partition coefficient

05/01/231 Sagar Kishor Savale

CONTENT

05/01/232

INTRODUCTIONDEFINITION DETERMINATION OF PARTITION

COEFFICIENTGENERAL FEATURESLIMITATIONREFERENCE

Sagar Kishor Savale

INTRODUCTION 1,4

05/01/233

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.

Sagar Kishor Savale

DEFINITION 1,2

05/01/234

The partition coefficient is defined as the ratio of unionized drug distributed between organic phase and aqueous phase at equilibrium.

FORMULA conc. of Drug in org.

phase.Partition coefficient(p)=

conc. of Drug in aq. Phase.

(p) Is the solute as the ratio of Conc in two phases.

Sagar Kishor Savale

05/01/235

The partitioning of a drug molecule between two phases can be quantified by a partition coefficient

‘p’=SA/SBIn whichSA means solubility of a compound in phase ASB means solubility of a compound in phase BThe org.phase usally chloroform and aq.

Phase usally waterDivided conc of org.phase and aq.phase.

Sagar Kishor Savale

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Complete description then exact aq.phase and org.phase should be specified

Example.Measure the organic phase partition coefficient is 1-

octanol.1-octanol is organic liquid that is immiscible with water.HoweverIt is not pure hydrocarbon.1-octanol good mimic of polarity of biological membrane

lipid.Because it is largely hydrocarbon. (P) Is provide relative solubility of compound in

aq.phase & org.phase As result (P) provide valuable information for drug

design..

Sagar Kishor Savale

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Log p values 1

Log p values for selected pharmaceuticals: It is important to determine the log p of any

new chemical entity.Chart gives log p values for selection of drug

substance.Compound Log P

Oxytetracycline -1.12Sulfadiazine 0.12

Aspirin 1.19Benzylpenicillin 1.83

Temazepam 2.19Lidocaine 2.26Atrazine 2.75Oxadizon 4.09

Permethrin 6.50Sagar Kishor Savale

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Compounds with negative log p values are compound with greater solubiliy in water than non polar oraganic phase.

Compounds polar that are well solvated in aq.Media but diffuse poorly into lipid rich media. The compounds have poor absorption from the gastrointestinal tract.

Compound with log p values between 0 and 0.1 also poorly absorbed into lipophilic media.

Sagar Kishor Savale

05/01/239

Log p

-1.0 0 1.0 2.0 3.0 4.0 5.0 6.0

Polar compounds

Good aq. Solubilty

Poor liquid solubility

Poor adsorption and distribution.

Compound of intermediate polarity

Good balance between aq. And lipid solubility.

Good absorption and distribution.

Non polar compounds

Poor aq. Solubility

Good lipid solubility

Slow excretion

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

Sagar Kishor Savale

DISTRIBUTION COEFFICIENT 4

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It is the ratio of sum of the concentrations of the

compound in each of the two phase.

The knowledge of pka value of a molecule helps to

determine apparent partition coefficient at any pH.

Sagar Kishor Savale

05/01/2311

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.

Sagar Kishor Savale

DETERMINATION OF PARTITION COEFFICIENT 1,3,4

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It can be measured by using following methods.

• Shake flask method.

• HPLC method.

• Computational determination of log P

Sagar Kishor Savale

SHAKE FLASK METHOD:


common method. Direct method experimentally determine the log p of

compound is called shake flask methodsome amount of drug is added, dissolved in octanol & water.Shake flask method is very straight forward Temp must be constantPROCEDURE:• Two solution are mixed.vigorous shaking• After which water and 1-octanol phase are allowed to settle for

24 hours • Two phases are seprated • Conc of compound in each layer determined by suitable

analytical method • Then resulting conc into directly (P) Eq.


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 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).

Simple and lab operative procedure.

Disadvantages:

Time consuming(>30min per sample)

Octanol and water must be mixed and equilibrated (takes 24hours)

Large amounts of material are required.


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:

Since the logP value is determined by linear regression,

several compounds with similar structures must have

known logP values.


Computational determination of log PThe method used by these software packages are

generally on hydrophobic fragmental constant. Developed by Rekker ,Hansch and LeoEffort has gone into developing software that can

calculate Log P values based on molecular structureLog P predicting software is common and widely

used Log p calculatig commands can also often be found

on molecular structure drawing software Log p compound nationally breaking the compound

up into series is known fragment.


These concept can be presented mathematically Log p=∑anƒn+∑bmFmWhere, 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 more reliable and accurateContinuous improvement in software and

databases of fragment constant 05/01/2320 Sagar Kishor Savale

General Features 4

Drugs partition themselves between the aqueous phase and lipophilic membrane.

If the partition coefficient of drug is more than one it is more lipophilicity

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 4

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.

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.


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


http://www.pharmainfo.net/reviews/partition

partition coefficient

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