The coefficients of most clinical relevance are the blood. P log10 partition coefficient partition coefficient, p organicaqueous where indicates the concentration of solute in the organic and aqueous partition. The partition coefficient is the measure of the lipophilicity of a drug and an indication of its ability to cross the cell membrane. Pdf electrochemical determination of partition coefficients. Liquidliquid extraction is a potential separation process for the purification of active pharmaceutical ingredients apis. The use of metabolism versus partition coefficient in. Usually, costintensive experiments have to be performed to select the most suitable solvent system and the best. The relationship of aqueous solubility with partition coefficient is examined in detail. K puu was determined for a set of compounds that are inhibitors and substrates of transporters from the slca family in. In this work, we develop a computational method to predict the effect of ph on the partition coefficient of ionizable drugs. Prediction of partition coefficients and permeability of drug. Pqv is the partition coefficient for the distribution of drug i between a particular vehicle and skin which for ideal solutions is equal to the concentration of the drug i in the skin cn divided by the concentration of the drug i in the vehicle cn. In formulation development the noctanolwater partition coefficient is commonly used.
Pdf calculating partition coefficient by atomadditive method. Calculating partition coefficients of small molecules in. The partition coefficient 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. Abraham2 1university of north texas, 2university college london. The media can be gases such as air, liquids such as water or olive oil, or complex mixtures such as blood or other tissues. Therefore, it is important to understand the intracellular free drug concentration and unbound distribution coefficient k puu to accurately determine the true potency of a compound, e. In the standard method, two calibration curves are required in order to obtain the concentration of drug. Several methods exist for the ca1culation of partition coefficients such as the group contribution approach proposed by hansch.
The noctanolwater partition coefficient, k ow is a partition coefficient for the twophase system consisting of noctanol and water. Various organic solvents are used in the determination of partition coefficient include chloroform, ether, amyl acetate etc. Unbound partition coefficient kpuu is important to an understanding of the asymmetric free drug distribution of a compound between cells and medium in vitro, as well as between tissue and plasma in vivo, especially for transportermediated processes. The octanolwater partition coefficient kow is a measure of the relative hydrophobicity and hydrophilicity of a chemical. Partition coefficients are used in the pharmaceutical industry to estimate how a drug may transfer between different biological environments 4,20 and are regularly used to predict a molecules hydrophobicity. Determination of unbound partition coefficient and in. Determination of unbound partition coefficient k and in. The liposomal membranewater partition coefficients of eight ionizable drugs. However, using in vivo methods to measure the logarithmic values of partition coefficient drug concentration ratios log p in humans is not possible, and to do so in animal models is expensive and time consuming. Hydrophobic drugs with high octanolwater partition coefficients are mainly distributed to hydrophobic areas such as lipid bilayers of cells. This method can serve as a useful tool for modern drug delivery. Ph partition theory of drug absorption is based on the assumption that the git is a simple lipid barrier to the transport of drugs and chemicals. Further, release of drug on to the skin surface is highly influenced by its partition coefficient and ph of. Calculating partition coefficient by atomadditive method article pdf available in perspectives in drug discovery and design 191.
For transdermal drug delivery systems saurabh vinod raut, lalita s. Propofol is slightly soluble in water and, thus, is formulated in a white, oilinwater emulsion. Abraham 2 1university of north texas, 2university college london. Electrochemical determination of partition coefficients of drugs. Prediction of partition coefficients and permeability of drug molecules in biological systems with abraham model solute descriptors derived from measured solubilities and watertoorganic solvent partition coefficients. The diffusion of drug molecules across ratecontrolling membrane or. Partition coefficient wikimili, the free encyclopedia.
Proposal of the netherlands for a new oecd guideline. This is particularly true for very hydro phobic compounds s 6. Partition coefficient noctanolwater using shake flask method the partition coefficient of n octanol and water can be determined by oecd standards test no. Logic lots of good interesting content edited by jacob o. Partition coefficients of pharmaceuticals as functions of. Partition coefficients are used extensively in chemical and environmental engineering to determine the behavior and fate of chemicals. Pdf partition coefficients of drugs in bilayer lipid.
This ratio is therefore a comparison of the solubilities of the solute in these two liquids. The second objective was to make a comparative analysis between the proposed hepatocyte composition. The p ow can be measured by determining the ratio of the concentration of the drug in octanol to its concentration in water at equilibrium. Determination of unbound partition coefficient and in vitro. In this work, we develop a computational method to predict the effect of ph on the partition coefficient of ionizable. The design of an extraction step requires knowledge of the api partition coefficient, which strongly depends on the solvent system and process conditions. The drug molecule must be unionised in aqueous solution. Aug 08, 2016 the predicted overall partition coefficient, as a function of ph, is also compared to experimental values whenever available. To measure the partition coefficient of ionizable solutes, the ph of the aqueous phase is adjusted such that the predominant form of the compound is unionized. Setup is done by our new solvation toolkit which automates the. Pdf determination of liquidliquid partition coefficients.
It is defined as the ratio between unionized drug distributed between the organic and aqueous layers at equilibrium. Method to determine log p the most common method for determining partition and distribution coefficients is the shake flask method. Drug lipophilicity is typically expressed in reference to the partition coefficient of an alcohol containing this many carbons and water. Determination of diffusion and partition coefficients of. The partition coefficient, p, of a drug is given by where drug octan1ol concentration of drug in octan1ol drug water concentration of drug in water a sample of the drug is shaken with a mixture of octan1ol and water and its concentration in each layer is determined. The partition coefficient of a drug may be determined by shaking it with equal parts of two. The noctanolwater partition coefficients were calculated for the hundred ninety three drugs by use of different theoretical procedures 2228. Alogps n this method, for the assessment of noctanolwater partition coefficient, was developed on the. K ow is also frequently referred to by the symbol p, especially in the english literature k ow serves as a measure of the relationship between lipophilicity fat solubility and hydrophilicity water solubility of a substance. Partition coefficient formula partition coefficients are described as the concentration ratio of a chemical amidst the two media at equilibrium. The octanolwater partition coefficient p ow is widely used to assessment of lipophilicity of drug.
In addition to the active component, propofol, the formulation also contains. Prediction of partition coefficients and permeability of drug molecules in biological systems with abraham model solute descriptors derived from measured solubilities and watertoorganic solvent partition coefficients william e. If a solute drug is added to two immiscible liquids such as oil. The influence of drug partition coefficient on follicular penetration. Prediction of partition coefficients and permeability of. They are used in drug design as a measure of a solutes hydrophobicity and a proxy for its membrane permeability. Every drug is xenobiotic because it is coming from outer source xeno and active in biological unit biotic. In petroleum engineers guide to oil field chemicals and fluids second edition, 2015. A molecule with this many carbons adopts a tubshaped conformation to avoid the destabilizing property of antiaromaticity. Lipophilicity of a drug is one of the parameters, which influence its biological activity. Partition coefficient formula definition and examples. For optimal permeability lipid water partition coefficient is expected to be 1 or greater. Definition 1,2 0428164 the partition coefficient is defined as the ratio of unionized drug distributed between organic phase and aqueous phase at equilibrium.
Aug 09, 2016 partition coefficients are used in the pharmaceutical industry to estimate how a drug may transfer between different biological environments 4,20 and are regularly used to predict a molecules hydrophobicity. Classification of steroid partition coefficients by a. Biological factor should also be considered such as skin irritation, site of application of the patch e. Accordingly the unionized form of an acid or basic drug, if sufficiently lipid soluble, is. The partition coefficient is the ratio of concentrations of unionized compound between the two solutions. Most drugs, however, are weak acids or weak bases that partially ionise when. Pdf the influence of drug partition coefficient on.
Pdf determination of octanolwater partition coefficient by normal. A partition coefficient is simply the ratio of the concentration of anesthetic in one phase or solvent compared to another. Pdf calculating partition coefficient by atomadditive. The octanolwater partition coefficient for propofol is 6761. We calculate partition coefficients from transfer free energies using molecular dynamics simulations in explicit solvent. Use of solubility parameters of drug and vehicle to. Partition coefficients of drugs in bilayer lipid membranes. In the physical sciences, a partition coefficient p or distribution coefficient d is the ratio of concentrations of a compound in a mixture of two immiscible solvents at equilibrium. A high partition coefficient implies that the drug is highly lipophilic. A simple method based on one phase measurement for. Our results show that the proposed method can provide satisfactory a priori prediction of ph dependency of kow without input of any experimental data.
If the partition coefficient of drug is more than one it is more lipophilicity if the. Here, we present a physicsbased approach that shows a strong linear correlation between the computed solvation free energy in implicit solvents and the experimental log pow on a cleansed data set of more than 17,500 molecules. Drugs with high partitioncoefficient value can easily permeate through biological membrane. Passage through lipid cell membrane by dissolution in membrane.
If the partition coefficient is high, it denotes high hydrophobicity high lipophilicity and such a drug will easily enter the lipid regions of the organs and stay for longer time and hence may prove toxic. Apr 28, 2016 definition 1,2 0428164 the partition coefficient is defined as the ratio of unionized drug distributed between organic phase and aqueous phase at equilibrium. Partition coefficient an overview sciencedirect topics. These methods result in good estimates of partition coefficients.
The required flux jss or input rate can be calculated from the pharmacokinetic properties of the drug, therapeutic concentration 10. In particular, three dissociation mechanisms were examined based on four relevant properties. Importance of partition coefficient in formulation development authorstream presentation. Drug diffusion through swollen polymer membrane conc. Numbers of compounds have been evaluated for penetration enhancing activity, including alcohols, azone, esters. Physicochemical and pharmacokinetic parameters in drug. The solute is mixed with water and the organic solvent such as octanol. Determination of log p for compounds of different polarity. Logarithmic partition coefficient comparison study and.
The logarithm of the octanolwater partition coefficient, logp, is a key physicochemical property for both pharmaceutical drugs and agrochemicals. The logarithm of the ratio of the concentrations of the unionized solute in the solvents is. Experimental determination of the octanolwater partition. The partition coefficient finds use in drug design, as it is a measure of the hydrophobicity of the drug concerned. Pdf a comparison of theoretical methods of calculation of partition. Basic considerations in the dermatokinetics of topical.
Importance of partition coefficient, solubility and. In this technique, the candidate drug is shaken between octanol and water layers, from which an aliquot is taken and analyzed. Kpuu was determined for a set of compounds from the slca family that are inhibitors and substrates of transporters in hepatocytes. The test guideline describes a method to determine experimentally pow values in the range log pow between 2 and 4 82. Slowstirring method for highly hydrophobic chemicals. Drug candidates are often screened according to logp, among other criteria, to help guide. Partitioning and lipophilicity in quantitative structure. The partition coefficient generally refers to the concentration ratio of unionized species of compound, whereas the. Conversely, estimates of water solubilities and noctanolwater partition coefficients using such.
As a result of its wide and varied applications, the partition coefficient is also referred to as kow or pow. Prediction of ph effect on the octanolwater partition. Evaluation of skin absorption of drugs from topical and. Importance of partition coefficient in formulation development. Determination of the membranebuffer partition coefficient of flunitrazepam, a lipophilic drug. The partition coefficient is an important measurement of the physical. It is usually expressed as the oilwater partition coefficient and it is a measure of the relative solubility of a solute in an organic phase vs water. Knowledge regarding how this value changes with the acidity ph value in the aqueous phase is important for understanding many biological activities. Partition coefficient p is the ratio of concentration of drug in noctanol phase divided by concentration of drug in aqueous phase. The concentration of propofol in whole blood at which rats recover the righting reflex was reported to be 2. The use of metabolism versus partition coefficient in predicting human intestinal permeability classification.
The partition coefficient, abbreviated p, is defined as a particular ratio of the concentrations of a solute between the two solvents a biphase of liquid phases, specifically for unionized solutes, and the logarithm of the ratio is thus log p 275ff when one of the solvents is water and the other is a nonpolar solvent, then the log p value is a measure of lipophilicity or hydrophobicity. What is the lipidwater partition coefficient of a drug. Partition coefficient noctanolwater using shake flask methodthe partition coefficient of noctanol and water can be determined by oecd standards test no. The noctanolwater partition coefficient log pow is a key physicochemical parameter for drug discovery, design, and development. Partition coefficients describe how a solute is distributed between two immiscible solvents. Electrochemical determination of partition coefficients of. The partition coefficient, p, of a drug is given by.
Log p values are widely used in bioaccumulation studies, in drug absorption and toxicity. Kpuu was determined for a set of compounds from the slca family that are inhibitors and substrates of transporters in hepatocytes and. A guide to the lipophilic nature of a drug is its partition coefficient between a fat like solvent and water or an aqueous buffer. Molecules of size larger than 500 daltons usually have more difficulty to penetrate through the sc bos, meinradi, 2000. Determining tissue partition coefficients of drugs will potentially enable 1 selection of a drug that is most appropriate for being retained in a target tissue for therapeutic effects, 2 selection of a drug that has the least affinity in a tissue to avoid side effects in that tissue, 3 identification of a drug with reduced nonproductive binding to barriers in transit before reaching a. As a result, the partition coefficient p is the quotient of two concentrations and is normally calculated in the form of its logarithm to base 10 log p, because p ranges from 104 to 108. In the physical sciences, a partition coefficient p or distribution coefficient d is the ratio of. The partition coefficient is a ratio of concentrations of unionized compound between the.
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