Partition coefficient

Contents

• Introduction

• Physico chemical properties

• Partition coefficient

Intended learning outcomes

At the end of this lecture, student will be able to:

• Explain the importance of partition coefficient in biological action steps to calculate the partition coefficient

INTRODUCTION

Drug molecules interact with biological structures

Drug effect

Lipoproteins/enzymes membranes

Nucleic acids

Drug effect is preceded by drug transport from site of application to site of action Is dependent on physiochemical properties.

PHYSICOCHEMICAL PROPERTIES

Interatomic distances

Intermolecular forces

Stereochemistry

Partition coefficient

Solubility

Ionization

All affect pharmacokinetics

PHARMACOKINETICS

PARTITION COEFFICIENT

• Hydrophobic bonding interactions are critical

• It can be approximated by partition coefficient

• Useful to know the hydrophobic bonding properties of substituent groups.

• Hydrophobic bonding constant π for a substituent is obtained as a difference In log P.

π = log PX - log PH

PX = PC for substituted compound

Thus, π describes the substituent.

REPRESENTATIVE π VALUES

Substituent	Aromatic	Aliphatic
C6H11	2.51	2.51
n-C4H9	2.00	2.00
Cl	0.76	0.39
H	0.00	0.00
NO2	-0.28	-0.82
COOH	-0.28	-1.26
OH	-0.67	-1.16

Calculation steps of Log P for OMA

(i) The molecule is dissected into its various groups, functionalities and substitutents.

(ii) Appropriate hydrophilic/lipophilic fragment constants are assigned and summed

(iii) Compounds with log Pcalc values greater than +0.5 are considered water insoluble (lipophilic) and those with log Pcalc values less than +0.5 are considered water soluble (hydrophilic).

Calculated log P Values for salicylic acid and p-Hydroxybenzoic acid:

Salicylic acid		p-Hydroxybenzoic acid
Value	Fragment	Value	Fragment
Phenyl	+2.0	Phenyl	+2.0
OH	-1.0	OH	-1.0
COOH	-0.7	COOH	-0.7
IMHB	+0.65	-	-
Sum	+0.95		+0.3
Prediction	Water insoluble	Prediction	Water soluble

Lipophilicity

Lipophilicity (‘fat-liking’) is the most important physical property of a drug in relation to its absorption, distribution, potency, and elimination.

Lipophilicity is often an important factor in all of the following, which include both biological and physicochemical properties:

• Solubility

• Absorption

• Plasma protein binding

• Metabolic clearance

• Volume of distribution

• Enzyme / receptor binding

• Biliary and renal clearance

• CNS penetration

• Storage in tissues

• Bioavailability

• Toxicity

The hydrophobic effect

Molecular interactions – why don’t oil and water mix?

• This is entropy driven (remember δG = δH – TδS). Hydrophobic molecules are encouraged to associate with each other in water.

• Placing a non-polar surface into water disturbs network of water-water hydrogen bonds. This causes a reorientation of the network of hydrogen bonds to give fewer, but stronger, water-water H-bonds close to the non- polar surface.

• Water molecules close to a non-polar surface consequently exhibit much greater orientational ordering and hence lower entropy than bulk water.

This principle also applies to the physical properties of drug molecules.

If a compound is too lipophilic, it may

• be insoluble in aqueous media (e.g. gastrointestinal fluid or blood)

• Bind too strongly to plasma proteins and therefore the free blood concentration will be too low to produce the desired effect

• distribute into lipid bilayers and be unable to reach the inside of the cell

Conversely, if the compound is too polar, it may not be absorbed through the gut wall due to lack of membrane solubility.

So it is important that the lipophilicity of a potential drug molecule is correct. How can we measure this?

Partition coefficients

Partition coefficient P (usually expressed as log10P or logP) is defined as:

P =[X]octanol / [X]aqueous

P is a measure of the relative affinity of a molecule for the lipid and aqueous phases in the absence of ionisation.

1-Octanol is the most frequently used lipid phase in pharmaceutical research. This is because:

• It has a polar and non-polar region (like a membrane phospholipid)

• Po/w is fairly easy to measure

• Po/w often correlates well with many biological properties

• It can be predicted fairly accurately using computational models

Calculation of logP

LogP for a molecule can be calculated from a sum of fragmental or atom-based terms plus various corrections.

logP = ∑ fragments + ∑ corrections

clogP for windows output

C: 3.16 M: 3.16 PHENYLBUTAZONE

Class	Type	Log(P) Contribution Description	Value
FRAGMENT	# 1	3,5-pyrazolidinedione	-3.240
ISOLATING	CARBON	5 Aliphatic isolating carbon(s)	0.975
ISOLATING	CARBON	12 Aromatic isolating carbon(s)	1.560
EXFRAGMENT	BRANCH	1 chain and 0 cluster branch(es)	-0.130
EXFRAGMENT	HYDROG	20 H(s) on isolating carbons	4.540
EXFRAGMENT	BONDS	3 chain and 2 alicyclic (net)	-0.540
RESULT	2.11	All fragments measured	clogP 3.165

What else does logP affect?

Distribution coefficients

• If a compound can ionise then the observed partitioning between water and octanol will be pH dependent.

• Distribution coefficient D (usually expressed as logD) is the effective lipophilicity of a compound at a given pH, and is a function of both the lipophilicity of the un-ionised compound and the degree of ionisation.