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28/09/2015
1
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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