Solubility and partition coefficient

SOLUBILITY & PARTITION COEFFICIENT
Detailed Review
- Manoj Kumar Tekuri
Presentation on

INTRODUCTION:-
• In spite of the scientific community’s continuing interest
over the past 90 years in partitioning measurements, no
comprehensive review of the subject has ever been
published.
• In fact, no extensive list of partition coefficients has
appeared in the literature.
• The largest compilation is that of Seidell;
• smaller compilations have been made by Collander, Von
Metzsch.G and Landolt.

• The task of making a complete listing is nearly impossible
since Chemical Abstracts has not indexed the majority of the
work of the last few decades under the subject of
partitioning.
• Actually, in recent years relatively few partition coefficients
have been determined in studies simply devoted to an
understanding of the nature of the partition coefficient.
• The vast majority have been measured for some secondary
reason such as the correlation of relative lipophilic character
with biological properties of a set of congeners.

HISTORY:-
• The distribution of a solute between two phases in which it is
soluble has been an important subject for experimentation and
study for many years. In one form or another this technique has
been used since earliest times to isolate natural products such as
the essences of flowers.
• The first systematic study of distribution between two immiscible
liquids which led to a theory with predictive capabilities was
carried out by Berthelot and Jungfleisch. These investigators
accurately measured the amounts present at equilibrium of both I2
and Br2 when distributed between CS2 and water.

• In 1891, Nernst made the next significant contribution to the
subject. He stressed the fact that the partition coefficient would be
constant only if a single molecular species were being considered
as partitioned between the two phases.
• As the primary example of a more exact expression of the
“Partition Law,” it was shown that benzoic acid distributed itself
between benzene and water so that
• Where Cs, is the concentration of benzoic acid in benzene, Cw, is
the concentration of benzoic acid in water, and K is a constant
combining the partition coefficient for the benzoic acid monomer
and the dimerization constant for the acid in benzene.

• During the early years of the twentieth century a great
number of careful partition experiments were reported in the
literature, most of which were carried out with the objective
of determining the ionization constant in an aqueous medium
of moderately ionized acids and bases.
• As a point of historical fact, the method did not live up to its
early promise, partly because of unexpected association in
the organic solvents chosen and partly because of solvent
changes.

• As early as 1909, Herzzl published formulas which related
the partition coefficient (P) to the number of extractions
necessary to remove a given weight of solute from solution.
His formula, with symbols changed to conform to present
usage, is as follows.
• If W ml of solution contains X0 g of solute, repeatedly
extracted with L ml of a solvent, and X1 g of solute remains
after the first extraction, then (X0 – X1)/L = concentration of
solute in extracting phase and X1 / W = concentration
remaining in original solution.

• During the 1940’s the mechanical technique of multiple extraction
was vastly improved, and countercurrent distribution became an
established tool for both the separation and characterization of
complex mixtures. It is beyond the scope of this review to deal
with the great wealth of literature on this subject.
• During the two decades bracketing the turn of the century, while
the partition coefficient was being studied by physical chemists as
an end in itself, pharmacologists became quite interested in the
partition coefficient through the work of Meyer and Overton
Zewho showed that the relative narcotic activities of drugs often
paralleled their oil/water partition coefficients.

• It is only the recent use of partition coefficients as extra
thermodynamic reference parameters for “hydrophobic
bonding” in biochemical and pharmacological systems
which generated renewed interest in their measurement.

DEFINITIONS: -
Solubility:
Quantitative terms: - The concentration of the solute in a saturated
solution at a certain temperature.
Qualitative way: - The spontaneous interaction of two or more
substances to form a homogeneous molecular dispersion.
IUPAC definition: - According to an IUPAC definition, solubility is
the analytical composition of a saturated solution expressed as a
proportion of a designated solute in a designated solvent.
Solubility may be stated in units of concentration, molality,
mole fraction, mole ration and other units.

• Absolute or intrinsic solubility: - The maximum amount of
the solute dissolved in a given solvent under standard
conditions of temperature, pressure and pH. It is a static
property.
• The extent of the solubility of a substance in a specific
solvent is measured as the saturation concentration, where
adding more solute does not increase the concentration of the
solution.
• Solubility is commonly expressed in units of concentration,
either by mass g per dl (100ml) of solvent, molarity, mole
fraction, molality, and other units.

• Dissolution is a process in which a solute substance solubilizes in a
solvent i.e. mass transfer from the solid surface to the liquid phase.
• Dissolution rate is defined as the amount of solid substance that goes
into solution per unit time under standard conditions of temperature, pH
and solvent composition. It is a dynamic process.
• Saturated solution is the one in which the solute in solution is in
equilibrium with the solid phase.
• An unsaturated solution is one containing the dissolved solute in a
concentration below that necessary for complete saturation at a definite
temperature.
• A supersaturated solution is one that contains more of the dissolved
solute that it would normally contain at a definite temperature, where
the undissolved solute is present.

Solubility definition in the United States of
Pharmacopoeia:
Description Forms
(Solubility Definition)
Parts of Solvent Required
for One Part of Solute
Very soluble <1
Freely soluble From 1 to 10
Soluble From 10 to 30
Sparingly soluble From 30 to 100
Slightly soluble From 100 to 1000
Very slightly soluble From 1000 to 10,000
Practically insoluble >10,000

THEORY: -
HENRY’S LAW
• The most general approach to distribution phenomena is to treat
the Partition law as an extension of Henry’s law. For a gas in
equilibrium with its solution in some solvent,
m/p = K
• Where m = mass of gas dissolved per unit volume and p =
pressure at constant temperature. Since the concentration of
molecules in the gaseous phase is proportional to pressure, p can
be replaced by C1 and the mass/unit volume of gas in solution
designated by C2. Equation can then be restated as C2/C1 = K.

• In the most general terms, then, the concentrations of any
singular molecular species in two phases which are in
equilibrium with one another will bear a constant ratio to
each other as long as the activity coefficients remain
relatively constant.
• Many large interesting organic compounds deviate
considerably from ideal behavior in water and various
solvents so that one is not always even reasonably sure of the
exact nature of the molecular species undergoing
partitioning.

Applications:-
• Solubility is of fundamental importance in a large number of
scientific disciplines and practical applications.
• Solubility of a substance serves as a standard test for purity.
• The action of a drug can be severely limited by poor aqueous
solubility. Similarly, side effects of certain drugs are the result of
their poor aqueous solubility.
• The solubility of drugs in GI fluids (dissolution) is an important
step for better absorption of drugs.
• Differences in solubility in various solvents often serve as a useful
means of separating one component from the other and for
purification purposes (Extraction and Recrystallization).

• Solubility is often said to be one of the "characteristic
properties of a substance," which means that solubility is
commonly used to describe the substance, to indicate a
substance's polarity, to help to distinguish it from other
substances, and as a guide to applications of the substance.
For example, indigo is described as "insoluble in water,
alcohol, or ether but soluble in chloroform, nitrobenzene, or
concentrated sulphuric acid".

• Solubility of a substance is useful when separating
mixtures. For example, a mixture of salt (sodium chloride)
and silica may be separated by dissolving the salt in water,
and filtering off the undissolved silica.
• The synthesis of chemical compounds, by the milligram in a
laboratory, or by the ton in industry, both make use of the
relative solubility’s of the desired product, as well as
unreacted starting materials, by-products, and side products
to achieve separation.

• Another example of this is the synthesis of benzoic
acid from phenyl magnesium bromide and dry ice. Benzoic
acid is more soluble in an organic solvent such
as dichloromethane or diethyl ether, and when shaken with
this organic solvent in a separatory funnel, will preferentially
dissolve in the organic layer. The other reaction products,
including the magnesium bromide, will remain in the
aqueous layer, clearly showing that separation based on
solubility is achieved. This process, known as liquid-liquid
extraction, is an important technique in synthetic chemistry.

Bio pharmaceutics Classification System (BCS) which classified the
drugs into one of the four groups based on the intestinal permeability and
solubility of drugs:
CLASS Solubilit
y
Permeabili
ty
Absorption
pattern
Rate-
limiting step
in
absorption
Examples
I High High Well absorbed Gastric
emptying
Diltiazem
II Low High Variable Dissolution Nifedipine
III High Low Variable Permeability Insulin
IV Low Low Poorly
absorbed
Case by case taxol

PARTITION COEFFICIENT
The movement of molecules from one phase to another is called
partitioning.
• If two immiscible phases are placed adjacent to each other, the solute will
distribute itself between two immiscible phases until equilibrium is
attained; therefore no further transfer of solute occurs.
• When a substance is added in excess quantity in two immiscible solvents,
it distributes itself between two liquid phases so that each becomes
saturated.
• The distribution or partition of a solute between immiscible liquids is
known as Nernst’s distribution law or simply distribution law or
partition law.

• Nernst’s distribution law states that when the added
substance is insufficient to saturate the immiscible liquids,
the solute distributes between the liquids in such a way that
at equilibrium the ratio of concentrations of the solute in the
two liquids is constant, at constant temperature.
• Partition(P) or distribution coefficient(D) is the ratio of
concentration of a compound in the two phases of a mixture
of two immiscible solvents at equilibrium

• Hence these coefficients are a measure of differential
solubility of the compound between two solvents.
• One of the solvents is water and the second one is
hydrophobic such as octanol. It is useful in estimating the
distribution of drugs within the body.
• It is the ratio of concentration of a substance in organic
phase to the concentration of substance in aqueous phase
at constant temperature.

It is given as: Equilibrium constant, 𝐾 =
𝐶𝑜
𝐶𝑤
Where,K= Partition coefficient/ distribution coefficient/
distribution ratio.
Co= Equilibrium concentration of substance in
organic phase.
Cw= Equilibrium concentration of substance in
aqueous phase.

General Features:
• Drugs partition themselves between the aqueous phase and lipophilic
membrane.
• If the partition coefficient of drug is more than one it is more lipophilic
• If the partition coefficient of drug is less than one it is less lipophilic.
• It is a 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.
• Hydrophilic drugs with low partition coefficient are found in hydrophilic
compartments such as blood serum.
• Partition coefficients have no units.

Limitations:
• Dilute solutions: The conc. of solute must be low in two solvents. This
law does not holds good when the concentrations are high.
• Constant temperature: Temperature should be 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: This is achieved by shaking the mixture for
longer time.
• Non-miscibility of solvents: So, the solvents are to be allowed for
separation for a sufficient time.

• The lipophilicity of an organic compound is usually described in
terms of a partition coefficient, log p, which can be defined as
the ratio of the concentration of the unionized compound, at
equilibrium, between organic and aqueous phases:
• Log P values have been studied in approximately 100 organic
liquid–water systems. Since it is virtually impossible to determine
log P in a realistic biological medium, the octanol:water system
has been widely adopted as a model of the lipid phase.

OCTANOL
Octanol and olive oil are believed to represent the lipophilic
characteristics of biological membrane better than other organic
solvents such as chloroform.
The n-octanol/water partitioning system mimic the lipid
membranes/water systems found in the body.
DISTRIBUTION COEFFICIENT or logD:
It is the ratio of sum of the concentrations of all forms of the
compound in each of the two phases.
To measure distribution coefficient, the pH of the aqueous phase is
buffered to specific value.

• 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.
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.

MEASUREMENT OF PARTITION COEFFICIENT:
It can be measured by using following methods.
• Shake flask (or tube) method.
• HPLC method.
• Electrochemical method.
• Slow-Stirring Method.
• Estimation method based on individual solubilities.

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.

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 24hours)
• Complete solubility must be attained and it is difficult to detect small
amounts of undissolved material.
• Large amounts of material are required.

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.
Disadvantage:
• The solute can absorb on the surfaces of the glass (or plastic)
equipment or at the interface between the two phases. To guard
against this the mass balance should be calculated.

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.

Advantages:
• Fast method of determination (5-20 min per sample).
Disadvantages:
• The solutes chemical structure must be known beforehand.
• Since the logP value is determined by linear regression, several
compounds with similar structures must have known logP values.

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.

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").

• This explains the poor correlation typically observed between
octanol solubility and Kow.
• The ratio was found to be somewhat more representative if one
uses octanol/saturated water and water/saturated octanol.
• As such, a ratio estimation would be a less preferred yet
acceptable alternative for the octanol/water partition coefficient
(Kow), but must be treated with caution as it would not have
been derived in the same manner as other KowS.

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

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.

• Partition principle is used in partition chromatography to separate
organic substance from mixtures.
• Complexation: Certain complexes partition difficulty to the
substrate and complexing agent. This change in lipophilicity will
affect the activity of the drug and can also be used to measure the
extent of complexation.
• Chemical modification: Chemical changes related to lipid
solubility and its effect on GI absorption are best exemplified by
barbiturates,

Solubility and partition coefficient

• Metallurgy: In metallurgy, the partition coefficient is an important
factor in determining how different impurities are distributed between
molten and solidified metal.
• Agrochemicals: Hydrophobic insecticides and herbicides tend to be
more active. Hydrophobic agrochemicals in general have longer half
lives and therefore display increased risk of adverse environmental
impact.
• Pharmacokinetics: In pharmacokinetics, the distribution coefficient has
a strong influence on ADME properties of the drug. More specifically, in
order for a drug to be orally absorbed, it normally must first pass
through lipid bilayers in the intestinal epithelium. For efficient transport,
the drug must be hydrophobic enough to partition into the lipid bilayer,
but not so hydrophobic.

• Pharmacodynamics: In this the hydrophobic effect is the major
driving force for the binding of drugs to their receptor targets. On
the other hand hydrophobic drugs tend to be more toxic because
they retained longer and have wider distribution within the body.
Hence it is advisable to make the drug as hydrophilic as possible so
the ideal distribution coefficient for a drug is usually intermediate.
• Like, preservative emulsions partition between the water and oil
phases; antibiotics partition from body fluids to microorganisms;
and drug and other adjuvants can partition into the plastic and
rubber stoppers of the containers. It is therefore is important that
this process is understood.

Drugs pKa pH/site of absorption
Very weak acids (pKa > 8.0)
Phenobarbital 8.1 Unionised at all pH values;
absorbed along the entire
length of GIT.
Hexobarbital 8.2
Phenytoin 8.2
Moderately weak acids (pKa 2.5 to 7.5)
Cloxacillin 2.7 Unionised in gastric pH and
ionised in intestinal pH; better
absorbed from the stomach.
Aspirin 3.5
Ibuprofen 4.4
Stronger acids (pKa < 2.5)
Disodium cromoglycate 2.0 Ionised at all pH values; poorly
absorbed from GIT.
Very weak bases (pKa< 5.0)
Theophylline 0.7 Unionised at all pH values;
absorbed along the entire
length of GIT.
Caffeine 0.8
Diazepam 1.7
Moderately weak bases (pKa 5 to 11.0)
Reserpine 6.6 Ionised at gastric pH, relatively
unionised at intestinal pH;
better absorbed from intestine.
Codeine 8.2
Amitriptyline 9.4
Stronger bases (pKa > 11)
Mecamylamine 11.2 Ionised at all pH values; poorly
absorbed from GIT.Guanethidine 11.7

Effect of Ionic Dissociation and Molecular Association on
Partition:
• During distribution, the solute may gets associated into molecules in
one liquid phase or may get dissociated into ions in either of the liquid
phase.
• The distribution law states that: ‘the ratio of undissociated or unionised
solute which is distributed between the two immiscible phases is at
equilibrium’. This is known as partition coefficient (K).
• The distribution law applies only to the concentration of the species
common to both phases, namely, the monomer or simple molecules of
the solute.

• Example: It can be described by distribution of benzoic acid
between the two liquid phases (i.e., oil phase and water phase).
When, benzoic acid is added to oil-water system, distribution of
benzoic acid takes place between oil and water phase.
• When it is neither associated in the oil nor dissociated into ions in
the water.
• The benzoic acid may get associated in the oil phase to form
molecules.
• Or, gets dissociated in water phase to form ions.

• Some drugs may be poorly absorbed after oral administration
even though they are available predominantly in the un-ionized
form in the gastrointestinal tract.
• This is attributed to the low lipid solubility of the un-ionized
molecule.
• This parameter therefore influences the transport and absorption
processes of drugs, and it is one of the most widely used
properties in quantitative structure–activity relationships.
• The greater the value of P, the higher the lipid solubility of the
solute.

• It must be clearly understood that even though drugs with
greater lipophilicity and, therefore, partition coefficient are
better absorbed, it is imperative that drugs exhibit some degree
of aqueous solubility.
• This is essential, because the availability of the drug molecule in
a solution form is a prerequisite for drug absorption and the
biological fluids at the site of absorption are aqueous in nature.
• Therefore, from a practical viewpoint, drugs must exhibit a
balance between hydrophilicity and lipophilicity. This factor is
always taken into account while a chemical modification is
being considered as a way of improving the efficacy of a
therapeutic agent.

• 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.

• 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.

• 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.

Lipophilicity and Drug Absorption:
• It is the pKa of the drug which determines the degree of ionisation
at a particular pH and that only the unionised drug, if sufficiently
lipid soluble, is absorbed into the systemic circulation.
• 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 and
lipid solubility (K0/w) high enough to facilitate the partitioning of
the drug in the lipoidal biomembrane and into the systemic
circulation.

• In other words, a perfect hydrophilic-lipophilic balance (HLB)
should be there in the structure of the drug for optimum
bioavailability.
• The lipid solubility of a drug is measured by a parameter called as
log P where P is oil/water partition coefficient (Ko/w or simply P)
value of the drug.
• This value is a measure of the degree of distribution of drug
between lipophilic solvents such as n-octanol and an aqueous
phase (water or a suitable buffer). In general, the octanol/pH 7.4
buffer partition coefficient value in the range of 1 to 2 of a drug is
sufficient for passive absorption across lipoidal membranes.

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

SOLUBILITY AND PARTITION COEFFICIENT
• The solubility and partition coefficient play a role of primary
importance in determining the presence, absence or the relative
intensity of biologic action.
• It is well recognized that increasing the non polar portion of a
molecular by increasing the length of hydrocarbon side chain
produces definite changes in the physical properties .
• The boiling point increases, solubility in water decreases, partition
coefficient increases, surface activity increases, viscosity
increases.
60

Solubility and partition coefficient
• Hansch etal. Observed a relationship between aqueous
solubilities of non electrolytes and partitioning. Yalkowsky
and Valvani obtained an equation for determining the
aqueous solubility of liquid or crystalline organic
compounds.
61

Logs = -logK -1.11 ∆Sf(m25) + 0.54
• S = aqueous solubility in Moles/litre
• K = octanol- water partition coefficient.
• ∆Sf = molar entropy of fusion
• mp = melting point of a solid compound on the
centigrade scale
62

• For a liquid compound, mp is assigned a value of 25. So the
second right hand term of equation becomes zero.
• The entropy of fusion and the partition coefficient can be
estimated from chemical structure of the compound.
• For rigid molecules, ∆Sf = 13.5entropy units(eu).
• For molecules with n greater than 5 non hydrogen atoms in a
flexible chain.
∆Sf = 13.5+ 2.5(n-5)eu
• Leo etal. Provided partition coefficients for a large number of
compounds.
63

• The normal aliphatic alcohols shows a regular increase in
antibacteral activity as the homologous series is ascended from
methyl through octyl alcohols.
• The branched chain alcohols are more water soluble and have
lower partition coefficients than the corresponding primary
normal alcohols.
• The partition co-efficient were first correlated with the
biological activity of hypnotic and narcotic drugs.
64

References:
1. D.M. Brahmankar, Biopharmaceutics and Pharmacokinetics-A
treatise. Vallabh Prakashan. P 27-48.
2. Patrick J. Sinko. Martin’s Physical Pharmacy and Pharmaceutical
Sciences. 6th Edition, p 182-195.
3. Thomas L. Lemke, David A. Williams. Foye’s Principles of
Medicinal Chemistry. 6th Edition. P 210-240.
4. Guidance for the implementation of research. ECHA (European
Chemicals Agency). Version-2.2. August 2013.
5. Chemical Reviews: Partition coefficients and their uses. ALBERT
LEO. Volume 71. Number-6. December 1971.

Solubility and partition coefficient

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