DISTRIBUTION COEFFICIENT

Physical Pharmaceutics I

Dr. Monica RP Rao

AISSMS College of Pharmacy

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❑ Nernst distribution law – In 1891 developed the concept of
distribution/partition coefficient

❑ States that excess solute will distribute itself between two immiscible
solvents/phases such that the ratio of its concentration in each solvent is a
constant.
❑ K = Co/Cw

❑ Organic phase and aqueous phase

❑ Where Cs is the concentration of solute in organic phase,
❑ Cw is the concentration of solute in water,
❑ K is distribution/partition coefficient (also referred to as a P)

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❑ Depends on solubility of solute in each solvent

❑ Spontaneous solute migration depending on affinity for each phase

❑ Organic solvents: CHCl3, CCL4, C6H6, n-Octanol

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❑ Condition for Nernst’s law:

❑ 1. Temperature constant

❑ 2. Same phases/solvents

❑ 3. Solute in same form in both phases

❑ 4. No dissociation or association

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Limitations:

• Dilute solutions: Law does not hold good when concentrations are high.

• Constant temperature: Kept constant throughout the experiment, since

solubility is dependent on temperature.

• Same molecular state: Solute must be in the same molecular state in both
the solvent. This law does not hold, if there is association or dissociation of
solute molecules in one of the solvents.

• Equilibrium concentration: Achieved by shaking the mixture for longer

time.

• Non-miscibility of solvents:

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 General Features:

❑ Drugs partition themselves between the aqueous phase and lipophilic

membrane.

❑ If K of drug is > 1, it is more lipophilic

❑ If K of drug is < 1, it is less lipophilic.

❑ Measure of how well substance partitions between lipid and water.

❑ Hydrophobic drugs with high partition coefficients are preferentially

distributed to hydrophobic compartments such as bilipid layers of cells.

❑ Hydrophilicdrugs with low partition coefficient are found in hydrophilic

compartments such as blood serum.

❑ Partition coefficients have no units.

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❑ Deviations from Nernst’s law:

❑ If solute undergoes dissociation/ionization in one of the solvents/phases

(water)

❑ If solute undergoes association in one of the solvents/phases (organic)

❑ Modified equation to calculate K

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❑ Deviations:

❑ Ionization in water

❑ Solute X – Exists in un-dissociated form in organic phase

❑ Exists in both un-dissociated and dissociated form in aqueous phase

❑ Consider only conc. of un-dissociated form which is common in both phases.

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 Different forms of benzoic acid

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 Effect of ionization: Benzoic acid in peanut oil and water

❑ Total conc. of benzoic acid (BA) in oil phase: Co = [HA]o= Undissociated BA

❑ Species common to both phases

❑ K = true distribution coefficient

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 Effect of ionization: Benzoic acid in peanut oil and water

Species distribution in aqueous phase:

Since: C = Co + Cw

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Straight line eqn.

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 ❑ Deviations:

❑ Association in organic phase

❑ Dimerization in benzene

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❑ Benzoic acid as solute between benzene and acidified water

❑ Association in organic phase (benzene)

❑ Mostly in associated form in benzene

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❑ As benzoic acid exists primarily as associated form in benzene:
❑ [HA]n = Co

[HA]o ≈ constant x

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 True distribution coefficient = K’ =
Cw

Taking log on both sides: log K = 1/n log Co – log Cw

log Cw = 1/n log Co – log K

y = mx + c

Plot of log Cw vs log Co

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 Significance/ Applications

Liquid-liquid extraction

Preservative conc. in emulsions

Bioavailability of drug

CNS action of drug

Narcotic action of drug

Selection of plastic packaging materials

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 Liquid-liquid extraction
• Extraction of a compound from one liq. Into other immiscible liq.

• Suppose:

• W g of solute to be extracted from V1 ml of first solvent (A) with V2 ml of

second solvent (B)

• Let: W1 g be weight of solute remaining in A after first extraction

• Hence: Conc. Of solute remaining in A : w1/V1 g/ml

• Conc. Of solute remaining in B : [w-w1] / V2 g/ml

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 Preservative conc. in emulsions

• Benzoic acid- Weak acid

• Undissociated BA crosses bacterial membrane

• Bacteria reside in aqueous phase

• Preservative will partition between oil and water

• Preservative efficacy depends on conc. of undissociated BA in

aqueous phase

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 • Preservative conc. in emulsions

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 This eqn. is used to calculate total conc. of BA (c) that must
be added to oil-water system so that after partitioning ,
sufficient amount of undissociated BA will be present in
aqueous phase.

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 • Bioavailability of drug
• Biological membranes: Made of Phospholipids
• Fluids in organs, cells and tissues: Aqueous
• Drug has to partition between aqueous and lipid phase to be absorbed
• So, partition coefficient is critical property affecting bioavailability

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▪ CNS action of drugs

▪ Blood - brain barrier

▪ Highly selective semipermeable border of endothelial cells that prevents

solutes in the circulating blood from non-selectively crossing into the
extracellular fluid of the central nervous system where neurons reside.

▪ Lipophilic molecules easily cross BBB

▪ Partition coefficient is predictive of ability to cross BBB

▪ Also Blood-CSF barrier, Blood-ocular barrier

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▪ Narcotic action of drugs

▪ Narcosis – mental state is affected

▪ Habit- forming / addictive

▪ CNS stimulants / CNS depressants

▪ Anxiolytics/ sedatives/hypnotics etc

▪ Cross BBB, Blood-CSF barrier

▪ Lipophilicity / partition coefficient influences addictive tendency of drugs

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 Selection of plastic packaging materials

❑ Plastic – lipophilic

❑ Other components in plastic container like plasticizers- lipophilic

❑ Liquid formulations containing oils or lipophilic drugs

❑ Partitioning of such drugs into container on long term storage

❑ Leaching of components of container into formulation

❑ Undesirable

❑ Compatibility testing between formulation and container is essential

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 Relationship between lipophilicity and pharmacological action

Drug K (CHCl3/water pH 7.4) K (n-octanol/water pH

7.4)

Minocycline 30 1.1
Doxycycline 0.48 0.6
Tetracycline 0.09 0.036
Oxytetracycline 0.007 0.025

Meningitis, General Anaesthesia

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 Neurotoxicity and Partition coefficient

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MEASUREMENT OF PARTITION COEFFICIENT

❑ Shake flask (or tube) method.

❑ HPLC method.

❑ Electrochemical method.

❑ Slow-Stirring Method.

❑ Estimation method based on individual solubilities.

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 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/ HPLC
ii. Carrier free radiotracer

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Advantages of shake flask method:

• Most accurate method.

• Accurate for broadest range of solutes(neutral or charged compounds).

• Chemical structure does not have to be known beforehand.

Disadvantages:

• Time consuming(>30min per sample)

• Octanol and water must be mixed and equilibrated (takes 24 h)

• Complete solubility must be attained and it is difficult to detect small

amounts of undissolved material.

• Large amounts of material are required.

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Carrier free Radiotracer:
• In this method a known amount of a radioactive material [attached to
the solute - radiolabelling] 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.

Disadvantage:
• The solute can absorb on the surfaces of the glass (or plastic)
equipment or at the interface between the two phases.

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Estimation method based on individual solubilities: -

• Based on the ratio of the solubility of the material in octanol and

water.
• For some substances (e.g. some surfactants and pigments) it is
technically not feasible to measure an octanol-water partition
coefficient.

• For such substances it may be possible to obtain a ratio of the

saturated water solubility and saturated octanol solubility.
• It does not include the interaction between the water and solvent
phase (i.e. a substance with high Kow is rather 'pushed out of the
water' than 'pulled into octanol").
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 Some octanol-water partition coefficient data:

Component logPo/w Temperature

Acetamide -1.16 25
Methanol -0.82 19
Formic acid -0.41 25
Diethyl ether 0.83 20
P-dichlorobenzene 3.37 25
Hexamethyl benzene 4.61 25
2,2’,4,4’,5-pentachlorobiphenyl 6.41 Ambient

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• Examples of polar or hydrophilic molecules that are poorly absorbed following oral
administration and, therefore, must be administered parenterally include gentamicin,
ceftrixine, and streptokinase.

• Lipid-soluble drugs with favorable partition coefficients generally are well absorbed
after oral administration.

• Very often, the selection of a compound with higher partition coefficient from a
series of research compounds provides improved pharmacological activity.

• Occasionally, the structure of an existing drug is modified to develop a similar

pharmacological activity with improved absorption. Chlortetracycline, which differs
from tetracycline by the substitution of a chlorine at C-7, substitution of an n-hexyl
(Hexethal ) for a phenyl ring in phenobarbital , or replacement of the 2-carbonyl of
pentobarbital with a 2-thio group (thiopental) are examples of enhanced lipophilicity.

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• It is important to note that even a minor molecular modification
of a drug also may promote the risk of altering the efficacy and
safety profile of a drug.

• For this reason, medicinal chemists prefer the development of a

lipid-soluble pro-drug of a drug with poor oral absorption
characteristics.

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 • Knowledge of partition is important to the pharmacist because
the principle is involved in several areas of current
pharmaceutical interest. These include preservation of oil-
water systems, drug action at nonspecific sites, and the
absorption and distribution of drugs throughout the body.

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 Lipophilicity and Drug Absorption:

❑ pKa of drug determines degree of ionisation at a particular pH

❑ Only the unionised drug, if sufficiently lipid soluble, is absorbed.

❑ Thus even if the drug exist in the unionised form, it will be poorly
absorbed if it has poor lipid solubility (or low Ko/w).

❑ Ideally, for optimum absorption, the drug should have sufficient

aqueous solubility to dissolve in the fluids at the absorption site

❑ Lipid solubility (K0/w) high enough to facilitate the partitioning of

the drug in the lipoidal biomembrane and into the systemic
circulation.
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 Comparison between Intestinal Absorption and Ko/w of the
ionised form of the drug:
Drugs KHeptane/Water % Absorbed
Rapid rate of absorption
Phenylbutazone 100.0 54
Thiopental 3.3 67
Benzoic acid 0.19 54
Salicylic acid 0.12 60
Moderate rate of absorption
Aspirin 0.03 21
Theophylline 0.02 30
Sulphanilamide <0.002 24
Slow rate of absorption
Barbituric acid <0.002 5
Sulphaguanidine <0.002 2
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 Thank you….

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