Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design:...

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1 Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical Chemistry, School of Pharmacy, University of Athens

Transcript of Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design:...

Page 1: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

How to calculate?

Anna Tsantili-Kakoulidou

Department of Pharmaceutical Chemistry, School of Pharmacy,

University of Athens

Page 2: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design

Important in :

• Passive diffusion transcellular permeability

• Hydrophobic binding to proteins plasma and tissue proteins,

active transport

metabolizing enzymes

receptors

Page 3: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design

Page 4: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design

Page 5: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

How to calculate?

• Reference System:

logPbio=alogPorg+b

octanol/water

cyclohexane/water

chloroform/ water

di-butyl-ether/water

Page 6: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

Direct measurement:

Shaking flask

Centrifugal Partition Chromatography (CPC)

Potentiometric titration

Indirect determination

Partition chromatography

HPLC

RP-TLC

Page 7: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

Shaking flask method: What to consider?

Partition conditions

• Mutual saturation of the two phases

• purity of solvents and solute

• solute concentration ~ 10-5 M

• pH control if necessary

• constant temperarure

• suitable volume ratio

• time for the achievement of equilibration

Page 8: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

Shaking flask method: What to consider?

Substance characteristics

• Is the substance pure?

• Is the substance stable?

• Is the substance volatile?

• Is the substances absorbed in glass?

Page 9: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

Shaking flask method: What to consider?

Quantitative substance analysis

• Suitable analytical technique

UV/Vis Spectrophotometry

HPLC

• Analysis of the two phases measurement of substance

concentration by means of calibration equations

• Analysis of aqueous phase only measurement of

absorbance (peak height, peak area) before and after

equilibration

Page 10: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

Analysis of aqueous phase only:

org

aqu

V

V

A

AAoP *

1

1

Page 11: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

Shaking flask method: Limitations:

logP range -2.5 to 4

tedious and time consuming

not suitable for all types of substances

Page 12: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

ALogP - A new automated log P direct partitioning workstation

• Chait, A. and Zaslavsky, B.

Analiza, Inc., 408 Glen Park Drive, Bay Village, OH 44140, USA

• The system performs direct partitioning, with sampling of both phases,

and as such enables the quantification of ionic and non-ionic

compounds alike. The total partitioning system volume is ca. 1 mL,

and the total dissolved sample volume is ca. 200 mL. This miniaturized

partitioning system is based on standardized 96-deepwell plates,

enabling complete automation with user-handling limited to the plate

level….

Lipohilicity in Drug Disposition, Lausanne 2000

Page 13: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

Centrifugal Partition Chromatography (CPC)

• Unique form of liquid-liquid chromatography free of a

solid support no problem of adsorption

• Two poorly miscible liquids are used as the stationary

and mobile phase

• Stationary phase is maintained by centrifugal and or

Archimedian screw forces - mobile phase is pumped

through the system

Page 14: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

Centrifugal Partition Chromatography (CPC)

• Hydrostatic Equilibrium Systems

high pressure

low retention of the stationary phase (50%)

• Hydrodynamic Equilibrium Systems

continuous mixing of the two phases

high retention proportion of the stationary phase

high partition efficiency

Page 15: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

Centrifugal Partition Chromatography (CPC):

What we measure?

aqueous solutionas mobile phase

organic solventas mobile phase

Page 16: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

Centrifugal Partition Chromatography (CPC):

Some system characteristics

• vertical coiled column

• horizontal flow-through multilayer CPC

• length : 50-60 m, id 2,6, o.d. 3,4 Vt ~300-320 ml

• high quality of tubing

• stable flow rate (0.5-10 ml/min)

• speed of rotation: 800-1000 r.p.m.

• precise determination of dead volume or to

• temperature control

Page 17: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

• Centrifugal Partition Chromatography (CPC):

Chromatographic conditions

• ‘Normal mode’ process Vt ~300ml

sample volume 20 μl containing 0.1-5mM

For logP> 0 the organic phase is the mobile phase

For logP< 0 the aqueous phase is the mobile phase

• ‘Reversed phase’ process Vt ~30ml

For logP> 0 the aqueous phase is the mobile phase

logP range -2 to 2

Page 18: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

Centrifugal Partition Chromatography (CPC):

Proposed operational flow rates in different logP ranges

For:

* logP > 2,5 or logP< -2,5 U=0,5 ml/min

* 1,5 <logP <2, or –2,5 < logP < -1,5 U=1 ml/min

* 0,5 < logP < 1 or -1,5 < logP < -0,5 U=3 ml/min

* 0 < logP <0,5 or –0,5 < logP <0 U=6 ml/min

Vt-VM: 88%, 86%, 83%, 77% for octanol/water system

Page 19: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

Centrifugal Partition Chromatography (CPC):

Advantages

• Precise and accurate

• No problems for adsorption, instability impurity

• and volatility of solutes

• Relatively less time consuming

• Small amount of sample

Page 20: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

• Centrifugal Partition Chromatography (CPC):

Limitations

• Low number of theoretical plates

• logP range -3 to 3

• Large amount of organic solvent , when using the

organic phase as mobile phase at a flow rate 3-6 ml/min

• a mechanical expertise needed

Page 21: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

Dual-phase Potentiometric Titration

Two linked titrations:

• alkalimetrical titration of a preacidified solution of a weak

acid to appropriate high pH;

• acidimetrical back titration after addition of octanol (or any

organic solvent immiscible with water)

Simultaneous measurement of pKa and logP

Page 22: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

Dual-phase Potentiometric Titration

Page 23: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

Dual-phase Potentiometric Titration

For a monoprotic weak acid:

P= (10 poKa-pKa -1) * Vaqu/Vorg

For a monoprotic weak base

P= [10 -(poKa-pKa) -1) * Vaqu/Vorg

Page 24: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

Dual-phase Potentiometric Titration

• especially standarized electrode

• use of background electrolyte (0.15 M KCl)

logP range -2 to 7

pKa range 0.6 to 13.3

Limitations: applicable to ionizable compounds;

special, rather expensive instrumentation

(Sirius instruments)

Page 25: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

Reversed phase chromatographic techniques

RP-TLC HPLC

Indirect determination of octanol water logP

Page 26: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

• Reversed phase chromatographic techniques

Chromatographic methods combine the possibility

of automation, high dynamic range, low

sensitivity to impurities and are compound

sparing

Page 27: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

Reversed phase Thin Layer Chromatography

1Rf RM= log -1

Rf

logP= aRM+b Isocratic values

} (Collander type equation)

logP= aRMw+bExtrapolated values

Page 28: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

Reversed phase Thin Layer Chromatography:

Conditions

Stationary phase:

Silica gel impregnated with a strong hydrophobic agent

(paraffin oil, silicone oil, usually 5%)

Silanized Silica gel, C2, C8, C18

low wettability

Mobile phase:

water + organic modifier (methanol, acetonitrile, THF)

Page 29: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

Isocratic RM values are converted to logP values by means

of a

Calibration equation

logP= aRM+b

Recommended to measure more than one isocratic RM

values, construct the corresonding calibration equations

and calcultae the average logP

Page 30: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

Reversed phase Thin Layer Chromatography

Extrapolated RMw

• RM= Aφ2 - Bφ+ C

• RM=-Sφ + RMw logP= a RMw + b

φ %

RMw

RM

Page 31: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

Reversed phase Thin Layer Chromatography

Isocratic versus extrapolated RM values

less experiments more general indices

possible lipophilicity inversion values in the same order of logP

avoid lipophilicity inversion

Do they contain the same information content?

Page 32: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

logP/RMw correlation

Reversed phase Thin Layer Chromatography

Page 33: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

High Performace Liquid Chromatography

retention times tr converted to capacity factors

tr-totr logk’= log( )

to

logP=a logk’ +b Isocratic capacity factors

} (Collander type equation)

logP=alogk’w+b Extrapolated capacity factors

Page 34: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

High Performace Liquid Chromatography: Conditions

Stationary phase:

Silanized Silica gel:

• chemical bonded octadecyl silica, ODS

silanophilic interactions,

pH limitations 2-7.4

• end-capped BDS, ABZ

reduced silanophilic interactions

pH limitations 2-7.4

Page 35: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

High Performace Liquid Chromatography: Conditions

Stationary phase:

• octadecyl-polyvinylalcohol copolymer gel, ODP

no silanophilic interactions

no pH limitations

large retentions times

longer equlibration time

• octanol coated ODS column

instability, column bleeding

Page 36: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

High Performace Liquid Chromatography: Conditions

Stationary phase:

• C18 derivatized Polystyrene-divivylbenzene

C18-PS-DVB suitable for alkane/water simulation?

• Immobilized artifficial membranes (IAM) suitable

for membrane simulation

Page 37: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

High Performace Liquid Chromatography: Conditions

Mobile Phase

• water (buffer) + organic modifier (not for octanol coated )

phosphate buffer methanol

MOPS acetonitrile (not suitable for ODP)

THF

+ masking agent (hydrophobic amine)

+ octanol (0.25%)

Page 38: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

High Performace Liquid Chromatography

Isocratic logk’ values are converted to logP values by means

of a

Calibration equation

logP= alogk’+b

Recommended to measure more than one isocratic logk’

values, construct the corresonding calibration equations

and calcultae the average logP

Page 39: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

High Performace Liquid Chromatography

• logk’=Aφ2-Bφ+C

• logk’= - Sφ+logk’w logP= a logk’w +b

φ %

logk

logkwlogk

Page 40: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

High Performace Liquid Chromatography

Linearity depends on:

Chromatographic conditions

organic modifier, pH

solutes (presence of strong hydrogen dond acceptors)

Page 41: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

High Performace Liquid Chromatography

Isocratic versus extrapolated logk’ values

less experiments more general indices

possible lipophilicity inversion values in the same order of logP

avoid lipophilicity inversion

They do not contain the same information content!

Results of LFER analysis (Abraham 1994)

Page 42: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

High Performace Liquid Chromatography

Isocratic versus extrapolated logk’ values

Under suitable chromatographic conditions and depending

on the stucture of the solutes 1:1 correlations between logP

and logk’w are found

logP= alogk’w +b

a ~1 b ~ 0

Page 43: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

High Performace Liquid Chromatography

Plot of logk versus φ - Lipophilicity inversion

Page 44: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

No octanol added octanol added

Lombardo et al. Lipohilicity in Drug Disposition, Lausanne 2000

Page 45: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to measure?

logPoct = 1.0890 ( 0.0969)* logk’w- 0.5435 ( 0.2768)

N = 27, R2 = 0.835, R = 0.914, s = 0.556, F = 126, q2 = 0.808

(No octanol added, 1 mL/min)

logPoct = 1.1014 ( 0.0389)logk’w - 0.0045 ( 0.0941)

N = 27, R2 = 0.970, R = 0.985, s = 0.238, F = 803, q2 =0.965

(Octanol added, 1 mL/min)

Page 46: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Χρωματογραφία Ακινητοποιημένων Τετνητών Μεμβρανών

Immobilized Artificial Membrane Chromatography

Page 47: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

47

Partition Coefficients in Drug Design:

How to calculate

• Substitution system Direct Calculation • Fragmental Systems ( based on the

• Atomic Contribution Systems additive/constitutivecharacter)

• Model based equations Indirect calculation

• Molecular Lipophilicity Potential

Lipophilcity=Hydrophobicity +Polarity

Page 48: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to calculate

Hansch’s Hydrophobic substituent constant π

Based on the additivity principle:

logP=logPH +Σπ

Page 49: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

49

Partition Coefficients in Drug Design:

How to calculate

Fragmental Systems

logP = anfn+ Q

Rekker’s fragmental system

Leo-Hansch’s fragmental system

Meylan-Howard fragmental system

Page 50: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

50

Partition Coefficients in Drug Design:

How to calculate

Rekker’s fragmental systemreductionnist approach

logP = anfn+ knCM

for octanol- water system: CM =0.289 original system

CM =0.219 revised system

Softwares

PROLOGP-cdr original system, modified

SANALOGP_EO original system

SANALOGP_ER revised system

Σf –Sybyl revised system

Page 51: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

51

Partition Coefficients in Drug Design:

How to calculate

Leo-Hansch’s fragmental system

constructionnist approach

logP = anfn+ bmFm

tested for 8000 compounds (Starlist)

r= 0,970 και s=0.398

Software: CLOGP

Page 52: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to calculate

Meylan-Howard fragmental system

• logP=(finI) +(cjnj) +0,229 regression

• fragments 130 analysis

• correction factors 235

• derived/tested for 2351 compounds

• n=2351 r =0,991 s=0,216

• Software : KOWWIN, LOGKOW

Page 53: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to calculate

Atomic Contribution Systems

logP=Σaiαi

• Broto

• Ghose-Crippen

• Klopman and Wang regression methods

• Suzuki-Kudo

• Dubost

Page 54: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

54

Partition Coefficients in Drug Design:

How to calculate

Atomic Contribution Systems

Broto’s system

• test series: 1868 compound (no possibility of internal

hydrogen bonds)• descriptors 222 (up to 4 atoms with specific bonding

pathways up to 4 )

Software : PROLOGP-atomic, MOLCAD

presision : 0.4 log units

Page 55: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

55

Partition Coefficients in Drug Design:

How to calculate

Atomic Contribution Systems

Ghose-Crippen system

test series: 830 compounds

descriptors: 110

precision : r=0,964 s=0,47

Softwares:

MOLCAD,Tsar 2.2, PROLOGP- atomic5 (modified),

HyperChem/Chemplus

Page 56: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to calculate

Atomic Contribution Systems

• Klopman -Wang system (Computer-automated structure

evaluation, CASE)test series: 935 compounds

descriptors: 10 atomic parameters + 76 ‘star centered’ fragemens + 2 Indicator variables 39 statistical

significant

Precision : r=0.965 s=0.385

Software: KLOGP

Page 57: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to calculate

Atomic Contribution Systems

Suzuki-Kudo system

test series: 1465 compounds

descriptors (Increments): 415+ 9 atom fragments

Mean absolute error: 0.35

Software: CHEMICALC-2

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Octanol-Water Partition Coefficients:

How to estimate

• Construction of Artificial Neural Networks

based on Electrotopological State Indices

(Interactive Analysis, AlogP)

http://146.107.217.178/lab/alogps/index.html

http://amorgos.pharm.auth.gr/HelSocMedChem/home.html

Page 59: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

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Partition Coefficients in Drug Design:

How to calculate

Model Equations based on Molecular

properties Conformation dependent

Size parameters, charge density, dipole moment

Sovent accassible surface area (with 1.4A

solvent ‘coat’)

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60

Partition Coefficients in Drug Design:

How to calculate

• Charge density method

(Klopman and Iroff ,1981)

Data set: 61 compounds

Huckel-type charge density calculation

logP=0.258+0.197NH_0.122NC-2.235NN-2.264NO+21.39Σq2C-

9.335Σq2N-5.452Σq2O+1.325NA+0.715NT+0.701NM

n=61 r2=0.988 s=0.13

Page 61: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

61

Partition Coefficients in Drug Design:

How to calculate

(Bodor and Huang, 1990))

charhe density, van der Waals radii, molecular surface area,

volume , ovality

logP=9.55-0.057D+1.039 Ialkane-17.377Qn4+32.243Qn2-

8.514Qn-5.419Qo4+20.346Qo2-4.625Qo-

5.004Qon+0.0052861MW-1.1414x10-4S2+0.059838S-

7.666O-5.596O2+0.083249nc-0.27406ABSQ+2.1050O4

n=302 r=0.978 s=0.305

Page 62: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

62

Limitations of Calculation Systems:

• positional isomers

• conformation effects

• zwitterions /charged molecules

• complex structures

Partition Coefficients in Drug Design:

How to calculate

Page 63: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

63

Partition Coefficients in Drug Design:

How to calculate

• 3-D description of lipophilicity based on a fragmental

system and s distance function

)(1

ij

N

i

i dfctfMLPj

)exp(1

)exp(1

1 bad

abfMLP

ij

N

i

ij

Page 64: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

64

Partition Coefficients in Drug Design:

How to calculate

• Molecular Lipophilicity Potential (Testa et al)

• Software CLIP

• logP=2.86x10-3 ΣMLP+ +1.52x10-3 ΣMLP- -0.10

n=114 r2=0.94 s=0.37

• logP=2.35x10-3 ΣMLP+ +1.78x10-3 ΣMLP- -0.39

• n=114 r2=0.89 s=0.53

Page 65: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

65

Εσρος της λιποπιφιλίας διαφορετικών διαμορφωμερών

Page 66: Partition Coefficients in Drug Design - η-Τάξη ΕΚΠΑ Partition Coefficients in Drug Design: How to measure? How to calculate? Anna Tsantili-Kakoulidou Department of Pharmaceutical

66

Partition Coefficients in Drug Design:

How to calculate

Abraham-Kellog

• Hydrophobic INTeractions

based on

Solvent Accessible Surface

Area (s),

fragment constants (α)

and a distance function (R)

• Software :HINT

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67

Prediction of logD

Software PROLOGD

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68

Partition Coefficients in Drug Design:

• How to measure?

• How to calculate?

Still a lot to be done!