Drug Development
How are drugs discovered and
synthesized
Definitions
Drug: Any substance that alters a chemical
process in the body
Pharmaceutical: A drug that is prescribed for
medicinal purposes, such as pain relief,
antibiotic or sedative
Drug Discovery
Most pharmaceuticals used today have their
origin in nature. A number of common drugs
and their natural origins are listed below
 Aspirin – Willow
 Penicillin – Mould
 Codeine – Opium poppies
History of Aspirin
1500 BC (?) Egyptians recorded a collection of recipes for medicines, which
included a recipe using an infusion of dried myrtle leaves (which
contain salicylic acid) to relieve back pain.
200 BC
100 AD
200
Hippocrates, a Greek physician, prescribes leaves and bark from
willow tree (which, like the myrtle tree, also contains salicylic
acid) to relieve fever and pain, including labor pains.
Greek surgeon Dioscorides mentions in his writings the use of
willow leaves to relieve pain.
Pliny the Elder, a Roman statesman, describes the use of willow
leaves in his writings, as does Galen, an alchemist/physician.
History of Aspirin
Middle
Ages
Europeans stop using willow bark remedies, as the willow bark supply is
earmarked for making wicker. Use of willow for medicinal purposes
banned in some places.
Before
1500
Native people of North America learn to make salicylate pain remedies
from birch bark.
2 July
1763
Edward Stone, an English clergyman, reports to the Royal Society of
London (world-renowned scientific group) of his successful experiments
involving the use of willow bark to reduce fever in fifty of his patients.
Meanwhile, on the European mainland, quinine is used to treat pain.
1828
Johann Büchner of Munich, Germany isolates pure salicin from willow
bark. Salicin is the compound in willow bark that relieves pain. The name
salicin was derived from salix, which is the Latin word for willow tree.
History of Aspirin
1835
Karl Lowig makes salicylic acid from meadowsweet flowers.
1838
Raffaele Piria converts salicin into salicylic acid. This is the first time
salicylic acid was obtained from willow bark in the laboratory.
1853
Charles Frederic Gerhardt first synthesizes acetylsalicylic acid, but he
fails to understand its molecular structure and its potential importance
to humanity. His ASA is not pure and therefore of limited use.
1859
H. von Glim also describes the preparation of ASA, but he, too, fails
to grasp its molecular structure. His ASA also is not pure.
Meanwhile, Herman Kolbe discovers how to synthesize salicylic acid
from coal tar. The method he used is still called the "Kolbe synthesis.
History of Aspirin
1869
Karl-Johann Kraut repeats the previous two scientists' experiments and gives
the first accurate information about the molecular structure of ASA, the ester
of salicylic acid (SA). His sample also was not pure, by his own admission.
1874
Salicylic acid is first made industrially using Kolbe's method in Dresden,
Germany. It is sold as a painkiller but severely irritates the stomach.
1897
On August 10, 1897, Felix Hoffmann, chemist in the Bayer chemical factory
in Germany, prepares the first pure sample of acetylsalicylic acid (ASA). His
laboratory journal notes the test he performed to assess the purity of his
product. This is the beginning of the story of aspirin as we know it today,
although the name, as of yet, has not been used.
1899
The first publication of clinical trial results appeared and showed the
promising healing effects of ASA. Bayer refers to ASA as "aspirin" for the
first time, and the company first distributes aspirin (as a powder) to
physicians to give to their patients.
History of Aspirin
1900
Bayer introduces the first water-soluble tablet form of aspirin.
This process cut production costs in half.
1915
Aspirin first becomes available without a prescription.
1948
Dr. Lawrence Craven discovers that men to whom he prescribed
aspirin suffered no heart attacks. He recommends "an aspirin a
day" to both patients and colleagues alike to decrease risk of heart
attack.
1971
John Vane, British pharmacologist, discovers that aspirin works
by inhibiting the production of prostaglandins
History of Aspirin
1980
FDA approves the use of aspirin to reduce the risk of stroke after
signs of TIA (transient ischemic attack) that forewarns of possible
impending stroke.
1982
John Vane receives the Nobel Prize for Medicine for his research
on prostaglandins.
1985
FDA approves aspirin to prevent heart attack in patients with
previous attacks or unstable angina pectoris.
1998
The FDA rules that aspirin can be labeled as being helpful in
preventing heart attacks and strokes in men and women when
taken in daily doses as low as 81 mg, the size of a child's aspirin.
The FDA also approves aspirin for use by patients during a
suspected heart attack.
Production of Aspirin
• Aspirin (acetylsalicylic acid) is an ester which
can be produced by reacting salicylic acid and
ethanoic (acetic) acid.
Production of Aspirin
• However the yield for this reaction is low as
the water produced can easily hydrolyze the
ester back into the alkanol and carboxylic acid.
Production of Aspirin
• If we react two ethanoic acid molecules
together we can produce a chemical that will
react with salicylic acid to produce
acetylsalicylic acid, but will not produce water,
therefore increasing the yield
Production of Aspirin
• The reaction of salicylic acid and ethanoic
anhydride is shown below
Aspirin in the body
• It has been found that aspirin is converted
back into the active ingredient salicylic acid in
the body.
• Salicylic acid is unpalatable and irritates the
stomach, however aspirin is tasteless and
causes less irritation.
Derivatives of Aspirin
• Chemists look for alterations to a drug to
make it more effective, have less side-effects
or to bypass patent laws.
• Some derivatives of aspirin are shown below
Pathways to drug production
Principles of Green Chemistry
Principles of Green Chemistry
4. Designing Safer Chemicals Chemical products should be
designed to effect their desired function while minimizing their
toxicity.
5. Safer Solvents and Auxiliaries The use of auxiliary substances
Principles of Green Chemistry
7. Use of Renewable Feedstocks A raw material or feedstock
should be renewable rather than depleting whenever technically
and economically practicable. 8. Reduce
Derivatives Unnecessary derivatization (use of blocking groups,
protection/ deprotection, temporary modification of
physical/chemical processes) should be minimized or avoided if
possible, because such steps require additional reagents and can
generate waste.
9. Catalysis Catalytic reagents (as selective as possible) are
Principles of Green Chemistry
10. Design for Degradation Chemical products should be
designed so that at the end of their function they break down
into innocuous degradation products and do not persist in the
environment. 11. Real-time analysis for Pollution
Prevention Analytical methodologies need to be further
developed to allow for real-time, in-process monitoring and
control prior to the formation of hazardous substances. 12.
Inherently Safer Chemistry for Accident
Prevention Substances and the form of a substance used in a
chemical process should be chosen to minimize the potential
for chemical accidents, including releases, explosions, and
fires.
Pathways to drug production