A large pharmaceutical company, such as
GlaxoSmithKline,
will make and test for drug activity 
many thousands of organic compounds each year.
For each compound that is eventually
marketed as a medicine,
perhaps 10,000 compounds will have been made but found unsuitable in some way.
Many drug molecules work by binding to
an enzyme
or to a receptor molecule on the outside
of a cell.
Such compounds can be quickly screened for biological activity
using robots to measure how well the
potential drug binds
to the enzyme or receptor.
This type of screening uses isolated
enzymes in cells
and requires only a few micrograms of
compound.
Pharmaceutical companies now use a number of techniques,
collectively called combinatorial
chemistry, that allows a few milligrams
of many related compounds to be made.
Chemists use the word synthesised.
These are computer controlled syringes that add reagents and solvents and carry
out other operations in a pre-programmed sequence.
In this machine
the syringes are here. It has four blocks, each with 96 reaction vessels.
The reagents and solvents are stored in these containers.
The ninety-six reaction vessels on this teflon block
are arranged in a twelve by eight array.
Ninety six different esters, for example,
could be made from 12 carboxylic acids
and eight alcohols.
The base of each vessel made of porous
teflon is called a frit.
The vessel is filled with reaction mixture by the syringe.
Emptying is done either by sucking out the liquid under vacuum or by forcing it out
under nitrogen pressure.
Scientists determine the type of compound that they hope will have the medicinal effect they require,
blocking the action of an enzyme or
binding to a receptor, for example.
Synthetic chemists work out a sequence of reactions that will produce the desired type of compound.
The combinatorial chemists
program the robot to carry out an
appropriate sequence of operations,
adding reagents, heating, agitating,
washing with solvents and so on.
These particular instructions tell the
instrument what solvents to use.
A typical run of the machine can take
around 12 hours
and can be done overnight. It'll produce a library
of 384 compounds with similar chemical
structures.
Combinatorial chemistry is often
carried out using beads
made from polystyrene resin.
This is called solid phase chemistry.
The resin is pipetted into the wells as a slurry with a liquid
that is then sucked out.
The resin has functional groups that allow the starting material to be bonded to it.
The new molecule is built up in stages
but remains attached to the resin so
that there's no chance of any of it being lost.
At the end of the reaction sequence
the products are released, cleaved, from
the resin,
usually using a strong acid. At the end
of the reaction sequence
the compounds are handled in plates like this.
Each plate contains an array of ninety six
different compounds. These can be sent
off for chemical analysis and biological
testing
still on the standard 96-well plates that are accepted by
all the instruments.
After many compounds have been prepared by combinatorial chemistry
a promising compound may be identified.
This is called a lead compound.
Compounds related to this are then made on a larger scale to identify the most effective compound.
This process is called
lead optimisation and the technique used
is called parallel synthesis.
The apparatus shown can be used to make compounds in quantities of
between 10 milligrams and 100 milligrams.
Parallel synthesis can replicate all the techniques that are possible using conventional apparatus with ground glass joints,
adding reagents,
stirring,
heating,
refluxing,
evaporating solvents and so on. However,
it is quicker because operations are
carried out in parallel
and related compounds are made in arrays of 24, rather than individually.
The most promising compounds that are identified after parallel synthesis
will be made on successively larger scales for further trials of effectiveness,
side effects, clinical trial and
registration as an approved drug.
The final stage before actual
manufacture
is the pilot plant in which quantities
of up to 100 kilograms can be made.
The whole process of discovery of a drug
and developing it into a medicine
typically takes 10 years
and can cost up to 450 million pounds.
