PHYSIO-CHEMICAL PROPERTIES OF THE DRUG

“It is the interaction of the drug with its environment”

Reducing the complexity

Biological process in drug action

Dissolution of drug in gastrointestinal fluids

Absorption from small intestine

Blood protein binding

Distribution of compound in tissues

Physical chemistry model

Solubility in buffer, acid or base

logP, logD, polar surface area, hydrogen

bond counts, MWt

Plasma protein binding, logP and logD

logP, acid or base

Underlying physical chemistry

Energy of dissolution; lipophilicity & crystal

packing

Diffusion rate, membrane partition coefficient

Binding affinity to blood proteins e.g. albumin

Binding affinity to cellular membranes

An oral drug must be able to:

§ dissolve§ survive a range of pHs (1.5 to

8.0)§ survive intestinal bacteria§ cross membranes§ survive liver metabolism§ avoid active transport to bile§ avoid excretion by kidneys§ partition into target organ§ avoid partition into undesired

places (e.g. brain, foetus)

What must a drug do other than bind?

liver

bileduct

kidneys

bladder

BBB

The pH-Partition Hypothesis on Drug Absorption

– This theory provides a basic framework for understanding of drug absorption from the GIT and drug transport across the biological membrane.

– The principle points of this theory are:

1. The GIT and other biological membranes act as lipid barriers.

2. The un-ionized form of the acidic or basic drug is preferentially absorbed.

3. Most drugs are absorbed by passive diffusion.

4. The rate of drug absorption and the amount of drug absorbed are related to its oil-water partition coefficient, the more lipophilic the drug, the faster is its absorption.

5. Weak acidic and neutral drugs may be absorbed from stomach but basic drugs are not.

Ionisation§ Ionisation = protonation or deprotonation resulting in charged

molecules§ About 85% of marketed drugs contain functional groups that are

ionised to some extent at physiological pH (pH 1.5 – 8).

The acidity or basicity of a compound plays a major role in controlling:

§ Absorption and transport to site of action • Solubility, bioavailability, absorption and cell penetration,

plasma binding, volume of distribution§ Binding of a compound at its site of action

• un-ionised form involved in hydrogen bonding• ionised form influences strength of salt bridges or H-bonds

§ Elimination of compound• Biliary and renal excretion• CYP P450 metabolism

Ionized form - gives good water solubility need for good binding of drug to receptor. Un-ionized form - helps to cross the cell membranes.

Equal ratio ionized : unionized = better pharmacokinetic and pharmacodynamic properties of the drug. Ionization and pH at Absorption site

The fraction of the drug existing in its un-ionized form in a solution is a function of both the dissociation constant and the pH of the solution at the absorption site.

IONIZATION (pKa)

IONIZATION of DRUGS

Drug Absorption & Transport Depends on:

Drug solubility

Partition coefficient

Ionization

Increased H2O solubility of ionized form

Superior passage of unionized (undissociated)

Drug Transport is a Compromise Between:

IONIZATION of DRUGS

IN GENERAL: drugs pass through membranes in undissociated form but act as ions, if possible

pKa range of 6–8 seems most favorable (for passive transport)

So the same compound will be ionised to different extents in different parts of the body.

This means that, for example, basic compounds will not be so well absorbed in the stomach than acidic compounds since it is generally the unionised form of the drug which diffuses into the blood stream.

How does pH vary in the body?

Fluid pH

Aqueous humour 7.2

Blood 7.4

Colon 5-8

Duodenum (fasting) 4.4-6.6

Duodenum (fed) 5.2-6.2

Saliva 6.4

Small intestine 6.5

Stomach (fasting) 1.4-2.1

Stomach (fed) 3-7

Sweat 5.4

Urine 5.5-7.0

CALCULATION OF IONIZATION

Ionizable drugs (weak acids & bases) do so, depending upon:

• Dissociation constant (pKa)

• pH of the environment

WEAKLY ACIDIC DRUGS

H3O + AHA + H2O

Ka = [H3O] [A]

[HA]

acid 1 base 2 conjugateacid 2

conjugatebase 1

pKa = pH + log [HA]

[A]

Ka

Henderson-Hasselbalch

When an acid or base is 50% ionised:

pH = pKa

§ For an acid:

Ka = [H+][A-]

[AH]% ionised =

100

1 + 10(pKa - pH)

HA H+

+ AKa

H+

+ BBH+ Ka

Ka = [H+][B]

[BH+] % ionised = 100

1 + 10(pH - pKa)

§ For a base:

§ The equilibrium between un-ionised and ionised forms is defined by the acidity constant Ka or pKa = -log10 Ka

Ionisation constants

WEAKLY ACIDIC DRUGS

pKa = pH + log [HA]

[A]

% ionized = [ionized]

x 100

[ ionized] + [unionized]

% ionized = 100

+1 antilog (pKa pH)-

- (pKa pH)1 +

100% ionized = 10

WEAKLY BASIC DRUGS

[H2O]

[H3O] [HO]Kw =

2

+ HOH3OH2O2Kw

[H3O] [HO]Kw =

Autoprotolysis Constant of Water (Kw)

pKw = pKa pKb+

use this equation to define the Kb term on next slide

Kw = Ka x Kb

WEAKLY BASIC DRUGS

base 1 acid 2conjugateacid 1

conjugatebase 2

KbB + H2O + HOHB

[B]

[HB] [HO]Kb = [B]

[HB]pKa = pH + log

% ionized = 100

+1 antilog (pH pKa)-- (pH pKa)1 +

100% ionized = 10

WEAKLY ACIDIC DRUGS

pKa pH % ionized5.4 7.4 100/1+10-2 = 100/1.01 = 99.01%6.4 7.4 100/1+10-1 = 100/1.1 = 90.91%7.4 7.4 = 50%8.4 7.4 100/1+101 = 100/11 = 9.09%9.4 7.4 100/1+102 = 100/101 = 0.99%

- (pKa pH)1 +

100% ionized = 10

WEAKLY BASIC DRUGS

pKa pH % ionized5.4 7.4 100/1+102 = 100/101 = 0.99%6.4 7.4 100/1+101 = 100/11 = 9.09%7.4 7.4 = 50%8.4 7.4 100/1+10-1 = 100/1.1 = 90.91%9.4 7.4 100/1+10-2 = 100/1.01= 99.01%

- (pH pKa)1 +

100% ionized = 10

IONIZATION SUMMARY

§ For an acid drug, the smaller the pKa, the stronger the acid

Remember

§ For a basic drug, the larger the pKa (i.e. the smaller the pKb), the stronger the base

IONIZATION SUMMARY

A useful relationship pKw = pKa + pKb

§ Acid strength may be expressed as Ka or Kb of its conjugate base.

§ Ka of an acid may be calculated if Kb is known.§ Stronger the acid, the weaker its conjugate base.

Acidic groups

knowing pKa and pH allows determination of % ionization

100% ionized when pHis 2 units above pKa

Basic groups 100% ionized when pHis 2 units below pKa

Acidic drugs that are highly ionized at pH 7.4

Drug pKa

ASA 3.49

Sulfisoxazole 5.00

Penicillin G 2.76All > 99% ionized

Basic drugs that are highly ionized at pH 7.4

Drug pKa

Procaine 8.80

Chlorcyclizine 8.15

Atropine 9.65All > 85% ionized

Groups on receptors may also be highly ionized at pH 7.4

Acidic groups pKa

glutamic acid 4.30

phosphoryl 1.00

aspartic acid 3.7

All > 99% ionized

Groups on receptors may also be highly ionized at pH 7.4

Basic groups pKa

lysine 10.5

glutamine 9.10

arginine 12.5

All > 98% ionized

propranolol

pKa = 9.45

What is the pKb? 4.55

What does this pKa refer to?

i.e. is there an acidic functional group?

OCH2CHCH2NHCHMe2

OH

B + H2O + HOHBKb

base 1 acid 2 conjugateacid 1

conjugatebase 2

Is drug acidic, basic, amphoteric?

IONIZATION Examples

IONIZATION Examples

sulfasalazine

pKa = 2.4, 9.7, 11.8

What do the pKa’s refer to?

i.e. are there acidic and/or basic functional groups?

Ka

acid 1 base 2 conjugateacid 2

conjugatebase 1

N

NHSO2 N N OH

COOH

H3O + AHA + H2O

IONIZATION of POLYPROTIC DRUGS

Polyprotic acids donate >1 proton

Each dissociation stage has an equilibriumexpression and therefore pKa.

pKa1 7.4

pKa2 ~ 12 - 13N

N OO

O

H

HEt

Ph

phenobarbital

It becomesprogressivelymore difficultto donateprotons

§ Methamphetamine, with a pKa of 9.87, is dissolved in a solution at pH 7.87:

§ Diethylbarbituric has an unionized H:B form, and an ionized B: form. It has a pKa of 8.0, and is dissolved in fluid with a pH of 7:

Change of the ionization state will affect:

1. Movement from aqueous phase to lipid upon crossing a membrane

2. Movement from aqueous phase to hydrophobic binding pocket

3. Movement from aqueous phase to location adjacent to a charged or polar residue in an active site

4. In order to elicit a pharmacological effect, drugs must be sufficiently soluble in water to be absorbed and distributed throughout the body. They must also have sufficient lipophilicity to be able to pass through biological membranes.

N H

O

HH

O

H

H S R.............. ............

Hydrogen Bond

– A stronger and important form of chemical bonding is the dipole-dipole bond, specific example of which is the hydrogen bond.

– A dipole results from the unequal sharing of a pair of electrons making up a covalent bond. This occurs when the two atoms making up the covalent bond differ significantly in electro-negativity.

Water Solubility and Hydrogen Bonding

Hydrogen bonding of an amine to water and a thiol to water

– Water has a dipole moment, due to the 104.5 degree bond angle, and the pull of electronegative oxygen on the attached hydrogens.

– This induced polarity gives water a higher boiling point and melting point than other hydrides (e.g. H-S-H, hydrogen sulfide, is a gas at room temperature).

– This dipole also allows water to hydrogen bond, and in pure water, it H-bonds to itself, forming a lattice (network).

– Ionized molecules carry charge and favor interaction with water dipoles making these molecules water-soluble.

– Other molecules, e.g., glucose, are not charged, but, have an uneven electron density and are thus polar molecules that interact with water dipoles and are freely soluble in water.

– This association with water molecules makes these water-soluble compounds less soluble in oils, fat, and lipid. These types of molecules are said to be hydrophilic (water-liking).

– In contrast, nonpolar and noncharged molecules tend to be much more lipid-soluble or hydrophobic (water-hating) or lipophilic (lipid-liking).

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

Lipophilicity

The hydrophobic effect

§ 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.

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

H

H

H

H

H

H

HH

H

H

H

H

OH

H

OH

H

HO

H

H

O

H

H

O HH O

H

HH

O

HO

H

H

OH

H

H

O O

H

H

H

O H

H

O

H

OH H

The hydrophobic effectThis 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?

Ø It is a means of expressing a drug's solubility is lipid versus water. A drug is added to a two-phase solution of oil (or other organic solvent like 1-octanol) and water, mixed, and the concentration of drug in the organic and water phases determined. The ratio of the two phases reflects the relative lipid/water solubility.

Partition Coefficient (Lipid/Water Partition Coefficient)

How does one determine a drug’s partition coefficient?

Organicphase

Aqueousphase

Organicphase

Aqueousphase

1. Add drug

2. Equilibrate

3. Determine [Drug]org and [Drug]aqu

4. Calculate Korg/aqu

Mathematically,

Korg/aqu = [Drug]org

[Drug]aqu

1. Add drug

2. Equilibrate

3. Determine [Drug]org and [Drug]aqu

4. Calculate Korg/aqu

1. Add drug

2. Equilibrate

3. Determine [Drug]org and [Drug]aqu

4. Calculate Korg/aqu

Mathematically,

Korg/aqu = [Drug]org

[Drug]aqu

Korg/aqu = [Drug]org

[Drug]aqu

Lipid-Water Partition Coefficient

The ratio of the concentration of the drug in two immiscible phases: a nonpolar liquid or organic solvent (representing the membrane); and an aqueous buffer, pH 7.4 (representing the plasma)

Lipid-Water Partition CoefficientThe higher the lipid/water p.c. the

greater the rate of transfer across the membrane

polarity of a drug, by increasing ionization will the lipid/ water p.c.

polarity of a drug, suppression of ionization will the lipid/ water p.c.

A drug’s partition coefficient, Korg/aqu is an index of the drug’s lipophilicity.

Log P = 1 means 10:1 Organic:AqueousLog P = 0 means 1:1 Organic:AqueousLog P = -1 means 1:10 Organic:Aqueous

In general, assuming passive absorption

Optimum CNS penetration around Log P = 2 +/- 0.7Optimum Oral absorption around Log P = 1.8 Optimum Intestinal absorption Log P =1.35 Optimum Colonic absorption Log P = 1.32 Optimum Sub lingual absorption Log P = 5.5 Optimum Percutaneous Log P = 2.6 (& low mw)

logPBinding to enzyme / receptor

Aqueous solubility

Binding to P450 metabolising enzymes

Absorption through membrane

Binding to blood / tissue proteins – less drug free to act

Binding to hERG heart ion channel -cardiotoxicity risk

So log P needs to be optimised

What else does logP affect?

– The partition ratio of a given drug will determine its solubility in plasma, its ability to traverse cell membranes, and which tissues it will reach.

– Drugs must have some aqueous solubility since this is essential for absorption through membranes, and for the production of an adequate concentration at the site-of-action.

– A balance between hydrophilicity and lipohilicity is necessary.  This must be taken into account when chemically modifying a drug for optimal activity.

The Ferguson Principle

The Ferguson Principle

ü Ferguson’s suggested in 1939 , the potency of drug for non-specific drugs is determined by its thermodynamic activity.

ü it states that the concentration of drug is directly proportional to its activity.

ü Concentration of drug can be measured by either Molarity (or) Partial pressure.

The relationship between physicochemical properties and drug action

“Theoretical representations”

The hypothesis states that, the higher the partition ratio P, the higher the pharmacological effect.

ü Ferguson Constant is represented by X where:

Ø High thermodynamic activity means that the activity of the drug is based on its physicochemical properties only, such as in a gaseous anesthetic. Such drugs are known as non-specific agents.

Ø Low thermodynamic activity means that the

activity of the drug is based on its structure rather than physicochemical properties.

Ø Agents in this category are called specific agents, and their activity at low concentrations infers that they have a specific receptor.