What’s in a medicine?

1. What’s in a medicine? Chemical Storylines

2. WM1 The development of modern ideas about medicine • Medicines have been used for thousands of years • Examples include feverfew for migraines and willow bark for pain relief • Their effectiveness was discovered by trial and error with no real scientific knowledge Key terms: • A drug alters the way your body works • A poison is simply a bad drug • Pharmacology is the study of drugs and their action

3. WM2 Medicines from nature • Modern medicine has some of its origins in folklore and herbal remedies • The “Doctrine of Signatures” which stated that “many remedies lie not far off from their causes” and “Culpeper’s Herbal” linked diseases and cures to celestial bodies • For this reason willow bark has been used as a remedy for fever • We now know that the substance extracted from bark is converted into the active chemical in the body • WM2.1 • CI13.2 • CI13.7 • WM2.2

4. WM3 Identifying the active chemical in willow bark • To identify the chemical structure of the extract, we need to do: • Chemical tests • Instrumental analysis • Three useful chemical tests are; • The aqueous solution is weakly acidic • Suggests a carboxylic acid group (-COOH) • It reacts with alcohols to make a fruity smelling compound • Suggests a carboxylic acid group (-COOH) • Neutral Iron (III) Chloride [FeCl3] gives a purple coloured complex • Suggests a phenol group (-OH joined to a benzene ring) • CI13.3 • CI13.4 • WM3

5. WM4 – INSTRUMENTAL ANALYSIS • 3 important instrumental techniques are then used to help identify the structure of salicylic acid; • Infra – red (i.r.) spectroscopy • Identifies functional groups present • Mass spectrometry • Identifies fragments of the structure • Nuclear magnetic resonance (n.m.r.) spectroscopy. • Identifies different hydrogen environments present • Ass 1 • CI6.4 (revision of IR) • CI6.5 Mass Spectrometry • WM4 “Using Spectroscopy”

6. Infra–red (i.r.) spectroscopy An i.r. spectrum provides information about which functional groups are present by the characteristic absorptions of their bonds. Here is the infra – red spectrum of salicylic acid O-H in carboxylic acid Aromatic C-H bonds C=O in carboxylic acid Phenolic O-H

7. N.m.r. spectroscopy • Nuclear Magnetic Resonance (n.m.r.) spectroscopy identifies the different chemical environments which hydrogen nuclei (“protons”) exist in in a molecule. • For salicylic acid there are 3 different environments for H nuclei…. • 1 proton in a COOH environment. • 1 proton in a phenolic –OH environment. • 4 protons attached to a benzene ring. • so we should see three peaks…..!

8. The Mass Spectrum of salicylic acid • Used to determine more details about the structure of molecule • Helps identify which isomer of a substance is present. • Each peak corresponds to a positively charged ion which comes from the parent molecule after it has broken into fragments. • The highest mass peak is for the molecular ion and tells you the Mr • This helps to confirm that the molecular formula is C7H6O3. • The other peaks are produced as the molecule is broken up. • This “fragmentation pattern” is characteristic of the compound and the molecule can therefore be identified.

9. Drawing the evidence together • Chemical Tests: • presence of a phenolic –OH group and a carboxylic acid group (-COOH) • IR spectroscopy: • presence of –O-H and –C=O bonds. • NMR spectroscopy: • H atoms in 3 different environments; • - OH • -COOH • - 4 attached to a benzene ring • Mass spectroscopy: • Salicylic acid is 2-hydroxybenzoic acid……

10. WM5 – THE SYNTHESIS OF SALICYLIC ACID AND ASPIRIN • A medicine from natural sources is not ideal • Supply may be seasonal • It may be affected by weather, disease, etc.. • It is not environmentally sound • Artificial production, or synthesis is far more reliable. • This is not a simple task • Larger, more complex molecules cannot simply be made from their elements. • A startingmaterial is needed which can be readily converted by introducing the active functional groups onto a molecule without disrupting its overall structure.

11. In the late 19th century Felix Hofmann developed a method for making 2-hydroxybenzoic acid industrially • This combined carbon dioxide with phenol. (Known as the Kolbe synthesis) • This has no bi-products and so has 100% atom economy • CI15.8 “Atom economy” • 2-hydroxybenzoic acid became commonly used as a medicine to cure fevers and suppress pain. • However, reports of side effects began to be reported. • Modification of the structure became necessary to reduce the irritating side effects, yet retain the beneficial ones. • CI13.5 Esters • WM5.1 Preparation of Aspirin • see CI 7.3 and CI Appendix 1:experimental techniques • WM5.3 Reaction type and atom economy

12. Hofmann prepared a range of related compounds • All with slightly modified structures • He tried out each one on his father! • In 1898, an effective derivative was found… • …an ester of 2-hydroxybenzoic acid called 2-ethanoyl hydroxybenzoic acid. • It is made by reacting 2-hydroxybenzoic acid with ethanoyl chloride or ethanoic anhydride in an ACYLATION reaction • This was given the name ASPIRIN. Ethanoyl group (an ACYL group)

13. WM6 Delivering the Product • Developing a new medicine costs an enormous amount of money • Patents ensure other companies can’t copy the medicine for a certain amount of time • Once the patents have lapsed anybody can produce and market the drug, • The company must charge enough during the period of the patent to recover their development, marketing and production costs • Most pharmaceuticals will have three names; • Chemical name (often very long and complicated) • Generic name (shorter name for the chemical) • Brand name (to market it under) • For example; • 2-(4-(2-methylpropyl)-phenyl) propanoic acid • Ibuprofen • Nurofen

14. The Safety of Aspirin • Manufacturers need to be able to analyse samples to ensure they contain the correct amount of active chemical • Hospitals need to be able identify chemicals and the quantities they are in. • WM6 “Aspirin Assay” • CI8.1 “Acids and Bases” • Like all medicines, aspirin is only safe if taken in the recommended dose • The lethal dose for and adult is about 30g (100 tablets)

15. WM7 – THE MIRACULOUS MEDICINE • 50 billion aspirin tablets are consumed in the UK each year! • It has a range of uses; • Headaches and as a general painkiller. • Arthritis • To avoid heart disease • To prevent blood clotting and help in the treatment of strokes. • Aspirin is over 100 years old and it has never been replaced, indeed new uses for aspirin are still being researched and developed.

16. WM8 – DEVELOPMENT AND SAFETY TESTING OF MEDICINES • Development and safety testing of a new drug can take 10-15 years and cost up to £350 million. The stages involved are; • Research • Development of synthesis methods. • Testing for; • Toxicity • Effectiveness • Side effects • Evaluation of data so far. • Modifications if necessary • Further testing until all criteria met. • Trials on patients. • License applications to market product. • Patent applications to protect investments. • Launch of drug!! • At each stage the financial implications of the drug, its market and potential profit margins must be taken into consideration.

17. Lead compound Lead compound