drug stability

Question 1

problems instability of a compound can cause

Answer 1

loss of drug through a chemical reaction leading to loss of efficacy
drug degrading into a toxic substance
degradation of the drug may render it aesthetically unacceptable
some compounds are acid labile and therefore would not be suitable in their current formulations for oral use.

Question 2

from knowledge of the chemistry of drug molecules it should be possible to predict

Answer 2

biological characteristics ; activity , absorption , metabolism , excretion
chemical behaviour on formulation and storage

Question 3

to understand chemical behaviour the pharmacist needs awareness of chemical reactivity

Answer 3

the mechanism of chemical process
quantitive methods used to describe changes - kinetics
knowledge of methods used to obtain experimental data

Question 4

beer Lambert law

Answer 4

A=Ecl

Question 5

different stages of investigation

Answer 5

stability of drug ingredients ;
physical form and chemical decomposition
changes during formation ;
manufacturing process
incompatibilities in formulation
changes during storage ;
factors which effect storage

Question 6

physical instability

Answer 6

volatility
loss or uptake of solvent
polymorphism
changes in heterogenous systems
denaturation( bio-molecules)
ionisation and solubility

Question 7

chemical instability

Answer 7

hydrolysis
oxidation
elimination ; decarboxylation , dehydration
racemisation and isomerisation
rearrangement ; photochemical or acid catalysed
photo degradation
incompatibilities
any chemical changes will depend upon the presence of reactive functional groups and the presence of reactants , particularly water and oxygen

Question 8

hydrolysis

Answer 8

the chemical reaction of a molecule with water
this may involve the substitution of a leaving group by a hydroxy group derived from a water molecule
The potential for a hydrolysis reaction to occur will arise when ever carbon is bonded to a more electronegative atom and hence appreciable polarisation in a covalent bond exists.
Thus a nucleophilic attack by a water molecule on an electron deficient carbon atom occurs with subsequent bond breaking
When the processes takes place in solution (usually
aqueous) and involves solvent molecules the process is
referred to as SOLVOLYSIS.

Question 9

Important types of molecules which undergo hydrolysis

Answer 9

Esters
Examples of pharmaceutically important esters include acetylsalicylic acid methyl salicylate
triglycerides (acylglycerols). Also cyclic esters, lactones such as pilocarpine
2. Lactones (cyclic esters)
3. Amides
4. Lactams (cyclic amides)
Ureas
Peptides
Sugars

Question 10

Factors which effect hydrolysis

Answer 10

Temperature – Arrhenius equation (see kinetics notes) – energy of molecules in transition states

Ionic strength (µ) Primary Salt effect (see kinetics notes) – stabilisation of transition states

Catalysis: acid/base
metal ion
internal molecular

4. Structure of reactant

Question 11

Temperature

Answer 11

The rate constants of most reactions increase as the temperature is raised. Most reactions in solution fall somewhere in the range spanned by the hydrolysis of methyl ethanoate (where the rate constant at 35 °C is 1.82 times that at 25 °C) and the hydrolysis of sucrose (where the factor is 4.13). The dependence of reaction rate on temperature is found experimentally. This data is usually represented by the Arrhenius equation gained from a plot of lnK against 1/T

Question 12

Ionic strength – primary salt effect

Answer 12

The effect of increasing ionic strength on reaction rates is known as the primary salt effect.

Generally, reactions between ions of like charges display a positive salt effect - that is the reaction rate increases with increasing ionic strength.

Conversely, reactions between ions of opposite charge display a negative salt effect - the reaction rate decreases with increasing ionic strength.

Reactions between neutral molecules and ions do not exhibit a primary salt effect.

Question 13

Catalysis

Answer 13

Acid / base catalysisEffect of hydrogen ion concentration
After temperature the second most important factor affecting drug degradation is pH. The effect of pH can be explained as the catalytic effects that hydronium or hydroxide ions have on the various chemical reactions.
This is particularly poignant in hydrolysis because the reaction involves the substitution of water.
Ester hydrolysis is a typical example of an organic reaction showing both acid and base catalysis. It has a minimum rate at about neutrality showing that the mechanism by which it follows must change.

Question 14

Acid catalysed hydrolysis

Answer 14

Mineral acid speeds up hydrolysis by protonating the carbonyl oxygen, thus rendering the carbonyl carbon more susceptible to nucleophilic attack. Acidic hydrolysis is reversible and hence the mechanism for hydrolysis when taken in the opposite direction is also the mechanism for esterification.

Question 15

Base catalysed hydrolysis

Answer 15

Base promotes hydrolysis of an ester by providing the strongly nucleophilic hydroxide (OH-) ion. The carboxylic acid is obtained as its salt, which can be liberated with the addition of mineral acid.
This reaction is essentially irreversible since the carboxylate anion shows little tendency to react with an alcohol.

Question 16

Metal ion catalysis

Answer 16

Polyvalent metal cations are able to form complexes by interaction with complimentary anionic groups or electronegative atoms carrying a -ve dipole charge within another molecule.
As a result of complex formation the molecule may assume a more favourable conformation so that the hydrolysis of a group (e.g. ester) in another part of the molecule occurs more easily.
As well as affecting the rate of hydrolysis of drug molecules, this type of mechanism may be an essential part of the action of hydrolytic enzymes in the body due to the formation of enzyme/substrate/metal ion complexes.

Question 17

Structure of reactant

Answer 17

Most drugs are poly functional molecules, so that the structure of the rest of the molecule may effect the chemical behaviour of another group.

The rate at which bond breaking occurs in hydrolysis will depend upon the degree of polarisation in the breaking bond.

Hence since oxygen is more electronegative than nitrogen, esters hydrolyse more rapidly than amides.

Question 18

Electronic effects

Answer 18

The presence of an electron withdrawing or donating group adjacent to a hydrolysable group will influence the formation a hydrolysis transition state and hence the rate of reaction.

This effect may be transmitted through several bonds where p bond systems are present (conjugated unsaturated bonds or aromatic rings).

Hammett substituent constant ( s ); value associated with electronic effect of group on reaction rate.
Measure of electron donating or withdrawing effect of a group.

Question 19

Steric (spatial)

Answer 19

Transition state is tetrahedral. (see earlier mechanism of hydrolysis)
Bulky groups effect development of the transition state.

Mathematical basis:
Taft substituent constants; value associated with spatial effect of group on reaction rate.

Measure of size of group and effect on formation of transition state

Question 20

Oxidation

Answer 20

Oxidation is defined as the interaction between oxygen molecules and all the different substances they may contact, from metal to living tissue. However it is more preciously described by the loss of electrons/ hydrogen: the gain of oxygen: an increase in oxidation state

Question 21

Factors effecting the oxidation process

Answer 21

Light – the energy achieved from a light source is capable of forming radical species

Sensitisers

Catalysts – oxidising agents that accept the electrons released in oxidation processes.

Hydrogen ion conc. (pH)

Temperature – although the rate of reaction generally increase with increasing temperature – there are exceptions. The oxidation of nitric oxide decreases with increasing temperature.

Question 22

Antioxidants

Answer 22

Substances that delay the onset of, or slow down the rate of oxidation. The most common types of lipid soluble antioxidants are mono or polyhydric phenols with ring substituents.

• Works either by inhibiting the formation of free radicals in the initiation step or interrupting propagation of the free radical chain.
• The proposed mechanism is believed to involve the antioxidant acting as a hydrogen donor and the phenol group forms radical intermediates that are relatively stable due to resonance delocalisation. This reduces the number of positions suitable for attack by molecular oxygen.

Question 23

RACEMISATION

Answer 23

Racemisation involves the inversion of stereochemistry at a chiral centre to create 50:50 mixture of enantiomers (apparently optically inactive.
Inversion at a chiral centre occurs readily when the centre is adjacent to a carbonyl containing system (ester or ketone)

The presence of a substituent hydrogen atom at the chiral centre

The process may be acid (enolic) or base (carbanionic) catalysed

In each case the chiral carbon changes from sp3 hybridised tetrahedral geometry) to sp2 (planar transition) during hydrogen migration or loss.

Question 24

Geometrical isomerisation

Answer 24

Interconversion of isomers between trans ↔ cis forms

Initiated by absorbance of photochemical energy