partition coefficient

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  • **Sagar Kishor Savale

    Sagar Kishor Savale

  • CONTENT**INTRODUCTIONDEFINITION DETERMINATION OF PARTITION COEFFICIENTGENERAL FEATURESLIMITATIONREFERENCESagar Kishor Savale

    Sagar Kishor Savale

  • INTRODUCTION 1,4**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

    Sagar Kishor Savale

  • DEFINITION 1,2** 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

    Sagar Kishor Savale

  • **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

    Sagar Kishor Savale

  • **Complete description then exact aq.phase and org.phase should be specifiedExample.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.phaseAs result (P) provide valuable information for drug design..Sagar Kishor Savale

    Sagar Kishor Savale

  • **Log p values 1Log 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.

    Sagar Kishor Savale

    Compound Log POxytetracycline-1.12Sulfadiazine0.12Aspirin1.19Benzylpenicillin1.83Temazepam2.19Lidocaine2.26Atrazine2.75Oxadizon4.09Permethrin6.50

    Sagar Kishor Savale

  • **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

    Sagar Kishor Savale

  • **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 excretionFig:Effect of log p values on solubility absorption and distribution of drug sunstances.Sagar Kishor Savale

    Log p-1.001.02.03.04.05.06.0

    Sagar Kishor Savale

  • DISTRIBUTION COEFFICIENT 4**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

    Sagar Kishor Savale

  • **

    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

    Sagar Kishor Savale

  • DETERMINATION OF PARTITION COEFFICIENT 1,3,4**It can be measured by using following methods.Shake flask method.HPLC method.Computational determination of log P

    Sagar Kishor Savale

    Sagar Kishor Savale

  • SHAKE FLASK METHOD:**Sagar Kishor Savale

    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 constant

    PROCEDURE:Two solution are mixed.vigorous shakingAfter 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.

    **Sagar Kishor Savale

    Sagar Kishor Savale

  • ContinueGive 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.

    **Sagar Kishor Savale

    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.

    **Sagar Kishor Savale

    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.

    **Sagar Kishor Savale

    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.

    **Sagar Kishor Savale

    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.

    **Sagar Kishor Savale

    Sagar Kishor Savale

  • These concept can be presented mathematically Log p=ann+bmFmWhere, a= Number of fragments of type n n=Fragment constant b=Number of correction of type m Fm=correction factor

    Computational determination log p is very convenientCalculated log p values more reliable and accurateContinuous improvement in software and databases of fragment constant

    **Sagar Kishor Savale

    Sagar Kishor Savale

  • General Features 4Drugs partition themselves between the aqueous phase and lipophilic membrane.If the partition coefficient of drug is more than one it is more lipophilicityIf 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.

    **Sagar Kishor Savale

    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.

    **Sagar Kishor Savale

    Sagar Kishor Savale

  • References:Humphrey moynihan, abina crean,2010,the physicochemical basis of pharmaceuticals,oxford indian edition.216-223.Leon Lachman,lieberman H. A.Z,1991, The Theory And Practice Of Industrial Pharmacy,third Edition,varghese Publishing House,Mumbai.188-189.The pharmaceutical codex principles and practice of pharmaceutics,twelth edition, cbs publishers and distributers, New delhi.70,188,313.http: //www.pharmainfo.net/reviews/partitioncoefficient**Sagar Kishor Savale

    Sagar Kishor Savale

  • **Sagar Kishor Savale

    Sagar Kishor Savale

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