Chemistry Reference
In-Depth Information
a process in preference to a few more, albeit high-
yielding, steps. Percentage yield for a particular
transformation only measures how efficiently the
major starting material (limiting agent) is converted
into the product. In practice, other implicit factors
such as reaction kinetics, impurity profile and
throughput often outweigh concerns over this sacred
number. A balanced perspective can be obtained by
taking into consideration the possible improvement
in yields during later stage of development. This
often results in the selection of a new process with
fewer steps, albeit of lower overall yield, over a
longer and higher yielding process. Risk tolerance
at different stages of drug development plays an
essential role in the decision process.
usually the more elegant one, questions must be
asked about what starting materials are used and
how available they are. Moreover, for scale-up it is
not uncommon for a longer sequence to be preferred
over a shorter one just for the existence of a crys-
talline intermediate as a purification point.
The order of steps generally falls into the category
of synthetic strategy. However, even within a defined
synthetic scheme, juxtaposing the order of trans-
formations often can bring about an unexpected
improvement in the economy of the process and
waste reduction, even if the overall yield remains the
same. Generally, low-yielding processes, e.g. resolu-
tion of enantiomers, should be carried out as early
as possible for the throughput and efficiency.
However, the advantage of doing so is often over-
looked when one focuses only at the overall yield.
For similar reasons, solvents and time-intensive
procedures should be deferred to the last stage of
the process because volumes become smaller due to
attrition towards the end.
2.6 Number and order of steps
Whereas many fine chemicals and reagents are quite
expensive and appear as the first order of concern
to the chemists, processing time and solvent usage
often account for a bigger proportion of the pro-
duction cost. Reduction of the number of bond
forming/breaking events and minimising the use
of protecting groups often will have a profound
effect on the overall efficiency. In addition, work-up
in-between steps usually involves extensive usage of
solvents and prolonged processing time. Moreover,
extra steps not only cause physical losses of material
but also introduce additional impurities along the
way. Combining compatible steps (telescoping)
together not only reduces waste and processing time
but also cuts down product losses during separation
and transfer. Unnecessary drying, solvent exchange
and chromatography should be eliminated when-
ever possible. The common practice in small-scale
laboratories of evaporating everything to dryness is
not only impractical on an industrial scale but is also
wasteful and sometimes hazardous.
However, carrying forward impurities often can
lead to new ones that are difficult to remove, jeop-
ardising the whole process. Thus, acceptable purifi-
cation means must be available to avoid the common
pitfall of piling junk over junk when such measures
are taken. This can be modulated by designing a
reaction sequence to achieve a maximum differ-
ence in physical properties (solubility, partition,
crystallinity, etc.) between the desired product and
everything else.
On the other hand, although a shorter synthesis is
2.7 Robustness
A good chemical process should not only be efficient
but also robust. The ability to be carried out consis-
tently, and at a different scale, is crucial in pilot
and production settings. Quality deviations can be
extremely wasteful in drug product manufacture.
Simplicity often is synonymous to robustness in
these cases. An elaborate green process can turn grey
very quickly when it becomes too sensitive to minor
aberrations in operating parameters. In general,
simplicity is the primary criterion when a process is
judged for its elegance. The reason is a rather obvious
one in that the more complex a process is, the more
chances there are of errors and waste being gener-
ated. This is not to downplay the importance of
innovative technologies, because the most creative
solutions to chemical problems usually are the
simple ones derived by sophisticated thinking. When
getting deeply involved in overcoming a particular
obstacle one must keep in mind that solutions
cannot be more complicated than the problems.
2.8 Solvents
With the exception of forming the desired solvate in
the final product, processing solvents do not con-
tribute to the effectiveness of the drug and their use
