ and old women who have come up with concoctions which supposedly combat diseases, for example hanging garlic bags around a person’s neck to drive away the plague, wearing copper bracelets to counteract arthritis or chewing the leaves of certain plants. Some of these remedies might have real significance.

Some of the most promising places to search for suitable plants are in the tropical rain forests, although even plants in places such as Milton Keynes seem to have medicinal uses, for example willow tree bark. The willow tree was the original source of aspirin-like medicines in Britain. It cured the pains from various complaints.
Herbal concoctions have been the basis of healing and also poisoning for centuries. Curare was used on the tips of poison darts to kill opponents, but in smaller quantities it was used as a muscle relaxant in surgery up to the 1960s.1 Foxglove (digitalis) extracts, as well as being poisonous, have been found to help reduce blood pressure and aid people with heart problems. ‘My mother-in-law used to wrap cabbage leaves around her arthritic knees to give her relief from pain just as her mother before had done’. In 2003 a short note in a British medical journal reported that this ‘old wives tale’ has been shown to have a scientific reason.2 Approximately 80% of modern drugs came initially from natural sources. There are more different species of plants in the rain forests than in any other area on Earth. Many of these species are yet to be discovered and studied in detail. Every year, thousands of plant samples are collected by drug companies to find out whether they have any anti-disease activity. Many of them do. In the mean time, we continue to destroy the rain forests just to obtain teak furniture or some extra peanuts, but that is another story.
The principles of how chemicals are isolated from plants will be used as an example. Aspirin has been chosen because it is one of the most widely used drugs in the world and it is also one of the most chemically simple, as well as one of the cheapest.
About 50 000 000 000 aspirin tablets are consumed each year throughout the world. On average, each adult takes the equivalent of 70 aspirin tablets (or tablets containing it) each year in the UK, but where did it all start?
Over 2400 years ago in ancient Greece, Hippocrates recommended the juice of willow leaves for the relief of pain in childbirth. In the first century AD in Greece, willow leaves were widely used for the relief of the pain of colic and gout. Writings from China, Africa and American Indians have all shown that they knew about the curative properties of the willow.
In 1763 the use of willow tree bark was reported in more specific terms by Reverend Edward Stone in a lecture to the Royal Society in London. He used its
extracts to treat the fever resulting from malaria (then common in Britain; there are some marshes in the UK where the malarial mosquito still persists). He also found that it helped with ‘the agues’, probably what is now called arthritis. Other common medicines of the time included opium to relieve pain and Peruvian cinchona bark for fevers (it contained quinine).
In the early part of the 1800s chemists in Europe took willow leaves and boiled them with different solvents to try to extract the active ingredients. In 1825 an Italian chemist filtered such a solution and evaporated away the solvent. He obtained impure crystals of a compound containing some of the active ingredient. Repeated recrystallization and refinement of his experimental technique produced a pure sample of the unknown material .
In 1828 Buchner in Germany managed to obtain some pure white crystals of a compound by repeatedly removing impurities from an extract of willow bark. He called it ‘salicin’ (Figure 1.2). It had a bitter taste and relieved pain and inflammation.
This same compound was extracted from a herb called meadowsweet by other chemists. Analysis of salicin showed it to be the active ingredient of willow bark joined to a sugar, glucose.
In the body, salicin is converted into salicylic acid and it was this that was thought to be the active ingredient that relieved pain, but it had such a very bitter taste that it made some people sick. Some patients complained of severe irritation of the mouth, throat and stomach.
The extraction process for making the salicin also proved long and tedious and wasteful of trees: from 1.5 kg of willow bark only 30 g of salicin could be
obtained.3,4 Once the formula was known for salicylic acid, a group of chemists tried to work out how to make it artificially by a less expensive and tedious process.