The principles of green chemistry herald a radical new approach that
is 'benign by design' - both in terms of the
process itself, its impact on patients and on the environment. Green
chemistry promises to make the chemical industry cleaner and safer,
while producing better, purer products in the process.
In a presentation at the British Association for the Advancement of
Science Conference in York on September 12, 2007,
Professor Steve Howdle outlined the green chemistry processes being
pioneered at The University of Nottingham, particularly the use of
supercritical fluids to replace conventional solvents such as benzene
and chloroform.
Professor Howdle's research focuses on exploiting the unique
properties of supercritical carbon dioxide (CO2). A
supercritical fluid is a solvent, with physical properties between
those of a gas and a liquid. At near-room temperature and under modest
pressure, supercritical carbon dioxide blurs the boundaries between
liquid and gaseous states.
The process can be used to make polymer drug coatings, using
biodegradable plastics, just like those used in dissolvable surgical
stitches. The polymer is used to encapsulate the drug before it is
injected into the body.
Conventional chemical processes often use high temperatures or
volatile, and potentially toxic, solvents such as chloroform, benzene,
and other volatile organic compounds (VOCs). Solvent residues may
remain in the product after manufacture and these can be toxic to the
patient and to the environment - requiring
special handling and recycling measures to prevent them from escaping
into the atmosphere.
They can also cause degradation of the drug. Many bioactive drug
compounds are adversely affected by high temperatures and conventional
solvents, which can destroy up to 50 per cent of the drug molecules
intended to help the patient.
But the clean green chemistry techniques being developed at Nottingham
aim to remove these conventional solvents from the process altogether.
Because supercritical fluids can be used to support solvent-free
chemical processes, creating new techniques that would be difficult or
impossible to achieve in normal solvents or by conventional processing.
Professor Howdle's research has demonstrated that biodegradable
polymers can be plasticised at near room temperatures using
supercritical CO2.
The low temperature means delicate bioactive components, such as
growth factors or proteins, can be mixed into the plasticised polymer
without any loss of activity.
The process overcomes a major obstacle to the development of new drug
delivery devices because it means that patients will be able to
receive biopharmaceuticals which do not survive conventional chemical
processing because they are either solvent or sensitive to heat.
Professor Howdle said: �Many very potent new drugs based on proteins
are being discovered all the time. But a major problem the
pharmaceutical industry faces is that they have to be wrapped up in
plastic to be delivered to the patient, so that there is controlled
release of the drug over time.
�Many of these new proteins are fragile and are damaged by high
temperatures and harsh solvents used in conventional processes. Our
process works in CO2 at close to room temperatures so the
molecule is not damaged by the mixing process, and we don't use normal
solvents we don't have toxic residues left behind in the product and
potentially ending up in the patient.
�The plastics are solids but when they are put under high pressure
from CO2, they turn into liquids -
they melt, and under these conditions, the bioactive drugs can be
mixed in. So we take particles of the drug and wrap every single one
up in biodegradable polymer, for injection under the skin.�
Once injected, the polymer begins to degrade and the drug starts to be
released and is picked up by the bloodstream -
but this is a gradual process, occurring over the course of several
days or a week. This provides a controlled release of the drug
prolonging the length of time over which active therapeutic is
released at the delivery site.
The polymer used is a biodegradable plastic based on lactic acid,
which is a natural compound produced in the body that the body is able
to get rid of in the usual way. It is used in dissolvable stitches and
has been used in the pharmaceutical industry in various guises for 30
years.
Compared to conventional methods for giving drugs to patients,
controlled drug delivery via injection has many advantages including
reduced dosing frequency and toxicity, improved efficiency and
convenience and therefore increased patient compliance.
Professor Howdle added: �Biodegradable polymers are particularly
attractive for use in drug delivery, as once introduced into the body
they require no retrieval or further manipulation and are degraded
into soluble, non-toxic by-products. Different polymers degrade at
different rates within the body and therefore polymer selection can be
tailored to achieve desired release rates.
�Thus the process allows for gradual, controlled release of a drug,
reducing side effects and improving quality of life. For the patient,
it could mean the end of twice-daily injections -
in favour of an injection once a week.�
Drug encapsulation techniques using green chemistry techniques are
currently in advanced tests at spin-out company Critical
Pharmaceuticals Ltd. - set up in 2002 by Prof
Howdle and colleagues � and expected to proceed to clinical trials
soon. Since the drugs and polymers being used have already been
approved separately, the process is likely to be available for
patients sooner than might otherwise be expected with an entirely
untested process.
As well as new methods of drug delivery, the use of supercritical
fluids offers cleaner, residue-free processes that can be harnessed to
produce other new polymer materials ranging from enhanced bullet proof
plastics through to detergents and coatings and even porous scaffolds
for tissue engineering.
Steve Howdle is Professor of Chemistry at the University of Nottingham
and the Chief Scientific Officer of Critical Pharmaceuticals Ltd. He
holds a Royal Society Wolfson Research Merit Award. At the BA meeting
he will be receiving the Royal Society of Chemistry �Interdisciplinary
Award�.
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