Monday, March 31, 2008

DRUG STABILITY

DRUG STABILITY


What Is Drug Instability?
“The incapacity or incapability of a particular formulation in a specific container to remain within a particular chemical, microbiological, therapeutical, physical & toxicological specification.”

What Is Drug Stability?
“The capacity or the capability of a particular formulation in a specific container to remain with in particular chemical, microbiological, therapeutical, physical & toxicological specification.”

FACTORS EFFECTING DRUG STABILITY:
Factors effecting the drug stability are as under
1. PH
2. Temperature
3. Moisture
4. Light
5. Radiations


TYPES OF DRUG INSTABILITY:

Drug stability can be divided into two major types

1. Physical degradation

2. Chemical degradation


PHYSICAL DEGRADATION:
Definition:
“Degradation, which results into the change of physical nature of the drug.”
Types:
Types of physical degradation are as under


1. Loss of volatile components
2. Loss of H2O
3. Absorption of H2O
4. Crystal growth
5. Polymorphic changes
6. Colour changes

1. Loss Of Volatile Components:

Volatile components such as
Alcohol ether
Iodine volatile oils
Camphor menthol
etc. escape from the formulations.
e.g.
Nitroglycerine from drugs evaporates.

2. Loss Of H2O:
· Loss of water from o/w emulsions thus its stability changes.
· Water evaporates causing the crystalline growth.
· This will result into ↑ in potency & ↓ in weight.

This tendency depends on temp. and humidity of surrounding environment.
e.g.
water evaporates from efflorescent salts such as Na2SO4, borax

3. Absorption Of H2O:
Hygroscopic drugs absorb the water from external atmosphere
causing the physical degradation.

Depends on temp and humidity of surrounding material
e.g.
· Glycerin suppositories may become opaque
· Gelatin capsule may soften
· Some deliquescent salts calcium chloride, potassium citrate.

4. Crystal Growth:
· In solutions after super saturation crystal growth occurs

Reason may be the fall in temp and a consequent ↓ in solubility of solute
e.g.
· Injection of calcium glucconate
· In suspensions crystals settle down and caking occurs and suspension becomes unstable.
e.g.
Ophthalmic preparations.

5. Polymorphic Changes:
In polymorphic changes crystal forms are changed. A stable crystal form loosens.

This may cause alteration in solubility and possibly crystalline growth in aqueous suspensions

6. Colour Changes:
Colour changes are of two types.

1. Loss of colour
2. Development of colour

1. Loss of colour is due to
· PH change
· Presence of reducing agent

2. Development of colour is due to
· Exposure to light

Preventive measures:
1. Loss of volatile components:
· Such product should be placed in well closed container
· ¯ In temp. ¯ Volatility

2. Loss of water:
Products should be placed in well-closed container.

3. Absorption of water:
Product should be placed in well-closed container.

4. Crystal growth:
For solutions
· Stabilizers are added

For suspensions
· Minimum temp. flocculation should be managed
· Incorporation of surface active agent
· By increasing viscosity of suspending material

5. Polymorphic changes:
Formulated products should contain a stable crystalline form of the drug.

6. Colour changes:
· PH should not be changed
· Exposure to light should be avoided

An attempt has been made to prevent the fading by incorporating UV light absorbing material.

CHEMICAL DEGRADATION:
Definition:

“Change in the physical nature of the drug is called as chemical degradation.”
Types:
Types of chemical degradation are as under

1. Hydrolysis
2. Oxidation
3. Decarboxilation
4. Isomerization
5. Polymerization

1. Hydrolysis:
Definition:
“It is defined as the reaction of a compound with water.”

Major cause of degradation of drug
Types:
It has two types
· Ionic hydrolysis
· Molecular hydrolysis
Ionic Hydrolysis:
“Hydrolysis, which occur when the salts of the weak acids & bases interact with water to give either alkaline
or acidic solutions”

e.g. CH3COOK gives alkaline while codeine phosphate gives acidic Sol when interact with water.
Molecular Hydrolysis:
“Hydrolysis, which involve the cleavage of drug molecule.
It is much slower and irreversible process.”
It is catalyzed by hydrogen or hydroxyl ion and specifically acid or base catalyzed.
Rate of decomposition depends on the pH of the system

e.g. The local anesthetics, amethocain and benzocain.
­ in temp. ­ the rate of degradation.

[Example of procaine chloremphenicol & asprin Bentley pg: 141]
Factors Effecting Hydrolysis:

· Moisture
· PH
· Temp.
· Type of the solvent



Preventive Measures:
Adjustment of pH:
Rate of decomposition is critically dependent
Upon pH.
In the case of acid-base catalyzed hydrolysis at minimum pH
The drug stability is maximum
This can be shown by plotting a relationship b/w log of the reaction velocity constant for decomposition and pH [curve Bentley pg: 154]
Maximum stability for different drugs at dif. pH
Atropine sulphate 3.8
Procaine 3.6
Benzocaine 4.9
Choice of solvent:
More we go away from the water hydrolysis¯

e.g.
Aspirin is unstable in aq. Sol. So it is formulated in alcohol i.e. propylene glycol.

In some cases non-aq. Solvent increases the instability of product
e.g.
Cyclamic acid in aq. sol. Hydrolyze in slow rate while in alcohol high rate.

Production of insoluble form of drug:
Hydrolysis occur only with that portion of drug which is in aq. Sol.
Hydrolysis can be minimized by
· By making suspensions
· By pH adjustment of the aq. Vehicle.
· By preparing insoluble salt of the drug.
e.g. insoluble procaine salt of benzyl penicillin.
· By preparing “transient derivatives” of the drug.
Addition of surfactants:
Addition of surface-active agents results into significant improvement of drug stability.
This occurs due to the micelles formation.
Surface active agents are of two types cationic and anionic. Anionic micelles are more effective.
Modification of chemical structure:
Change of chemical structure of a chemical drug may prevent the hydrolysis
e.g. Alkyl to alkyl chain.
Presence of complexing agent:
By the presence of a compound, which would form water, soluble complex with drug the rate of decomposition may be decreased.
e.g. caffeine decrease the rate of decomposition of local anesthetics such as benzocaine, procaine & amethocaine.
2. Oxidation:
Definition:
“Removal of an electropositive atom, radical or electron, or the addition of an electronegative atom or radical.”

Types:
Oxidation has two types
· Auto-oxidation
· Photo-oxidation
Auto-oxidation:
“Oxidation in which the oxygen present in the air is involved.”
This process proceeds slowly under the influence of atmospheric oxygen
e.g. Oil, fats & unsaturated compound can undergo auto- oxidation

Photo-oxidation:
“Oxidation in which removal of the electron is involved with out presence of O2.”
This type is less frequently encountered
e.g. It occurs in adrenaline, riboflavin & ascorbic acid etc.

Susceptibility:
Susceptibility of the compound oxidation can be predicted from a knowledge of its standard oxidation-reduction potential Eo given by
the relation

0.0592 [oxidized form]
Eh = Eo + log
n [reduced form]


Compounds with higher Eo has greater tendency to be oxidized.
[Examples Bentley’s pg: 142 & 143]
PREVENTION:

i.The presence of antioxidants:
The decomposition of mainly readily oxidize able materials can be prevented by the addition of antioxidants which retard the oxidation process
e.g.
· Tocopherol
· Gallic acid & gallates
· Butylated hydroxanisol
· Butylated hydroxytoluene
· Nordihydroguaiaretic acid

ii.The presence of reducing agent:
Oxidation of pharmaceutical products can be retarded by the addition of reducing agents they are equally effective against oxidizing agents and atmospheric oxygen.
e.g.
· potassium metabisulphites
· sodium metabisulphites

iii.Removal of oxygen:
By limiting the contact of drug with the atmosphere, those oxidative decompositions dependent upon atmospheric oxygen may be often minimized.

iv.The presence of surface active agent:
Oxidizable materials such as oil soluble vitamins essential oils and unsaturated oils have been formulated as solubilized and emulsified products

v.Adjustment of pH:
Many of those oxidative decompositions involving a reversible oxidation reduction process are influenced by the hydrogen ion concentration of the system.

3. Decarboxilation:
“Elimination of CO2 from a compound.”

e.g.
· When sol. Of NaHCO3 is autoclaved.
· autoclaving the tuberculostatic agent sodium aminosalicylate

4. Isomerization:
“Conversion of an active drug into a less active or inactive isomer having same structural formula but different stereochemical configuration.”
Types:
· Optical isomerization
· Geometrical isomerization

5. Polymerization:

“Combination of two or more identical molecules to form a much larger and more complex molecule.”
e.g.
Degradation of antiseptic formulations and aldehydes is due to polymerization.