E-DRUG: isomers, enatiomers, epimers
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WB]
Dear E-druggers,
I should like to answer to Stevan Gressitt's question on enantiomers and
cost
price.
A racemic mixture consists of two enantiomers in equal quantity. Here an
asymmetric carbon determines the stereoisomery of the molecules. In short,
one
enantiomer will be levatory whereas the other turns polarized light in the
opposite direction.
I stick to one example: Fenfluramine (long time known as an adequate
appetite
controlling drug) from the Servier Company in France. This racemic mixture
product results from a very easy and cheap synthesis.
When it became known that the most interesting properties of the molecule
were
"located" in the dextro isomer, an enantiomeric splitting was done. The
resulting product "dex-fenfluramine" was then prepared by enantiomeric
splitting, e.g. by crystallization techniques. This product was considerably
more expensive than the mixture although the enantiomeric purity was only
about 98%.
Many years ago - in the mid eighties- we felt that this might be an
interesting molecule for future work. Hence we synthesized dex-fenfluramine
by
an asymmetric synthesis process. This means that we succeeded in finding a
method which would fix that particular carbon atom in such a position that
its
chirality would no longer be changed by the further building up of the
molecule. It was high brow chemistry in those days but we made a 100% pure
compound at industrial scale and at a cost price that was in the range of
that
of the racemic mixture. This is a rather unique example of "cheaper"
synthesis. In general the production and purification of a pure enantiomer
is
not so easy and will therefore lead to an API that is fairly expensive,
probably twice or more than the price of the mixture. We later applied
similar
techniques to e.g ibuprofen in order to make
S(+) Ibuprofen. Unfortunately such a process could only be made acceptable
in
economical terms if mass production would follow. This would require serious
investments from the side of the bulk manufacturer.
Example from epimers: Here alpha and b�ta forms exist but their position
around a carbon atom is not defined like in the enantiomers, the
substituting
group on an non asymmetric carbon stands above or under a certain plane and
is
by convention given the name of alpha or b�ta. The antimalarial drugs
derived
from Artemisinin are interesting examples. The mother compound Artemisinin
has
a lacton structure. Upon reduction of this lactone function into a lactol
function two epimers are created, one alpha, the other b�ta. The relative
amount of each depends on the reaction conditions and the solvents used.
This lactol (known as Dihydroartemisinin (also called Artenimol) is used for
the production of the antimalarials artesunate and artemether. (Artemisinin
is
not a very interesting compound pharmacologically. In itself it is not
reactive and derivatives can only be made by activating certain centers in
the
molecule; the obvious one is an action on the lacton group, turning it into
a
lactol, being a hemiacetal OH, a quite reactive center for derivatisation)
Artesunate is the succinic acid ester of dihydroartemisinin existing in
alpha
position. This esterification reaction is done under alkaline conditions and
yields only the alpha epimer. No other products are formed. Hence this is
relatively cheap. The purification is easy and the yields are high.
The synthesis of Artemether requires an acidic medium and here a mixture of
two epimers: alpha and b�ta are formed in a
25/75 % ratio. The purification is not easy and several crystallization
steps
are needed (each time losing material) before a pure b�ta product is
obtained.
This has a serious impact on the cost price and therefore artemether (pure
b�ta-artemether) costs almost 3 times as much as artesunate.
Is it necessary to do this separation? In the case of artemether the answer
is
positive. The mixture alpha/b�ta is not stable over time, it becomes sticky,
the crystalline structure disappears, it turns yellow and undergoes
degradation. It is not apt for decent pharmaceutical work. Furthermore,
I.C.H.
rules force us to make enantiomeric or epimeric pure compounds
Can the alpha epimer be used? Yes, it has the same pharmacological
properties
of b�ta artemether but the production of pure alpha artemether requires
tedious chemical processing and purification making the molecule very
expensive. (For those interested I have a supply of small quantities of the
alfa epimer, it has a melting point of 100�C in contrast to that of the b�ta
epimer which melts at 84�C.).
And at the level of Dihydroartemisinin? Nobody appears to be interested in
separating the epimers, one of them dominates largely. They can be separated
by hplc and for the quantification the peaks of both alpha and b�ta are
added
up. The mixture of alpha/b�ta dihydroartemisinin is an amorphous sticky
powder, not particularly good for tabletting work.
Best regards,
Herwig Jansen, M.D., Ph.D.
FHjansen@skynet.be
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