Second Level Students

Mariza Fouad Farag

Lecturer of Pharmaceutics

Faculty of Pharmacy

Mansoura University

Stability and types of stability

Types of Drug Instability

Physical degradation

Chemical degradation

Hydrolysis, Isomerization and Racemization

Dehydration, Decarboxylation and Elimination

Oxidation, Photodegradation

It is the ability of a drug substance or the

pharmaceutical dosage form to maintain

the physical, chemical, therapeutic and

microbial properties during the time of

storage and usage by the patient. It is

measured by the rate of changes that take

place in the pharmaceutical dosage forms.

Importance of studying drug stability

1. Safety of the patient:

a-Chemical and physical degradation of drugsubstances may change their pharmacologicaleffects, resulting in altered therapeutic efficacy.

b- The drug may degrade to a toxic substance.Therefore, it is important to determine not onlyhow much drug is lost with time but also what areits degradation products.

In some cases, the degradants may be of knowntoxicity.

For example, the drug pralidoxime degrades underbasic pH conditions, giving the toxic productcyanide.

Importance of studying drug stability

2. Pharmaceuticals should be stable and

maintain their quality until the time of

usage or until their expiration date.

3. The quality should be maintained under

the various conditions that

pharmaceuticals encounter, during

production, transportation, and

storage in hospital and community

pharmacies, as well as in the home.

Toxicological

Chemical

Physical

Microbiological

Therapeutic

Types of Stability

Chemical Each active ingredient retains its chemical

integrity, and labeled potency, within the specified

limits.

Physical The original physical properties, are retained

including appearance, palatability,

uniformity, dissolution, and suspendability.

Microbiological Sterility or resistance to microbial growth is

retained according to the specified requirements.

Antimicrobial agents that are present retain

effectiveness.

Therapeutic The therapeutic effect remains unchanged.

Toxicological No significant increase in toxicity occurs

It is the inability of a particular formulation

in a specific container to remain within a

particular chemical, microbiological,

therapeutical, physical & toxicological

specification.

Physical

degradation

Types of Drug Instability

Chemical

degradation

Volatile components such as alcohol, ether,

iodine, volatile oils, camphor, and menthol,

escape from the formulations.

Example: In tablets containing volatile drugs, such

as nitroglycerin, the drug may migrate between

tablets in the container, resulting in a lack of

uniformity among the tablets.

Prevention: nitroglycerin tablets should be

preserved in tight containers, of glass, at

controlled room temperature.

Loss of volatile components

Loss of water from liquid preparations (ex.:

o/w emulsions) leads to stability changes.

Water evaporates causing the

crystallization of the drug, which may lead

to :

increase in potency and

decrease in weight.

This tendency depends on temperature and

humidity of surrounding environment.

Prevention: through storage of products in

well closed containers.

Loss of water

Hygroscopic drugs (or pharmaceutical preparations

that are hygroscopic in nature) absorb the water

from external atmosphere causing physical

degradation. This depends on temperature and

humidity of surrounding material.

Example: Glycerin suppositories may become

opaque.

Gelatin capsule may soften

Some deliquescent salts calcium chloride, potassium

citrate.

Prevention: through storage of products in well

closed containers.

Absorption of water

Crystal growth occurs in solutions after super

saturation.

This may occur due to the fall in temperature

and a consequent decrease in solubility of the

solute.

Examples:

Injection of calcium gluconate.

In suspensions, crystals settle down, bind

together forming a hard cake that is difficult

to redisperse, and suspension becomes

unstable.

Crystal Growth

Prevention of crystal growth:

◦ Storage in an environment with minimum

temperature fluctuations.

◦ Use of particles of narrow size range.

◦ Addition of surface active agents, which

are absorbed onto the crystal surface,

thus inhibiting the deposition of solute

molecules.

◦ Increasing the viscosity of the suspending

medium.

In polymorphic changes, crystal forms are

changed upon storage.

This may cause alteration in solubility.

Prevention: formulated products should

contain a stable crystalline form of the

drug.

Polymorphic Changes

Colour Changes

Colour changes are of two types

Loss of colour

due to:

·PH change

·Presence of reducing agent

Development of colour

due to:

Exposure to light

Prevention:

◦ PH should not be changed.

◦ Exposure to light should be avoided.

◦ Prevention of fading by incorporating

UV light absorbing material.

Chemical Degradation Pathways

Hydrolysis

Dehydration

Isomerization

Racemization

Elimination

Oxidation

Photodegradation

Complex interactions with excipients

1- Hydrolysis

It is one of the most common

reactions seen with pharmaceuticals,

and is often the main degradation

pathway for drug substances having

ester and amide functional groups

within their structure.

Hydrolysis

Although hydrolysis will occur mainly with

drugs in aqueous solution, suspensions

and solid dosage forms are also

susceptible to hydrolysis.

Ex: Aspirin hydrolysis.

Moisture is rapidly absorbed on to the surface of aspirin

particles

causing solution of a portion of the drug

in water layer around the particles

As the aspirin in

solution hydrolyses,

more of the solid

material dissolves

and decomposition

continues

Ester

Hydrolysis

Hydrolysis

Amide

Hydrolysis

Hydrolysis

R1-COOR2 R1-COOH + R2OH

Ester hydrolysis is characterized by rupture of the

covalent bond between the carbonyl carbon (C=0) and

oxygen, resulting in producing acid and alcohol.

The reaction is catalyzed by acids or alkalies.

Ester Hydrolysis

H2O or H+ or OH¯

acid

alcohol

covalent bond between

the carbonyl carbon (C=0)

and oxygen

Aspirin

Atropine

Benzocaine

Procaine

Ethylparaben

Scopolamine

Aspirin (Acetylsalicylic acid) hydrolysis:

Procaine

H+ or OH¯

P- aminobenzoic acid

Amide hydrolysis is characterized by rupture of the

covalent bond between the carbonyl carbon (C=0)

and nitrogen atom.

Amide Hydrolysis

Acetaminophen

Chloramphenicol

Lincomycin

Indomethacin

Sulfacetamide

Paracetamol (Acetaminophen)

1. Hydrolysis is frequently catalysed by

hydrogen ions (specific acid-catalysis) or,

hydroxyl ions (specific base-catalysis).

Several methods are available to stabilize asolution of a drug which is susceptible to acid–base hydrolysis.

The usual method is to determine the pH ofmaximum stability and to formulate theproduct at this pH.

2. Alteration of the dielectric constant by theaddition of non-aqueous solvents such asalcohol, glycerin or propylene glycol mayreduce hydrolysis.

3. Adding a compound that forms a complex

with the drug can increase stability.

Ex:

The addition of caffeine to aqueous solutions

of benzocaine, procaine and tetracaine was

shown to decrease the base-catalysed hydrolysis

of these local anaesthetics in this way.

Erythromycin is susceptible to acid

catalyzed dehydration.

Sugars such as glucose and lactose are

known to undergo dehydration.

2- Dehydration

It is the process of conversion of a

drug into its optical or geometric

isomers, which are often of lower

therapeutic activity.

Examples :

◦ Vitamin A (cis–trans isomerisation).

◦ Epinephrine (adrenaline) undergoes

racemization under strongly acidic

conditions.

3- Isomerization and Racemization

4- Decarboxylation and Elimination

Drug substances having a carboxylic acid

group are sometimes susceptible to

decarboxylation.

Example: 4-Aminosalicylic acid

Examples: p-aminobenzoic acid

Hydrolysis of procaine yields p-aminobenzoic

acid, which in weakly acidic solution,

decarboxylates slowly into aniline.

Decarboxylation and Elimination

p-aminobenzoic acid Aniline

Aniline darkens on exposure to light,

and this explains the development of

colour in old procaine injections.

H+

5- Oxidation

Oxidation is a well-known chemical

degradation pathway for pharmaceuticals.

Autoxidations occur spontaneously

under the initial influence of atmospheric

oxygen and proceed slowly at first and

then more rapidly.

Oxidation

Oils and fats containing unsaturatedlinkages in the molecules are moresusceptible to autoxidation.

Examples:

◦ Methyldopa and epinephrine.

◦ Polyunsaturated molecules such as vitamin A.

◦ Hydrocortisone.

◦ Volatile oils e.g. clove and cinnamon changecolour, odour and consistency due toautoxidation.

◦ Fixed oils e.g. arachis oil develop an unpleasantodour and taste (become rancid).

1. The oxygen in pharmaceutical containers should be

replaced with nitrogen or carbon dioxide.

2. Contact of the drug with heavy-metal ions such as

iron, cobalt or nickel, which catalyse oxidation,

should be avoided; and storage should be at

reduced temperatures.

3. Use of antioxidants

Anti oxidants are added to pharmaceutical

formulations as oxygen scavengers – that is

they have a higher capacity to undergo oxidation

than the drug moiety.

Examples:

sodium metabisulfite

ascorbic acid

Thiourea

thioglycolic acid.

4. Use of Chelating agents

Chelating agents form complexes with

heavy metal ions and prevent them from

catalyzing oxidative decomposition.

Some good examples of chelating agents are:

ethylenediamine tetracetic acid derivatives and

salts

dihydroxyethyl glycine

citric acid and tartaric acid.

Examples of drugs that degrade when

exposed to light include riboflavin and folic

acid.

Pharmaceutical products can be adequately

protected from photo-induced decomposition

by the use of coloured glass containers

(amber glass) and storage in the dark.

Coating tablets with a polymer film containing

ultraviolet absorbers has been suggested as

an additional method for protection from light.

6- Photodegradation