Drugs – Structure and Properties

Learning outcomes

• At the end of this section the student shall be able to:

– differentiate acidic from basic drugs

– predict ionization of a drug at different pH

– estimate acidity/basicity of a drug solution

– predict solubility, absorption and distribution of a drug at different body compartment

– discuss the effect of acidity, size, shape, and stereochemistry of a drug on its activity

Physicochemical properties of a drug

A drug molecule is a compound that has the ability to bind specifically to a receptor

It should also be absorbed, distributed, metabolized and excreted by the body

This depends on the physicochemical properties of a drug including

1. Acid-base property

2. Water-lipid solubility

3. Size

4. Steric effect

5. Conformational isomerism

6. Optical isomerism

7. Geometric isomerism

1. Acid-base properties

Most drugs behave as weak acids or bases in solution and might be ionised at physiological pH (pH = 7.4)

Ionization of a compound plays a major role in controlling:

Absorption and transport to site of action

Binding of a compound at its site of action

Elimination of compound

• Biliary and renal excretion

• CYP P450 metabolism

Acid-base chemistry • Acidity or basicity of a compound is estimated by

measuring its dissociation in water and is expressed using pH

An acidic solution has pH < 7

A basic solution has pH > 7

For pure water pH = 7

• The strength of an acid or bases is expressed using pKa

– The lower the pKa the stronger the acid

• Note: pKa of a basic compounds is the value of its conjugate acid.

– Thus for basic compounds the higher the pKa the stronger the base.

Acid-base properties of drugs

• For a drug molecule to be an acid or a base depends on the nature of its functional groups.

– A drug molecule with a functional group that can donate hydrogen ion (H+) will be an acid

– A drug molecule with a functional group that can accept hydrogen ion (H+) will be a base

Common acidic functional groups

Common basic functional groups

Note: pKa of a drug does not tell if the drug will behave as an acid or a base in a solution. e.g amines (pKa ~ 9) are basic while phenols (pKa ~ 10) are acidic

Common neutral functional groups

Acidity and basicity of salts • When a salt is hydrolyzed in water it dissociates

completely to give anion and cation

• The resulting solution can be basic or acidic depending on the constituents of the salts:

Salt Acid/base property Example

strong acid + strong base neutral NaCl

strong acid + weak base acidic NH4Cl

weak acid + strong base basic CH3COO-Na+

weak acid + weak base neutral CH3COO-NH4+

Henderson-Hasselbalch equation

Henderson-Hasselbalch equation

For a dissociation of a weak acid

In general the degree of dissociation of a weak acid in water can be determined using the Henderson-Hasselbalch equation. Which is derived as follows:

• This equation is also used for a weak base BUT the degree of ionization will be (Recall for a basic compound the pKa refers to its conjugated acid)

Acidic/base Dissociation • Dissociation of acidic/basic molecule depends on their

strength (i.e. pKa) and is affected by pH of the medium

• pH = pKa compound is approximately 50% ionized

• pH < pKa + 1 compound is approximately fully unionized

• pH > pKa + 1 compound is approximately fully ionized

• Recall: for a basic compounds the pKa is the value of its conjugate acid.

– Thus in the intestine (pH = 7-8) weak acids will be ionized while weak bases will be neutral

– Hence: weakly acidic oral drugs will have reduced absorption

2. Water-Lipid solubility

A successful drug must exhibit solubility to some extent in both water and lipid environments

Because:

– extremely water-soluble drugs may be unable to cross lipid barriers

– very lipophilic drugs will be trapped in lipid and will not be able to reach their target quickly

Predicting solubility • A drug molecule will be soluble in water or in

nonaqueous lipid solvent

• A molecule that dissolves in water is hydrophilic (lipophobic)

• A molecule that dissolves in lipid solvent is lipophilic (hydrophobic)

• Solubility in water or lipid depends on functional groups and occurs via intermolecular bonds including

– van der Waals forces – dipole-dipole bonding – ionic interaction – ion-dipole bonding

Predicting solubility Bond Description Energy

kcal/mol Solubility

(Water/lipid) Functional group

Comments

van der Waals forces electrostatic interaction due to distortion of covalent bonds

0.5 – 1.0 lipid

Hydrocarbons distance temperature-dependent

Dipole-dipole occurs between permanent dipoles (e.g Hydrogen bond)

1 – 10 water Polar groups (e.g. alcohol, ketone, thiols, acid, ethers, amines)

distance temperature-dependent

Ionic interaction attraction between a negative and a positive charged atom

5 water Acid, bases, salts

least affected by distance and temperature

Ion-dipole when an ion pair attract a dipole or induce a dipole in a neighboring nonpolar molecule

1 – 7 water Polar groups (e.g. alcohol, ketone, thiols, acid, amines)

insensitive to temperature or distance

Intermolecular bonds

van der Waals also called induced dipole-induced dipole interaction

Dipole-dipole Ionic interaction

Ion-dipole R4N

+------NR3

ion-induced dipole K-I -------I-I

Predicting solubility

• Many drugs are poly-functional and can make all types of intermolecular interactions

• Water/lipid solubility can be predicted by weighing the contribution of each functional group in the compound

• There are two approaches for that: 1. Empirical: based on carbon solubilizing

potential of functional groups

2. Quantitative: calculating logP (log of partition coefficient)

Predicting water solubility – Empirical approach

• A molecule is water soluble if the solubilizing potential of FG exceed the total number of carbon atoms present.

• Note: ionized functional group has solubilizing potential of 20 to 30 carbon atoms.

Water solubilizing potential of organic functional

groups in mono- or polyfunctional molecules

No of carbon atoms in a

molecule

Functional group Monofuntional Polyfunctional

Alcohol 5 – 6 3 – 4

Phenol 6 – 7 3 – 4

Ether 4 – 5 2

Aldehyde 4 – 5 2

Ketone 5 – 6 2

Amine 6 – 7 3

Carboxylic acid 5 – 6 3

Ester 6 3

Amide 6 2 – 3

Urea, carbonate,

carbamate

2

Water solubility is defined as >1% solubility

Predicting water solubility – Quantitative approach

In this approach water/lipid solubility is estimated by measuring partition coefficient (P)

Partition coefficient (P) is the ratio of concentrations that a substance partition itself between two immiscible liquids

𝑃 = [Drug]org

[Drug]aq

It is usually expressed as LogP

If LogP < +0.5 a compound is water soluble

If LogP > +0.5 a compound is water insoluble

If a compound ionizes during experiment the partition coefficient will be apparent

𝑃𝑎𝑝𝑝

= 𝑃 × 𝑓𝑢𝑛𝑖𝑜𝑛𝑖𝑧𝑒𝑑

Determination of LogP

• LogP can be determined by two methods:

1. Experimental method using chromatography

or the shake-flask method

– Experimentally measured logP are referred as MlogP

2. Summation of hydrophobic-hydrophilic

constants (π) assigned to different functional groups

– Calculated LogP are referred as ClogP

Calculating logP using π values

• LogP are calculated using the equation

logP = π (π values are the contribution of each functional group)

FG Symbol πaromatic πaliphatic

floro F 0.13 -0.17

chloro Cl 0.76 0.39

bromo Br 0.94 0.60

iodo I 1.15 1.00

alkane C 0.50 0.50

phenyl C6H5 2.13 2.13

acid COOH -0.32 -1.26

1o amide CONH2 -1.49 -1.71

amide NHCOR -0.97 -0.97

ketone COCH3 -0.55 -0.71

nitrile CN -0.57 -0.84

alcohol OH -0.67 -1.12

ether OCH3 -0.02 -0.47

ester COOCH3 -0.64 -0.91

1o amine NH2 -1.23 -1.19

2o amine NHR 0.47 -0.67

3o amine N(CH3)2 -0.18 -0.32

nitro NO2 -0.28 -0.85

IMHB IMHB 0.65 0.65

The π values are obtained as: π = logPx – logPH

where, logPx is value for derivative, logPH is value for parent compound

Note: π is +ve for lipophilic group π is -ve for hydrophilic group

Note: LogP also depends on other factors such as the capacity of a group to form intramolecular hydrogen bond (IMHB)

logP Values for salicylic and p-Hydroxybenzoic acid

Salicylic acid p-Hydroxybenzoic acid

Fragment Value Fragment Value

Phenyl +2.13 Phenyl +2.13

OH -0.67 OH -0.67

COOH -0.32 COOH -0.32

IMHB +0.65

LogP +1.79 +1.14

Prediction Water insoluble Prediction Water insoluble

Importance of LogP Lipophilicity (LogP) is used to predict: Solubility, Absorption,

Membrane penetration, Plasma protein binding, Distribution, Target recognition, CYP450 interactions etc.

logP Binding to target

Aqueous solubility

Binding to metabolising enzymes

Absorption through membrane

Binding to blood proteins

Solubility of salts

• Solubility of organic salt in water depends on the degree of its dissociation

– Salt of strong acid/strong base > strong acid/weak base > weak acid/weak base

• Also on molecular weight, high molecular weight salts are less soluble in water

Water solubilities of different salt forms of some drugs

0

5

10

15

20

25

100-

150

150-

200

200-

250

250-

300

300-

350

350-

400

400-

450

450-

500

500-

550

550-

600

600-

650

650-

700

700-

750

750-

800

800-

850

850-

900

900-

950

950-

1000

Molecular Weight

fre

qu

en

cy %

3. Molecular size Molecular size is one of the most important

factors affecting biological activity

Most of the oral drugs have molecular weight < 500

4. Steric Effects

Bulky substituent appended close to pharmacophore may impede the geometry of interaction between a drug and its receptor

Steric effect is estimated by The Taft steric parameter (Es)

5. Conformational isomerism Conformational flexible drugs are able to bind to different

subtypes of a receptor.

For example, acetylcholine exhibits both muscarinic and nicotinic activity.

Flexible molecules have increased likelihood of drug toxicity due to their ability to interact with undesirable receptor sites

6. Optical isomerism Only one of the

enantiomers will have the maximum affinity to the receptor.

– The better fitting enantiomer is called the eutomer,

– the lower affinity is called the distomer.

– eudismic index: The ratio of activity of the eutomer and distomer is expressed as:

A

B

C

D

Drug

Biomolecular target

Desired responce

D

B

C

A

No desired resonceSide effects??

EI = log affinityEu – log affinityDist

Stereoisomers and Pharmacological Activity Pharmacological activity Example

Both show same type and

potency The R and S isomers of chloroquine

Show activity of same

type but one is weaker

Oestrogenic activity of E –diethylstilbestrol is only 7%

that of Z-isomer

Show activity of a

different type

S-Ketamine is an anaesthetic but R-Ketamine is a

psychotic

One active the other

inactive S--Methyldopa is a hypertensive but R is inactive

Same activity but different

side effects

Thalidomide: both R & S isomers are sedative but S is

also teratogenic

7. Geometric isomerism

the Cis/Trans (E/Z) isomers of a drug will have different binding affinity to the same receptors

For examples: – the Z isomers of antipsychotic drugs, thiothanxenes

are several times more active than their E isomers

– cis-diethylstilbestrol has only 7% of the oestrogenic activity of trans- diethylstilbestrol

Lipinski’s rule of five

Druggable molecule should possess these characteristics:

– A molecular weight of less than 500

– A logP value of less than 5

– Few than 5 H-bonding donors (Sum of NH and OH)

– Less than 10 H-bonding acceptors (Sum of N and O)