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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
05/01/236
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
05/01/237
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
05/01/238
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
05/01/2310
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
05/01/2312
It can be measured by using following methods.
• Shake flask method.
• HPLC method.
• Computational determination of log P
Sagar Kishor Savale
SHAKE FLASK METHOD:
05/01/2313 Sagar Kishor Savale
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.
05/01/2314 Sagar Kishor Savale
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.
05/01/2315 Sagar Kishor Savale
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.
05/01/2316 Sagar Kishor Savale
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.
05/01/2317 Sagar Kishor Savale
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.
05/01/2318 Sagar Kishor Savale
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.
05/01/2319 Sagar Kishor Savale
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.
05/01/2321 Sagar Kishor Savale
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.
05/01/2322 Sagar Kishor Savale
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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05/01/2324 Sagar Kishor Savale