PHYSICOCHEMICAL PRINCIPLES OF DRUG

ACTION

• PARTITION COEFFICIENT

Group members:
Maria 260110152014
Sarva 260110152019
Syahirah 260110152016
Prediction of Relative Solubility

The relative solubility of drug molecule is:

 Function of the presence of both lipophilic and hydrophilic features within

its structure.

 It also serve to determine the extent interaction of drug molecule with lipid
and/or aqueous phase.
Laboratory Estimated of Relative Solubility

 The relative solubility of a drug molecule can be determined in the

laboratory.

 The ratio of the solubility of the compound in an organic solvent to the

solubility of the same compound in an aqueous is called partition
coefficient (P).

𝐃 𝐥𝐢𝐩𝐢𝐝
 P=
𝐃 𝐰𝐚𝐭𝐞𝐫

 Partition coefficient (P) is a measure of the solubility of a drug in

aqueous and lipid phases
For an example:

𝐃 𝐧−𝐨𝐜𝐭𝐚𝐧𝐨𝐥
P=
𝐃 𝐩𝐡𝐨𝐬𝐩𝐡𝐚𝐭𝐞 𝐛𝐮𝐟𝐟𝐞𝐫

• n-octanol (lipid phase)

• Phosphate buffer of pH 7.4 (aqueous phase)

• P is often expressed as a log value

Mathematical Estimation of Relative Solubility

 Solubility contributions (groups and substituents) are expressed as:

• Hydrophilic = negative value
• Lipophilic = positive value

Log P = Ʃπ
• Log P = log of partition coefficient
• Ʃπ = sum of hydrophilic-lipophilic constants
 Compound with log P:
• More than +0.5, water insoluble (lipophilic)
• Less than +0.5, water soluble (hydrophilic)
Hydrophilic-Lipophilic Fragment Constants
For an example:
π values for various substituents on aromatic rings

Substituents Π Value
CH3 + 0.52
OH - 1.67
CONH3 - 0.49
CF3 + 1.16
Cl + 0.71
Br + 0.86
F + 0.14
 Anileridine

Fragments π
2 amines -2.0
9 aliphatic carbon +4.5
2 phenyl ring +4.0
1 ester -0.7
Log P = +5.8

Prediction: water insoluble

The Lipinski "Rule of Five"

States that compounds are likely to have good absorption and permeation
in biological systems and are more likely to be successful drug candidates
if they meet the following criteria:
• five or fewer hydrogen-bond donors Not too polar
• ten (2 x 5) or fewer hydrogen-bond acceptors
• molecular weight less than or equal to 500 Not too big

• calculated logP less than or equal to 5 Not too hydrophobic

*Compound classes that are substrates for biological transporters

are exceptions to the rule.
Impact of Partition Coefficient on Drug Action
 The relative solubility of a drug molecule greatly affects:

 Routes of administration

 Absorption

 Distribution

 Elimination

 Higher/ smaller values of (Log P):

 Solubility in plasma (distribution)

 Lipid barriers (brain & neuronal tissues)

 Trapping (first site of loss)

 MEASUREMENT OF PARTITION COEFFICIENT:

It can be measured by using following methods.

• Shake flask (or tube) method.

• HPLC method.

• Electrochemical method.

• Slow-Stirring Method.
Shakeflask method:
• common method.
• some amount of drug is added, dissolved in octanol & water.
• The distribution of solute is measured by two methods.
i. UV-Visible spectroscopy
ii. Carrier free radiotracer
UV-Visible spectroscopy:

• In this method, after dissolving the drug between two phases, they are separated.

• Standard dilutions are prepared.

• The absorbance is measured at suitable wavelength.

• By using calibration curve, the concentration of the sample in both organic and
aqueous phase can be measured

Carrier free Radiotracer:

• In this method a known amount of a radioactive material is added to one of the

phases.

• The two phases are then brought into contact and mixed until equilibrium has
been reached. Then the two phases are separated before the radioactivity in each
phase is measured.
HPLC method:

• By correlating its retention time with similar compounds with known logP
values.

• HPLC is performed on analytical columns packed with a commercially

available solid phase containing long hydrocarbon chains (e.g. C8, C18)
chemically bound onto silica.

• Mixtures of chemicals are eluted in order of their hydrophobicity, with

water-soluble chemicals eluted first and oil-soluble chemicals last.

• This enables the relationship between the retention time on such a (reverse
phase) column and the n-octanol/water partition coefficient.
Electrochemical method:

In this polarized liquid interfaces have been used to examine the thermodynamics
and kinetics of charged species from one phase to another.

Two methods exist:

ITIES, interfaces between two immiscible electrolyte solutions.

Droplet experiments – here a reaction at a triple interface between a conductive solid,

droplets of a redox active liquid phase and an electrolyte solution- used to determine the
energy required to transfer a charged species across the interface.
Slow-Stirring Method:
• More recent method developed as an alternative to the shake flask
procedure.

• Emulsion formation will be reduced.

• Requires a few days to reach equilibrium.

• Difficult to adapt to a high throughput approach.

Radiolabelled substances – which may be synthesized for use in other tests –

can be very useful for accurate log Kow determination.
Applications:
• Solubility of drugs in water and other solvents and in mixture of solvents can be predicted.

• Drug absorption in vivo can be predicted.

• The oil-water partition coefficients are indicative of lipophilic hydrophilic character of drug
molecules.

• Structure activity relationship (SAR) for a series of drugs can be studied.

• Extraction: Drugs from biological fluids such as blood, tissue and urine can be extracted
efficiently by the principle of Multiple Extraction.

• Emulsions: Effective concentration of preservative can be established for the storage of

emulsion and other dosage forms.

• Release of drugs from ointments and creams can be predicted

The Ferguson Principle
 The concentration (molarity/ partial pressure) of a drug in plasma is
directly proportional to its activity

𝑃𝑡 𝑆𝑡
X= X=
𝑃0 OR 𝑆0

Pt = partial pressure St = molar concentration

required for pharmacology required for pharmacology
effect effect

P0 = partial pressure pure S0 = molar concentration pure

substances substances.

 X = 0.1- 1.0, drugs has high thermodynamic activity

 X < 0.1, drug has low thermodynamic activity
 Higher thermodynamic activity means:

The activity of drugs is based on its physical properties only

 Lower thermodynamic activity means:

The activity of drugs based on its structure rather than physical properties

 Depending upon the degree to which chemical structure affects biological

action, drugs can be classified as:

 Structurally non-specific (X = 0.1 to 1)

 Structurally specific (X < 0.1)

Structurally Non-specific & Specific Drugs
Structurally Non-specific Drugs Structurally Specific Drugs
They have no specific site of action. They act at specific sites, such as
receptor/ enzyme.

The activity depend on physical Biological action is related to the

properties chemical structure.

Effective only in high concentrations. Effective in a relatively low

concentration.

Example of these drugs are: Example:

-Gaseous anesthetics (diethyl ether, - -Epinephrine
N2O, CHCl3) -Tolbutamide
-Antiseptic
-Sedative & hypnotics