preformulation : Introduction and physical properties (click here )
CHEMICAL PROPERTIES
Hydrolysis
Drug molecules interact with water (drug) molecules to yield breakdown product.
Susceptible to the hydrolytic process: esters, substituted amides, lactones, and lactams.
E.g.: Anesthetics, antibiotics, vitamins and barbiturates.
1. Ester Hydrolysis:
Acid + Alcohol (involves rupture of a covalent linkage between a carbon atom and an
oxygen). Catalysts – polar nature such as mineral acids, alkalies or l certain enzymes –
capable of supplying H++ and OH− ions.
Kinetic study of hydrolysis of Aspirin was done in various buffer solutions. It was
observed e.g. Aspirin is most stable at 2.4, at pH 5 to 7, degradation is pH independent and
above pH 10 stability decreases with increase in pH.
Factors to be considered in Hydrolysis :
- pH
- Type of solvent: solvent lower dielectric constant Eg.: ethanol, glycols, mannitol etc.
- Complexation : steric or polar effects. Eg.: caffeine with benzocaine – electronic influence of complexing agent - alters affinity.
- Surfactants: nonionic , cationic , anionic stabilizes drug against base catalysis. Eg: 5% SLS – 18 folds increase in t1/2 of benzocaine Modification of chemical structure Salts and esters.
2. Amide Hydrolysis:
Hydrolytic reaction results Amide Acid + Amine. E.g.: Chloramphenicol, Nicinamides.
Ring alterations: hydrolysis proceed as a result of ring cleavage. ring cleavage.
E.g. Pilocarpine.
Oxidation and Reduction: Second Most Common Way
Oxidation: Presence of oxygen
- Initiated by heat, light or trace metal ions that Initiated by heat, light or trace metal ions that produce organic free radicals.
- These radicals propagate the oxidation reaction, which proceeds until inhibitors destroy the radicals or until side reactions eventually break radicals the chain.
- E.g. Dopamine.
Substance is oxidized when:
- If electrons are removed from it.
- Gains electronegative atoms or radicals or loses electropositive atoms or radicals.
- Addition of oxygen and removal of hydrogen.
- Most common: Autoxidation (free radical chain process).
- Involves homolytic bond fission of a covalent– each atom retains one of the electrons of original covalent bond.
Racemization
Racemization is the process in which one enantiomer of a compound, such as an
L-amino acid, converts to the other enantiomer.
- The compound then alternates between each form while the ratio between the (+) and (–) groups approaches 1 : 1, at which point it becomes optically inactive.
- If the racemization results in a mixture where the enantiomers are present in equal quantities, the resulting sample is described as racemeric or a racemate.
- The inter-conversion from one isomer to another can lead to a different pharmacokinetic properties (ADME) as well as of different pharmacological and of toxicological effect.
- Example: L-epinephrine is 15 to 20 times more active than D-form, while activity of racemic mixture is just one half of the L-form.
- It depends on temperature, solvent, catalyst and presence or absence of light.
- Biological significance: Many psychotropic drugs show differing activity or efficacy between isomers, e.g. Amphetamine is often dispensed as racemic salts while the more active dextro-amphetamine is reserved for severe indications; another example is Methadone, of which one isomer has activity as an opioid agonist and the other as an NMDA antagonist.