Why are physicochemical properties of

drugs important?
Approximately 30-40% of potential
drugs are
later rejected for their inappropriate
pharmacokinetic (ADME) parameters
ADME
Absorption
Distribution
Metabolism
Elimination

Acidity and basicity of

drugs

Drugs are weak organic acids (acetylsalicylic acid ) or weak organic bases
(procaine), or their salts (ephedrine hydrochloride).
The degree of ionized drugs are in solution is highly dependent on the pH.
Ionization of a drug has an important effect on its absorption,
distribution and elimination.
There are many examples of the alteration of pH to change these
properties.

The pH of urine may be adjusted (for example by administration of

ammonium chloride or sodium bicarbonate) in cases of overdosing with
amfetamines, barbiturates, narcotics and salicylates, to ensure that
these drugs are completely ionized and ready for excretion.

The pH of the urine may be altered to prevent ionization of a drug in

cases where reabsorption is required for therapeutic reasons.
Sulphonamide crystalluria may also be avoided by making the urine
alkaline.

Table shows the nominal pH

values of some body fluids and
sites, which are useful in the
prediction of the percentage
ionisation of drugs in vivo.

Acid drugs (HA)

HA + H2O H3O+ + Anon-ionized drug

ionized drug

for diluted solutions, the dissociation constant K a is:

[H3O +]. [A-]
[molar concentrations of the reactants]
Ka = -----------------[HA]
Ka values can be expressed in the form of their negative
logarithm (pKa ):
pKa = - log Ka

% dissociated acid = 100 / 1 + 10

(depending of the pH value)

pKa pH

Basic drugs (B)

B + H2 O
BH + + OHunionized drug ionized drug

for diluted solutions, the dissociation constant is:

[BH +]. [OH-]

[molar concentrations of the reactants]
Kb = ----------------- [B]

In this expression, Kb is the dissociation constant of the base and reflects

the force of the base. The equilibrium of the proton transfer, which includes
the base form, can be expressed with form of conjugate acid BH +:
BH + + H2O
B + H3 O +
[H3O +]. [B]
Ka = ----------------- [BH +]

% dissociated base = 100 / 1 + 10 pH pKa

(depending of the pH value)
5

The pKa and pKb values provide a convenient means of comparing

the strengths of weak acids and bases.

The lower the pKa , the stronger the acid.

The lower the pKb , the stronger is the base.

Both acidic and basic drugs are exactly 50% ionized at the pH of
their pKa values.

Ionic form of the drug has a positive or negative electrostatic

charge and preferentially dissolves in water (blood).

Non-ionized drug molecule is electroneutral and is better dissolved

in lipids.

The drug passes through the hydrophobic lipid membrane in its

non-dissociated form.

The degree of ionization of the drug in cell membrane is therefore

an important parameter that determines what amount of the
undissociated drug (soluble in lipids (fats) is available for transport
across lipid membrane.
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10

pKa can be determined by several

methods:

potentiometry

spectrofotometric methods (ultraviolet (UV) spectrophotometry)

using the partition coefficient (in the case of ionizable drugs)

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Theoretical methods for pKa

prediction

SPARC

use computational algorithms based on fundamental chemical

structure theory to estimate a variety of chemical reactivity
parameters (such as ionization pKa , kinetics, heat of vaporization,
diffusion coefficient, etc.).

Jaguar -The pKa Prediction Module

The module uses a combination of correlated ab initio
quantum chemistry, a self-consistent reaction field (SCRF)
continuum treatment of solvation, and empirical corrections
to repair deficiencies in both the ab initio and continuum
solvation models.
This combination leads to high accuracy for a wide range of
organic compounds, in conjunction with tractable
computational requirements.
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Drug lipophilicity

Is an important physico-chemical parameter that influences the distribution and destiny of drugs in the
body.

Lipophilicity is the measure of the partitioning of a compound between a lipidic and an aqueous phase.

Lipophilicity is one of the most informative physicochemical properties in medicinal chemistry and
since long successfully used in quantitative structure activity relationship (QSAR) studies.

Its important role in governing pharmacokinetic and pharmacodynamic events has been extensively
documented.

Increased lipophilicity was shown to correlate with:

poorer aqueous solubility,

increased plasma protein binding,
increased storage in tissues
more rapid metabolism and elimination.
increased rate of penetration through the skin,
sometimes with a shorter duration of action

Lipophilicity is also a highly important descriptor of blood brain barrier (BBB) permeability.

Last, but not least, lipophilicity plays a dominant role in toxicity prediction .

partition coefficient P , is defined as the ratio of the concentrations of a neutral compound in organic
and aqueous phases of a two - compartment system under equilibrium conditions. It is commonly used
in its logarithmic form, log P . Whereas 1 - octanol serves as the standard organic phase for
experimental determination, other solvents are applied to better mimic special permeation conditions
such as the cyclohexane water system for BBB permeation.
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 during the transport of biological systems

drug exceeds the interphase interface
between polar and lipid bi-phase
most drugs are transported to the site of
action by blood;
water solubility makes dissociation of the
drug and the disposition for the reactions
drug solubility in lipids allows drug to pass
throught the lipid membranes, also the
increased concentration in the lipophilic
nerve tissue
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 drug solubility in water and lipids are applied side by side,

we evaluate them in relation to each other
lipophilicity is defined by the distribution of substances between
water and non-aqueous phase:

P = corg / caq
P
- is the partition coefficient of the system
n-octanol - water
- informs about the ratio of drug solubility
in an aprotic environment (lipids)
and protic environment (in water)
- it informs about the amphiphilic nature of the substance in vitro
- parameter P (log P) is considered the most important
lipophilic
parameter, which is fairly good correlation to the overall biological
effects in many groups of drugs
18

In the case of ionizable compounds in the distribution of non-ionized form in

the octanol phase depends on the pH value at which was experiment maked

Effective lipophilicity of the compound is given by the distribution

coefficient D.

Distibution coefficient (at a given pH) is a function of lipophilicity non-ionized

compounds and the degree of ionization.

The ionization of acids and bases in the first degree of distribution coefficient
can be calculated from the equation:

for acid HA: HA = H

for the base B:

According to this hypothesis, only non-ionized form of the compound is able

to
distribution in non-aqueous phase. If this condition is performed, then
compound shows a maximum value of the lipophilicity under the pKa
value of the acid and above the pKa value of the base.

+ A-

BH + = H

D = [HA]org / [HA]aq + [A-]aq

+

+B

D = [B]org / [B]aq + [BH+]aq

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Experimental determination
partition coefficient

Shake - Flask Method (in combination with UV spectroscopy)

(The method usually involves the following: solubilization of the compound in a mixture of mutually
presaturated buffered water and octanol, separation of octanol and aqueous phases, and direct
measurement of the solute concentration in both phases. )
Potentiometric Method

(The potentiometric method for log P determination has been correlated with the shake - flask
method .

The potentiometric log P is characterized by comparing an aqueous pKa to an apparent pKa

measured in the two phase system (generally octanol water) using difference curve analysis .

Therefore, the method is appropriate only for ionizable compounds with accurately determined
aqueous pKa values. )
Chromatographic Methods

(lipophilicity can be determinated by liquid chromatography, including reversed phase, thin - layer,
micellar, reversed - phase (RP) HPLC, RP - ion - pair and countercurrent chromatography.

from TLC RF values, respectively. RM of HPLC and GC P calculated from the retention times tM)
Electrophoretic Methods

(Microemulsion electrokinetic chromatography (MEEKC), a variation of the capillary electrophoresis

method

The method only suitable for estimating log P of neutral compounds. )

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Theoretical calculations of
lipophilicity
most used methods are:
Substructure - based Methods
Fragmental Methods (1.)
Atom - based Methods (2.)
Property - based Methods (3.)
Methods based on 3D structure representation
Methods based on topological descriptors

Substructure - based approaches cut molecules into fragments or down to the

single - atom level; summing the substructure contributions gives the final log P .

Property - based approaches utilize descriptions of the entire molecule including

molecular lipophilicity potentials (MLP), topological indices or molecular properties
like charge densities, volume and electrostatic potential to quantify log P .

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Fragmental Methods
Fragmental methods cut molecules down into fragments and
apply correction factors in order to compensate for
intramolecular interactions.
Defining fragments larger than single atoms guarantees, that
significant electronic interactions are comprised within one
fragment; this is a prime advantage of using fragments. On the
other hand, fragmentation can be arbitrary and missing
fragments may prevent calculation. These are the main
disadvantages.
reductionistic approaches:
KLOGP and KOWWIN

CLOGP and ACD/LogP

are based on the principle of constructionism.

AB/LogP
combines the advantages of both reductionistic and constructionistic
approaches by using hierarchical cluster analysis.

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Atom - based Methods

Atom - based methods cut molecules down to single atoms and

commonly do not apply correction rules.

Since the partition coefficient is not a simple additive property, the

constitutive feature is covered by classifying huge numbers of atom
types according to structural environment. An advantage of atom based methods is that ambiguities are avoided.

software packages such as MOLCAD, TSAR, PROLOGP, ALOGP98 and

XLOGP.
MOLCAD, TSAR and PROLOGP are based on the original Ghose
Crippen approach .
ALOGP98 is based on a refined version .
XLOGP is the only atom - additive method applying corrections .

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25

Methods Based on 3D Structure

Representation

For two relatively immiscible solvents log P can be considered proportional to the molar
Gibbs free energy of transfer between octanol and water:
Eq. (1)

Empirical Approaches
SPARC

Methods Based on Quantum Chemical Semiempirical Calculations

QLOGP

Approaches Based on Continuum Solvation Models

A) COSMO - RS (Full) Approach
B)COSMOfrag (Fragment - based) Approach
Ab Initio Methods

Models Based on MD Calculations

QikProp is based on a study which used Monte Carlo simulations to calculate 11
parameters
QikProp does not perform MD simulations but calculates required parameters from
supplied 3D structures of molecules

MLP Methods
Hydrophobic Interactions (HINT)
Calculated Lipophilicity Potential (CLIP)

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Methods Based on Topological

Descriptors

One of their main advantages is speed

Speed renders these methods an important tool for predicting
large datasets, in particular for screening virtual combinatorial
libraries.

MLOGP
MLOGP uses the sum of lipophilic (carbons and halogens) and hydrophilic
atoms (nitrogens and oxygens) as two basic descriptors.

Graph Molecular Connectivity

TLOGP

Methods Based on Electrotopological State (E - state)

Descriptors

VLOGP
ALOGPS
CSlogP
A_S+logP
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Drug solubility

The solubility of drugs in water is important for oral drug absorption.

To simplify, a drug must be soluble in the aqueous contents of the

gastrointestinal lumen to be orally absorbed.

Drug solubility in DMSO is important in the biology testing of a compound

formatted as a DMSO stock solution.

Solubility is the amount of a solute that can be dissolved in a specific solvent

under given conditions.

depends on the nature of the solvent and temperature

the degrees of drug solubility is defined by European Pharmacopoeia 8th Edition

An important feature of the ADME properties of drug

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 increased water solubility:

- Chemical modification of the molecule by substitution
with

Neutral hydrophilic group

Ionizable organic acids or basis
Preparation of salts
Using appropriate solubilizers (benzoate, Sodium salicylate
as solubilizers for purine alkaloids)

reduction of water solubility:

- Modification of the structure
- Design the less soluble salt

increase the solubility lipids:

- Blocking of hydrophilic groups (eg esterification)
- The introduction of lipophilic substituents (eg alkyl,
halogens)
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Drug salts
The selection of an appropriate
salt form for a potential drug
candidate is an opportunity to
modulate its characteristics to
improve bioavailability, stability,
manufacturability, and patient
compliance.

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Drug salts
Most used drug salts
Anions

Hydrochloride
Citrate
Chloride
Bromide
Acetate
Maleate
Mesylate
Phosphate
Sulphate
Tartrate
Nitrate

Most used drug salts

Cations
Sodium
Potassium
Calcium

Aminoacids

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Prediction of the
solubility

Drug solubility is one of the important factors, which affect

the movement of a drug from a site of administration into
the blood.

Knowing of drug solubility is important. It is well known that

insufficient solubility of drugs can lead to poor absorption
[1]. Investigation of the rate-limited steps of human oral
absorption of 238 drugs (including warfarin) has been
shown [1] that the absorption of a drug is usually very low if
the calculated solubility is <0.0001 mg/L.

1. Y.H. Zhao, M.H. Abraham, J. Lee, A. Hersey, Ch.N. Luscombe, G. Beck, B.

Sherborne, I. Cooper, Pharm. Res. 19 (2002) 1446.

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Prediction of the
solubility
Log S an intrinsic solubility in neutral state is indicative of a
compounds solubility (S).
When experimental solubilities of compound is not known, the log S
values can be calculated using ALOGPS a predictor.
This method uses E-state indices as descriptors and a neural
network [2] as the modeling engine.
Another methods for prediction of solubility:
AC logS
AB/logS

[2] I.V. Tetko, V.Y. Tanchuk, T.N. Kasheva, A.E.P. Villa, J. Chem. Inf. Comput. Sci. 41
(2001) 1488.
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