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INFLUENCE OF
PHYSICOCHEMICAL PROPERTIES

Nyi Mekar Saptarini

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1. Structure
Drugs act by binding to their target domains:
stereoelectronic structures are complementary via weak
electrostatic bonds (hydrogen bonds and van der Waals
forces) or stronger covalent bonds.
The bonds only be formed if the compound close enough to
its target
drug must have a chemical structure and a
shape that are compatible with its target domain.
Some structural features impose degree of rigidity, others
make the structure more flexible.
Other structures give rise to stereoisomers, which can
exhibit different potencies, types of activity and unwanted
side effects.

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2. Stereochemistry
Some enantiomers can to racemise under
physiological conditions.
Ex. Thalidomide racemate (1950s) was sedative:
R-enantiomer had the teratogenic properties.
Thalidomide is now used in the treatment of
multiple myeloma.

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2.1. Structurally rigid groups

Rigid group are unsaturated groups of all types
and saturated ring systems: esters, amides,
aliphatic conjugated systems and aromatic and
heteroaromatic ring systems.
The binding of rigid structures to a target site give
information about the site shape, the nature of
the interaction, ligand conformation.
Rigid structures can be replaced by alternative
rigid ones of a similar size and shape to form
analogues that may have different binding
characteristics and activity or potency
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2.2. Conformation
Schueler and Archer (1960s): the flexibility of the
structures (ligands and receptors) accounted for the
same ligand being able to bind to different receptor.
Archer: ligand has different conformations when it
bound to the different receptor.
Ex. acetylcholine exhibits both muscarinic (anti or
staggered form) and nicotinic activity (syn or eclipsed
form) based on observation of anti conformation of 2tropanyl ethanoate methiodide binds to muscarinic
receptors & the syn conformation binds to nicotinic
receptors
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Flexibility degree improves the drug action

flexible structure able to adjust to give a better fit
to its target site.
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The introducing conformational restrictions

methods are by using bulky substituents,
unsaturated structures, small ring systems, steric
hindrance.

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The flexibility degree in a drug improves the

action
adjustable to give a better fit to its
target site.

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2.3. Configuration
Configurational centres impose a rigid shape on
sections of the molecule in which they occur

geometric and optical isomerism.
Structures with different shapes and properties
will behave differently in biological systems

differences in their potencies and/or activities.
The stereochemistry affect the pharmacodynamic
& pharmacokinetic properties.

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3. Solubility
The solubility in water and lipids is an important
factor in its effectiveness as a therapeutic agent
and in the design of its dosage form.
The absorption from the GI tract by passive
diffusion & distribution through the circulatory
system depends on water solubility.
The passage through other membranes depend
on balance of water and lipid solubilities.
The solubility depends on the chemical structure,
polymorphic form & the nature of the solvent

determined by experiment at 25 & 37 C.
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3.1. Solubility and the physical nature

of the solute
The solubility of solids in all solvents is temperature dependent.
Solubility product (Ksp): the equilibrium constant for a
heterogeneous system at constant temperature, comprising of a
saturated solution of a sparingly soluble salt CxAy in contact with
undissolved solid salt.
The larger Ksp, the more soluble the salt.

The solubility of a solute that ionises in solution will be depressed

by the presence of an ion from a different source
the common
ion effect.
Ex. the presence of A ions from an ionic compound BA that
produces A ions in solution will depress the ionisation of an ionic
compound CA and its solubility.
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Uncharged molecules are transported more easily

through biological membranes than charged
molecules.
The solubility of liquids in solvents usually
increases with temperature.
The solubility of a gas in a liquid depends on the
temperature and pressure of the gas, its structure
& the nature of the solvent
Henrys Law.
Kg is a characteristic property of the gas.
Henrys Law applies separately to each of the
components of a mixture of gases.
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4. Solutions
A solution consists of particles, molecules or ions (0.1
1 nm) dispersed in a solvent.
As a solute particle moves through the solvent, it is
surrounded by solvent molecules
solvation or
hydration (water).
Solvated molecules are bound to the solute by a variety
of weak attractive forces: hydrogen bonding, van der
Waals forces & dipoledipole interactions.
The solvent molecules stabilise the solution by
preventing the solute particles coagulating which can
be precipitated.
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Polar solutes have permanent dipoles & have

strong electrostatic attractive forces between
their particles and the polar water molecules

form stable aqueous solutions.
Non-polar compounds are soluble in nonaqueous solvents (hexane and lipids) via
hydrophobic interactions & hydrogen bonding.

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5. Solubility and the structure of the

solute
The water solubility depend on the number
and nature of the polar groups in its structure:
size and nature of the compounds carbon
hydrogen skeleton.
Polar groups that ionise in water
higher
water solubility than those that do not ionise.
The lipid solubility depends on the nature and
number of non-polar groups in its structure.
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6. Salt formation
Salt formation improves the water solubility of acidic
and basic drugs because the salts dissociate to produce
hydrated ions: kation & anion.
The pH of the biological fluid may affect the solubility
of a drug & its activity.
Acidic drugs are converted to their metallic or amino
salts, the salts of organic acids are normally used for
basic drugs.
The water solubility of a salt depend on the structure
of the acid or base used to form the salt.

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The function of water-insoluble salts

formation are used in:
1. drug delivery
unstable salt dissociate in the small
intestine to liberate the component acid
and base. Ex. erythromycin stearate.
stable salt to delivery to its site of action.
Ex. pyrantel embonate
2. drug depot: suspension to im injection. Ex.
penicillin G procaine.
3. change the drug taste: more palatable
(tasteless). Ex. chlorpromazine embonate
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7. The incorporation of water

solubilising groups
The type of group
The incorporation of polar groups into the structure make a
better water solubility compounds.
Polar groups are ionised or attracted with water via
relatively strong intermolecular forces.
Strong polar: alcohol, amine, amide, carboxylic acid,
sulphonic acid and phosphorus oxyacid groups.
Less polar: ether,aldehyde and ketonic functional groups.
Weakly polar: carboxylic acid esters, aryl halides, alkyl
halides.
Non polar: methyl, fluoro and chloro groups.

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Groups that are bound to compounds by

less reactive CC, CO and CN bonds are
irreversible attached.
ester, amide, phosphate, sulphate and
glycosidic links are metabolised to reform the
parent lead
prodrugs.

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The position of the water solubilising group

The position of the new water solubilising group
 depend on the compoundreactivity & the
pharmacophore position.
 not involved in the drugreceptor interaction
to preserve the pharmacological activity.
The structure contains aromatic ring need
electrophilic substitution, ex. aldehyde groups to
oxidation reduction, nucleophilic addition and
condensation.
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8. The effect of pH on the solubility of

acidic and basic drugs
Biological fluids are complex systems (contain variety
of different solutes)
effect drugs solubilities &
bioavailabilities.
An acidic or basic pH will enhance or reduce the
ionisation of drugs
changes drug solubility &
absorption through membranes.
HendersonHasselbalch equation for degree of
ionisation drugs at different pH values:
weak monobasic acidic drugs
weak monoacidic basic drugs
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Aspirin
slightly ionised in the stomach (1:316)
almost completely ionised in the intestine (316:1)
Aspirin are more easily transferred through a membrane in
unionised form
readily absorbed in the stomach than in the
intestine.
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The solubility of compound, which contain acidic & basic

groups (protein) is complicated by internal salt formation.
Proteins have lowest solubilities near their isoelectric
points: the solution contains the internal salt (zwitterion).
The variations of solubility affect the therapeutic
effectiveness & influence the design of the dosage forms.

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The electrolytes in an aqueous solution

increase the solubilities of other electrolytes.
reduces the solubility of nonelectrolytes.
The cations and anions from the electrolyte form stronger bonds
with the water
hydrates, more soluble than the nonelectrolyte
molecules.
The ions displace the non-electrolyte molecules from their weaker
hydrates with a subsequent reduction in the solubility of the nonelectrolyte.

If sufficient electrolyte is added to solution, the non-electrolyte is

precipitated
salting out.
The non-electrolytes reduces dielectric constant
reduces the
degree of ionisation of the electrolyte
decrease in the solubility
of the electrolyte.
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9. Partition
Partition coefficients (P): measure of the compound
distribution between two immiscible solvents.
Valid when solubility and transport by diffusion
through a membrane are the main factors controlling
drug action.
P is a constant for constant temperature (+ 5 C) &
ideal dilute solutions.

organic phase: n-octanol, butanol, chloroform, olive oil

aqueous phase: water, phosphate buffer at pH 7.4
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high P value: hydrophobic, readily diffuse into

lipid membranes & fatty tissue, but reluctant
to leave & not be readily transported through
the membrane via diffusion
could fail to
reach the action site in effective quantity.
low P value: hydrophilic, reluctant to enter
lipid material & stay in the aqueous medium.

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If hydrophobicity is the most important factor

in drug action
increased hydrophobicity
will increase the action.
Ex. general anaesthetics are believed to act by
dissolving in cell membranes.
Diethyl ether (P 0.98), chloroform (P 1.97) &
halothane (P 2.3)
halothane is the most
soluble in lipid membran & the most potent.
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10. Surfactants and amphiphiles

Amphiphiles contain region that soluble &
insoluble in the same solvent.
Surfactants are compounds that lower the
surface tension of water, contain hydrophilic
& hydrophobic groups.

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Classification based on the nature of their hydrophilic groups:

Cationic surfactants have a positively charged hydrophilic group.
Anionic surfactants have a negatively charged hydrophilic group.
Ampholytic surfactants have electrically neutral structures
(positive & negative charges, zwitterions).
Non-ionic surfactants do not form ions in solution.

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Surfactants dissolve in the aqueous medium &

lipid membranes
accumulate at the interface:
antiseptic & disinfectant action of non-ionic and
quaternary ammonium surfactants.

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surfactant concentration
the system changes from

a true solution to a colloidal solution (micelles,
energetically favourable): critical micelle concentration
(cmc).
cmc is temperature dependent (25 C).
Ex. the cmc for sodium dodecyl sulphate is 0.08
mol/dm at 25 C.
Concentrations < cmc
spherical
cylindrical,
laminar and other forms.

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The physical properties of surfactant solutions

change at the cmc point
indicator for the onset
of micelle formation & determine the cmc value.

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10.1 Drug solubilisation

Incorporation into suitable micelles used to
solubilise water-insoluble drugs, depends on
the structure.
Drugs are held in the micelle by
intermolecular forces of attraction: hydrogen
& hydrophobic bond.

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The position of drugs in the micelle:

non-polar drug tend to accumulate in the hydrophobic core.
water-insoluble polar drug are orientated with their polar
groups towards the surface.
polar drug depend on the relative affinities for the aqueous
medium:
 strong affinity
polar group being near or on the
surface.
 weak affinity
polar group being located further into
the interior.

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Disadvantages of using micelles as a delivery

vehicle:
drugs absorption & activity is dependent on it
being released: ionic surfactants can react
with anionic and cationic drug.
more rapid decomposition because of close
proximity to each other.
reduce the rates of hydrolysis & oxidation.
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