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Physiochemical properties
of drugs
Using the Sirius T3 to make measurements
Physiochemical properties of drugs
Physiochemical properties
Instrumentation
A drug’s physiochemical properties affect its
liberation, absorption and distribution.
Various experimental techniques may be used. Developments in
•
computer-controlled (robotic) instruments, and
Four important physiochemical properties
are:
•
computer programmes (to carry out complex calculations)
•
acid dissociation constants and pKa;
have streamlined the measurements. Click below for more
information.
•
partition and distribution coefficients and
logP and logD;
•
solubility and logs;
•
dissolution rates.
These may be determined experimentally.
Sometimes they are calculated using
molecular modelling.
Physiochemical properties
They do not provide information about a
compound’s effect as a drug, but they do tell
us about what might happen to the
compound in the body.
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
Samples for analysis
The start of the analytical journey
Who for?
Samples come from pharmaceutical
companies and university research
departments.
Samples arrive at Sirius Analytical Services from all over the
globe.
What types of samples?
Information about the samples and analytical requests are logged
on a computerised system.
They arrive carefully packaged and with instructions about what
analyses the client wants.
Two types are received:
•
•
Large numbers of structurally similar
compounds. The clients are trying to
find answers to questions such as “How
do structural differences affect logP
values?” This is important since the
drug must stick to cell membranes, but
not too tightly.
Receiving samples
One or two formulations containing the
medicinal drug. The clients want to
know how their physiochemical
properties compare so that the
optimum formulation can be found.
Reminder: A medicinal drug needs the optimum physiochemical properties so that the processes of liberation,
absorption, distribution, metabolism and excretion can happen effectively. Formulations are mixtures of the drug with
other ingredients. These can physiochemical properties such as dissolution rates.
Physiochemical properties of drugs
Preparing for analysis
The instrument
Tiny quantities
The analytical unit is described in an earlier video clip. It contains a
pH electrode, a UV detector, a variable speed stirrer and a bundle
of tiny plastic tubes.
No matter what physiochemical property is
being determined the first step is to weigh
a suitable quantity of the compound.
Less than a milligram (0.001 g) is needed.
The tubes deliver measured volumes of liquids such as water,
acid, base and octan-1-ol. Volumes as small as 0.0004 cm3 can be
measured out.
Setting up the instrument
Regular calibration checks are made on
the instrument.
Apart from weighing the sample all other
operations are carried out by a computercontrolled robot.
For a given physiochemical property
determination, such as pKa or logP, the
appropriate programme must be selected
to ensure the correct sequence of
operations.
Reminder:
•
Key physiochemical properties of a medicinal drug or formulation that are determined are:
acid dissociation constants and pKa
•
partition coefficients and logP
•
solubility and logs
•
dissolution rates
Physiochemical properties of drugs
Determining pKa
So for a solution in which
Most drugs ionise in aqueous solution. They are
weak acids or weak bases. The dissociation
constant, Ka, for a weak acid is given by:
H A 
K 

a
HA

and
pK a   log 10 K a
A   HA

pH  pK a
In the titration of a monobasic, [A−] = [HA] the
pH of the solution at the halfway to the endpoint point of the titration graph equals pKa.
Using these equations we can derive:
pH  pK a
A 
 log

HA
pKa
pH
half-way point
end point
Volume of KOH(aq) added
However, a number of assumptions and
approximations. Complex computerprogrammes used in the instrumental method
reduce these considerably and give a more
accurate value for pKa.
Physiochemical properties of drugs
Determining logP
D
In drug discovery and development, lipophilicity is
usually expressed by the partition between water and
octan-1-ol.
The partition coefficient, P, of a drug is given by:
P
drug moleculeo
drug moleculew
where
[drug molecule]o = concentration of drug in octan-1-ol
[drug molecules]w = concentration of drug in water
In the traditional shake flask
method, a sample of the drug is
shaken with a octan-1-ol/water
mixture and its concentration in
each layer is determined.
Drugs that ionise in water
The situation is more complex with drugs that
ionise in aqueous solution – and that is most of
them. These drugs are characterised by their
distribution constant, D. Its value depends on pH.
Determining logD at various pHs allows logP to be
calculated.
drug moleculeo
drug moleculew  drug ionw
Where,
[drug molecule]o = concentration of drug in its molecular
form in octan-1-ol;
[drug molecule]w = concentration of drug in its molecular
form in water;
[drug ion]w = concentration of drug in its ionised form in
water.
The distribution constant depends on pH. A plot of pH
against logD gives a curve with a horizontal section at
lower pH values. In this range, distribution is not pH
dependent and logD = logP.
Physiochemical properties of drugs
Determining logs
It has been said that low solubility is top of the
list of undesirable properties of a potential
medicinal drug. So being able to measure
solubility and, if necessary, modify a compound
to alter its solubility without affecting its
therapeutic properties is important.
Equilibrium solubility
The equilibrium solubility of a compound is the
concentration of a saturated solution in contact
with an excess of undissolved solid.
Traditionally, excess compound is shaken with a
solvent until a saturated solution is produced
with an excess of the solid compound present. It
is an accurate but very time-consuming method.
Kinetic solubility
Pharmacologists also measure kinetic solubility.
Precipitation is brought about by, for example,
changing the polarity of the solvent. The
concentration at which a precipitate first appears
is measured. This is the compound’s kinetic
solubility.
Kinetic solubility of a weak acid
The kinetic solubility in water of a drug that is a weak acid is
determined by:
•
dissolving the acid in a known volume of base, e.g.
potassium hydroxide solution;
•
adding an acid, e.g. hydrochloric acid, until a precipitate is
detected (the UV sensor ‘sees’ the first formation of
cloudiness).
Rather than solubility, logs is usually calculated.
Physiochemical properties of drugs
Reporting back
Once the required measurements
have been made the results are
reported back to the client.
Reminder:
•
Key physiochemical properties of a medicinal drug or formulation that are determined are:
acid dissociation constants and pKa
•
partition coefficients and logP
•
solubility and logs
•
dissolution rates