Distribution Coefficient (Partition

Law)
The relationship of dissolved substances distributed
between two solvents that do not mix
Nerst: if a solut is distributed to

in two solvents that do not mix, solut will be partitioned

between the two solvents.
In a balanced state, the ratio of valuable solut
concentration remains at a fixed temperature.
Con. of dissolved subs in the organic phase
=
C2 
= Kd
konsentrasi zat terlarut dalam fase air C1

Solvent
D=
CO
Dissolved
Substances
Organic (O) water Cw
Iodium CCl4 water 85
Iodium CS2 water 414
Iodium CHCl3 water 131
Brom (C 2H 5)O water 0.125
succineic CCl4 water 30
acid
❑ The price of Kd does not depend on the total
concentration of solut in both phases.
❑ Kd depends on the temperature, the second type of solvent, the
type of solut.
❑ Partition law applies only to diluted solutions and the
state of solut is the same (no change) in both solvents.
❑ Partition law does not apply if distributed soluts are
associated or associated with solvent phases.
❑ If the ideal state (dissolved substances do not
experience association, dissociation or polymerization)
Kd = D.
 The best and most popular methods
 Can be done in both macro and micro level
 No need for special / advanced tools
 The separation process is simple, fast and easy
 Used in the industry to eliminate unwanted
substances in products
 Examples: purification of kerosene, cooking oil,
purification of NaOH in the process of electrolysis.
Extraction classification
Based on extracted mixture form
❑ Solid-liquid Extraction
❑The extracted substances are found in a mixture in the
form of solids.
❑This extraction is widely done in an effort to isolate the
efficacious substances contained in natural steroids,
hormones, antibiotics, lipids in grains.
❑Liquid-liquid extraction (solvent extraction)
❑The extracted substances are contained in a liquid
mixture.
❑example: separation of iod or metals in water.
❑ Continuous extraction
❑ The same solvent is used repeatedly until the
extraction process is complete'
❑ Tools: soxhlet.
❑ Staged extraction
❑ At this extraction, each time the extraction is
always used a new solvent until the extraction
process is complete.
❑ Tools: separating funnels.
Soxhlet Tool Separation Funnel
Extraction techniques
 In liquid-liquid extraction, continuous or gradual
methods can be carried out.
For the gradual method:
 techniques by adding a solvent extracter that
does not mix with the first solvent through a
separating funnel
done dissing until there is an equilibrium
concentration of solut in both solvents.
silenced for a while formed 2 layers.
 Low solubility in the water phase
 Low viscosity to prevent emulsion from forming
 Low toxicity
 Not flammable
 Large Kd price for dissolved substances
 Small Kd price for contaminants
 Easily take back dissolved substances and
solvents (note the boiling point).
DRUG DISTRIBUTION COEFFICIENT
Coefficient of distribution (coefficient of partition) of a
drug: the equilibrium level of the drug in both phases
that do not mix.
Kd = CA atau P = [obat] lipid
CB [obat]ater
In the living system Kd is difficult to measure.
Kd is determined in vitro by using n-octane as
lipid phase and pH 7.4 phosphate buffer as water
phase. Kd is an additive trait for molecules
each function group also establishes the pattern,
lipophilic properties & molecular hydrophyll.
 The coefficient of distribution is very influential on the :
 Characteristics of drug transport
 How the drug reaches its working side in terms of use
 How the drug penetrates and crosses a number of cells to reach
the working side

E.g. drugs that are very soluble in water, can not afford
quickly passes through lipid fluid to reach lipid-rich organs
(brain & nerve tissue), but through blood by diffusion from
water phase to phase the other can finally get to the
destination.

 Determination of which tissues can be achieved by a particular

compound
 How depressants, anesthestics, hypnotics, disinfectants work
OVERTON HYPOTHESIS - MEYER
 19th century Overton & Meyer hypothesize that work
Narcotics of the drug is a function of the coefficient of distribution
of a compound between the medium of lipids and water.

Conclusion :
 All lipid-soluble neutral substances have depressive
properties of nerves
 Such activity is very noticeable in lipid-rich cells
 The effect rises with the increase of the coefficient of
partitions regardless of the structure of the substance.
Various variations of drugs of different chemical types ✓
produce the same narcotic work at the same
concentration in fat cells (cell membranes).
 Mulin made modifications to Mayer's theory.
in addition to the concentration of anesthestics in the

membrane, volume is also important expressed in the
fraction of volume.

Volume fraction = mole fraction x partial molar volume

 Anesthestics enliven cell membranes

 Anesthesia occurs when the critical loading value is achieved,
about 0.3 – 0.5% of its original volume.
 The surface area of the membrane also expands.
FERGUSON RULES (1939)
 Fergusson expands hypothesis for anesthestics given
as gas phase by inhaled

 Regardless of biophase (anesthethetic working side

or absolute concentration of substances in
gas/liquid phase Anestethic effects occur within
a constant range of thermodynamic activity
Aktivitas termodinamik : a = Pi(for gas)

Ps
Pi = partial steam pressure in the air Ps =
pure substance steam pressure
Si = concentration of dissolved drug molar
Ss = solubility of medicinal molars.
 Ferguson states that the same level of drug work will
occur in the thermodynamic activeness of the same drug
in the solution

 Highest price for thermodynamic activity = 1

is a saturation point

 Thermodynamic activity is useful for distinguishing typical

and un khas structured drugs.


Non specific structured drugs work on activity
thermodynamic high (0.01 – 1) active only at high doses Its
biological activity is not related to chemical structure.
Different compounds biological activity is the same

Typical structured drugs most of the compounds are used
for treatment.

 Shows pharmacological effects related to its

thermodynamic activity.

 Active at concentrations corresponding to very low

thermodynamic activity (< 0.001)

 Similar chemical structure produces the same effect with

the same mechanism

 Changes in chemical structure alter its chemist

properties pharmacological properties change

Typical structured compound antaraksi with typical and
highly selective drug receptors

 Generally macromolecule structures are lipoproteins or

glycoproteins

 Low receptor density for each unit of membrane surface

( 10 – 10,000 receptors/μm2.

Note: the group of drugs is not typical general anestethic

Its structure ranges from noble gases (Ar, Xe) to complex
steroids.
Anesthetic pharmacology complex and extensive.
 DEFINITION 1 ,2

The coefficient of partitions is defined as the ratio of

uniformized drugs distributed between organic phases and
watery phases on equilibrium.
Formula
conc. of Drug in org. phase.
Partition coefficient(p) = conc. of Drug in aq. Phase
.

(p) Whether the substance is dissolved as

a Kons ratio in two phases.
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 Partition of drug molecules between two phases can be quantified
with partition coefficient
‘p’=SA/SB
Di mana
SA means solubility of compounds in phase A SB means solubility
of compounds in phase B
Org Phase org. Usually chloroform and aq. Ordinary water phase
Divided org.phase and aq.phase.

04/28/16 Sagar Kishor Savale 19

❑Complete description then exact aq.phase and org.phase
should be specified
Example.
Measure the coefficient of organic phase partitions is 1-octane. 1-octane
is an organic liquid that cannot mix with water.
However
It's not pure hydrocarbons.
1-octaneol mimics the lipid polarity of biological membranes. Because
it's mostly hydrocarbons. (P) Provide relative solubility of compounds
in aq.phase & org.phase
As a result (P) provides valuable information for the design of the drug .

04/28/16 Sagar Kishor Savale 20

 Log p values 1
This allows the relationship between the retention time on the column
(reverse phase) and the n-octane/water partition coefficient..

Compound Log P
Oxytetracycline -1.12
Sulfadiazine 0.12
Aspirin 1.19
Benzylpenicillin 1.83
Temazepam 2.19
Lidocaine 2.26
Atrazine 2.75
Oxadizon 4.09
Permethrin 6.50

04/28/16 Sagar Kishor Savale 21

  Compounds with negative p log values are compounds with
greater solubility in water than non-polar oraganic phases.
 Polar compounds are well dissolved in aq. Media but
poorlyfused into lipid-rich media. The compound has poor
absorption of the digestive tract.
 Compounds with a log value of p between 0 and 0.1 are also
poorly absorbed into the lipophilic medium.

04/28/16 Sagar Kishor Savale 22

 Log p -1.0 0 1.0 2.0 3.0 4.0 5.0 6.0

Polar compounds Compound of Non polar compounds

Good aq. Solubilty
Poor liquid solubility
Poor adsorption and
distribution.
intermediate polarity
Poor aq. Solubility
Good balance
between aq. And lipid Good lipid solubility
solubility.
Slow excretion
Good absorption and
distribution.

Fig:Effect of log p values on solubility absorption and distribution of

drug sunstances.

04/28/16 Sagar Kishor Savale 23

 DISTRIBUTION COEFFICIENT 4

❑ This is the ratio of the number of concentrations of

compounds in each of the two phases.
❑ Knowledge of the pka value of a molecule helps
determine the coefficient of partitions visible at any
pH.

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 Wheres
[Drug molecules] o = concentration of the drug in its molecular form in
octane-1-ol;
[Drug molecules] w = concentration of the drug in its molecular form in
water; [Drug ions] w = concentration of the drug in the form of ionized in
water.

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 DETERMINATION OF PARTITION
COEFFICIENT 1,3,4

It can be measured by using following methods.

• Shake flask method.

• HPLC method.

• Computational determination of log P

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S H AK E F L AS K M E THOD:

04/28/16 Sagar Kishor Savale 27

 common method.
❑ A direct method that experimentally determines the
compound's p log is called the shake flask method
❑A number of drugs are added, dissolved in octane & water.
❑Method Method shake shake very straight forward
❑EmpTemp must be constant
PROCEDURE:

• Two solutions are mixed. Strong vibrations

• After that the water and phase 1-octane are allowed to settle
for 24 hours
• Two phases separated
• The concentration of compounds in each layer is determined
by the appropriate analytical method
• Then generated conc into direct (P) Equation.
04/28/16 Sagar Kishor Savale 28
Continue…

 Give the (P).and convert into log p value

The distribution of solute is measured by methods.

1. UV-Visible spectroscopy-
 In this method, after dissolving the drug between two phases, they are

separated.

 Standard dilution is prepared.

 Absorbance is measured at the appropriate wavelength.

 Using a calibration curve, the concentration of samples in organic

phases and water can be measured.

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 Advantages of shake flask method:

 The most accurate method.

 Accurate for a wide dissolved range (neutral or charged compound).
 Simple and lab operating procedures.

Disadvantages:

 Takes (> 30 minutes per sample)

 Octane and water should be mixed and balanced (it takes 24 hours)

 Large quantities of materials are needed..

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 HPLC method:

 By correlate retention times with compounds similar to known logP

values.
 HPLC is performed on analytical fields packed with commercially

available solid phases containing long hydrocarbon chains (e.g. C8, C18)
which is chemically fastened to silica.
 The mixture of chemicals is dilution according to its hydrofobisity, with

water-soluble chemicals first dilution and chemicals soluble in the last oil.
 This allows the relationship between the retention time on the

column (reverse phase) and the n-octane/water partition

coefficient.

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 Advantages:

 F a s t method of determination (5-20 min per sample).

Disadvantages:
 Si nce l ogP val ues are deter mi ned by l i near

r e gre s s i on, some compound s of t he same

s t r uc t ur e must know t he l ogP val ue .

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 Computational determination of log P
 T h e me th o d s u sed b y th e se so f tw a re p ack ag e s are
g en e ra l ly o n co n s tan t s o f hy d ro p h o bi c fr ag men t s .
D ev e lo p e d b y R ek k e r, H an s ch an d L eo . F fE ffo rt
h a s d ev el o p ed so f tw a re th a t can ca l cu l a te l o g P
v a l u es b a s e d o n m o l e c u la r s t r u c t u re .

Log P prediction software is common and widely

used.

Command calculation logs can also be found on the

software by drawing molecular structures. The log
component rationally breaks down the component to
a specific fragment.

04/28/16 33
Logp=∑anƒn+∑bmFm
These concept can be presented mathematically

Where,
a= Number of fragments of type
n ƒn=Fragment constant
b=Number of correction of type
m Fm=correction factor
Computational determination log p is very convenient
Calculated log p values are more reliable and accurate
Continuous in software and constant database of
fragments

04/28/16 Sagar Kishor Savale 34

 General Features 4
 Partition the drug itself between the water phase and the lipophilic
phase
 If the coefficient of partitioning the drug is more than one, it is
more lipophilic
 If the coefficient of partitioning the drug is less than one, it is less
lipophilic.
 This is a measure of how well the partition of the substance
between the lipids and the water.
 Hydrophobic drugs with high partition coefficients are preferred
to be distributed to hydrophobic compartments such as bilipid cell
layers.
 Hydrophilic drugs with low partition coefficients are found in
hydrophilic compartments such as blood serums.
 No partition coefficient (no unit)
21 04/28/16
 Limitations 4

 Diluted solution: The conc. dissolved substances should be low in two

solvents. This law does not apply if the concentration is high.
 Constant temperature: The temperature should be kept constant during
the experiment, as solubility depends on the temperature.
 Same molecular state: Solut must be in the same molecular state in both
solvents.
 Concentration of equilibrium: This is achieved by whisking the mixture for
a longer time.
 Non-solvent miscirbility: So, solvents should be allowed for separation for a
considerable time.

04/28/16 Sagar Kishor Savale 36

 References:

1) Humphrey moynihan, abina crean,2010,the

physicochemical basis of pharmaceuticals,oxford indian
edition.216-223.
2) Leon Lachman,lieberman H. A.Z,1991, The Theory And
Practice Of Industrial Pharmacy,third Edition,varghese
Publishing House,Mumbai.188-189.
3) The pharmaceutical codex principles and practice of
pharmaceutics,twelth edition, cbs publishers and
distributers, New delhi.70,188,313.
4) http: //www.pharmainfo.net/reviews/partitioncoefficient

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