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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 2-tropanyl 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 � Henry’s Law.

• Kg is a characteristic property of the gas.

• Henry’s 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 & dipole–dipole 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 non-

aqueous 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 compound’s 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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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

The function of water-insoluble salts

formation are used in:

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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 C–C, C–O and C–N 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 drug–receptor 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.

• Henderson–Hasselbalch 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 non-

electrolyte.

• 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:

• drug’s 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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