Aspirin (1) is just one of a family of products called salicylates. They are based on salicylic acid (Formula 2) and
include methyl salicylate (3), commonly known as oil of wintergreen and sodium salicylate (4) a readily soluble form of salicylic acid.
Salicylates are found naturally in many plants including willow and poplar trees, pansy, milkwort, olive, jasmine, myrtle and in small quantities in fruits such as orange, strawberry, apple, cherry, plum, raspberry and grape.
The antipyretic and analgesic properties of salicylates have resulted in widespread usage in herbal preparations since the time of Hippocrates in 400BC and probably much earlier.
A general method of synthesis of aspirin from phenol is described in Scheme I.
Phenol is mixed with hot aqueous sodium hydroxide, heated to 130°C and evaporated to dryness. The dry sodium phenate is cooled to 100°C and then an excess of dry carbon dioxide is added at 5-6 atmospheres. The resulting mixture is heated to 150-170°C for several hours. The pressure is reduced and the crude sodium salicylate is cooled and crystallised as the hexahydrate. This is then dissolved and the solution is acidified with sulphuric acid to precipitate technical grade salicylic acid. The salicylic acid is acetylated with acetic anhydride at 98°C for 2-3 hours. The resulting solution is filtered, the temperature reduced to O°C and the resulting solid is recovered by filtration or centrifugation.
Like most medicines aspirin tablets contain more than just aspirin, this is to help in the tablet formation process and also to aid performance when the patient uses it. Most tablets will include materials to help the powder flow during manufacture e.g. talc, something to lubricate the powders during the compression process e.g. food waxes or salts of fatty acids, a disintegrant to ensure the tablet falls to pieces once it is in water or in the stomach e.g. starch, and a bulking/compression aid which is a material making the tablet a reasonable size to handle and to help the powders from which the tablet is made hold together after they have been compressed. Other ingredients may include flavours and sweeteners to improve taste – which is important for tablets that disperse in the mouth or are dissolved in water before use. Dispersible and soluble tablets also usually include agents to make them effervesce, this is usually a weak acid such as citric and a bicarbonate or carbonate salt.
Further details of this can be found in reference 1.
A major consideration in formulating tablets is the chemistry of the active ingredient and aspirin is no exception. In fact aspirin presents many challenges to the formulator – although it has some good points as well!
Unlike most drug materials, aspirin is excellent at making tablets. Tablets are formed by mixing the powders of the formula together (i.e. aspirin and some of the components mentioned above). These are fed into a tablet press where a dose of powder is fed into a tablet shaped die and then compressed together between two punches at high pressure. For materials such as aspirin, the structure of the crystals is such that they can deform and form bonds between each other without the need for any additional binders.
The other ingredients that go with the aspirin have to be selected with care as it is prone to hydrolysis, breaking down into acetic acid and salicylic acid (try smelling some very old tablets – they may smell of vinegar due to the release of acetic acid). This hydrolysis reaction occurs more quickly in the presence of water and so materials with low moisture content may be selected – this is why you never see an aspirin liquid mixture! The hydrolysis reaction can also be promoted by the presence of alkali materials and so effervescent agents and lubricants need to be selected carefully.
It’s important to consider what happens to the tablet when the patient takes them. Early tablets were simple swallow tablets – which were swallowed whole and gradually disintegrated in the stomach. Because this led to local high concentrations of aspirin that could cause damage to the stomach lining in many patients new formulations were produced to avoid this:
