Chemistry Reference
In-Depth Information
Chapter 12: Waste Minimisation in
Pharmaceutical Process Development:
Principles, Practice and Challenges
TONY Y. ZHANG
1 Introduction
formulation, marketing, competition, R&D risk and
profit. The quality of synthetic routes for the manu-
facture of active pharmaceutical ingredients directly
affects the availability of these products to the world
population.
The annual production of bulk active ingredient
ranges between a few kilograms for some protein
drugs to thousands of tonnes for antibiotics (veteri-
nary use accounting for a major share), with the
general trend moving towards highly potent, lower
volume compounds. The regulatory environment of
pharmaceutical industry dictates that strict control
over product quality and consistency must be in
place for bulk drug manufacturing. Any changes in
synthetic route must be validated and approved vig-
orously to ensure the quality and safety of the drug
products. At the same time, the need for innovative
products to address emerging epidemics such AIDS
and hepatitis, the escalating cost of pharmaceutical
R&D and fierce competition within the industry
creates a great sense of urgency to reduce the devel-
opment time from discovery to launching. Designing
a high-quality process within a short time frame that
will withstand the test of time during the product
life-cycle is the ultimate challenge for the process
chemist. As a result, incorporation of waste minimi-
sation and pollution controls in the designing phase
of process research and development is not only
good environmental practice but also makes sound
business sense for an industry that strongly endorses
the triple bottom line of social benefits, environ-
mental protection and profitability.
The use of chemistry for pollution prevention is
referred to generally as green or sustainable chem-
istry [2-4]. The general public usually interprets
the word 'green' as good for the environment, and
may even conjure up a certain political philosophy.
Although the term 'green chemistry' was coined in
the late 1980s, the fundamental principles were
From the launching of aspirin in 1899 to the decod-
ing of the human genome at the turn of the new mil-
lennium, the last century has witnessed the birth
and exploding growth of medicinal chemistry and
the modern pharmaceutical industry. Although
there are still many unmet medical needs, great
strides have been accomplished in chemistry and
biology that have made pharmaceuticals one of the
most cost-effective means for maintaining human
health. Table 12.1 offers a glimpse of the structures,
biological functions and targeted disease areas for the
best selling prescription medicines in 1999 [1].
As seen from Table 12.1, pharmaceuticals encom-
pass a wide array of molecules of different complex-
ities. Except for the proteins, they tend to have a
molecule weight of 200-800 Da and on average the
synthesis of these compounds might take 8-12 steps.
With the exception of metformin, which is not much
more complicated than urea (the first organic mol-
ecule ever synthesised), virtually all of the top-
selling pharmaceuticals contain one or more cyclic
components. Among these 23 active pharmaceutical
ingredients, 21 contain at least one nitrogen atom,
13 have at least one chiral centre, 5 are natural or
side-chain-modified products and 2 are produced by
recombinant DNA technology. Although protein
therapeutics will likely account for an even larger
share due to the advent of genomic research and
breakthroughs in drug delivery technologies, small
molecules are expected to maintain their dominance
in the near future. This means that chemical syn-
thesis will continue to be the mainstay of the phar-
maceutical industry. Even though the total sales
figure is a useful indication of the market demand
for a particular drug, the unit selling price is gov-
erned by a group of factors, including cost for man-
ufacturing the active pharmaceutical ingredients,
306
