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 Solubility

Permeability

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,

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,

• 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 absorptionVery weak acids (pKa > 8.0)Phenobarbital 8.1 Unionised at all pH values;

absorbed along the entire length of GIT.

Hexobarbital 8.2Phenytoin 8.2Moderately 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 3.5Ibuprofen 4.4Stronger 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 0.8Diazepam 1.7Moderately weak bases (pKa 5 to 11.0)Reserpine 6.6 Ionised at gastric pH, relatively

unionised at intestinal pH; better absorbed from intestine.

Codeine 8.2Amitriptyline 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

60

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.

61

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.

62

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

63

• 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.

64

• 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.

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.

Thank you….