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Physiochemical properties
of drugs
Some background to the Sirius T3
Physiochemical properties of drugs
LADMET and drug discovery and development
The following extract is taken from an article by Dr Jianling Wang and Dr Laszlo Urban in Drug Discovery World
(2004).
The increased costs in the discovery and development of new drugs, due in part to the high attrition rate of drug
candidates in development, has led to a new strategy to introduce early, parallel evaluation of efficacy and
biopharmaceutical properties of drug candidates.
Investigation of terminated projects revealed that the primary cause for drug failure in the development phase was
the poor pharmacokinetic and ADMET (Absorption, Distribution, Metabolism, Discretion and Toxicity) properties
rather than unsatisfactory efficacy. In addition, the applications of parallel synthesis and combinatory chemistry to
expedite lead finding and lead optimisation processes has shifted the chemical libraries towards poorer
biopharmaceutical properties.
Establishments of high throughput and fast ADMET profiling assays allow for the prioritisation of leads or drug
candidates by their biopharmaceutical properties in parallel with optimisation of their efficacy at early discovery
phases. This is expected to not only improve the overall quality of drug candidates and therefore the probability of
their success, but also shorten the drug discovery and development process.
Physiochemical properties of drugs
An opportunity
Measurement of the
physiochemical properties of
drugs has always been
important, but high throughput
and fast ADME profiling has
become increasingly important as
scientists seek ways of
shortening the drug discovery
and development process.
In this short video sequence John
Cromer, Chief Scientific Officer at
Sirius Analytical, describes where
the need or an instrument that
determined pKa values came
from and how this led to the
development of the T3.
The development, construction and use of the T3 brought together aspects of chemistry, engineering, technology,
mathematics and computer programming.
On the next slide john describes what it can do.
Reminder:
LADME are the stages that happen when a medicinal drug is taken (usually in a formulation):
Liberation
–
Absorption
–
Distribution
–
Metabolism
–
Excretion
Physiochemical properties of drugs
The Sirius T3
The Sirius T3 can determine a
number of physiochemical
properties that influence the
potential of a compound to be a
medicinal drug. The four most
important ones are:
•
acid dissociation constant,
Ka, and pKa;
•
partition coefficient, P, and
logP;
•
solubility, s, and logs;
•
dissolution.
These are important in two main
areas of research and
development:
•
drug discovery,
•
drug formulation.
Reminder:
The solubility, dissolution rate, ionisation (pKa) and lipophilicity (logP) of a drug have a significant
effect on its LADME properties.
Physiochemical properties of drugs
Making the T3
The Sirius T3 consist of over
5000 parts. These are
manufactured around the world
and brought to the UK where
they are assembled in the Sirius
workshops.
The software that controls the
robot and that carries out the
complex mathematical
calculations is written at Sirius.
Once assembled an instrument is
tested for about two weeks using
standard samples (substances
whose characteristics are well
established).
Following successful testing it is
packaged and shipped to the
purchaser.