DRUGS STABILITY

Lect. (1)
5th year/pharmacy
Department of Pharmaceutics /IUA
 Objectives

• To define drugs stability

• To enumerate the reasons behind of drugs stability
• To know the physical instability
• To know chemical decomposition chemical
degradation pathways of drugs.
•
 Outlines

 Definition of drugs stability

 Reasons for studying stability
 Physical instability of drugs
 Chemical decomposition of drugs
 Drugs stability

• Stability of drugs can be defined as the capability

of the drugs or drug products to retain their
physical, chemical, microbiological, and
therapeutic characteristics within the during the
period of shelf life.
• The stability of a drug product is expressed as the
expiry period or technically as shelf life.
 Expiration period is a valuable quality-attribute for all
pharmaceutical dosage forms.
The expiration data should be preferably accompanied
by details of specific storage conditions as provided in
the pharmacopoeia for this purpose (preservation,
packaging, storage and labelling).
• Adequate stability data acquired by the manufacturer
should be available to support the expiration period and
storage condition s specified.
• A manufacturer is obliged to indicate the shelf Life of a
drug on the label which usually between (1-5) years
depending of types of formulations ,storage conditions
and regulatory requirements.
 Reasons for studying stability

1. Product instability or chemical degradation of the

API may lead to lowering concentration e.g.
Digoxin , Theophyline may lead to ineffective
dosage form.
2. Drug decomposition may lead to toxic products e.g.
p-amino salicylic acid to pa- minophenol which is
toxic.tetracycline to epianhydrotetracycline
3. Instability may be due to change in physical
appearance e.g. creaming of emulsions and creams
and caking of suspensions. Or color changes ,ect
4. Assurance to the patient; stating expiry date on
product means manufacturer assure the patient would
receive a uniform dose through the shelf life.
5. Legal requirement by health authority ; The drug
control Administration insists on manufacturers on
conducting the stability studies identify strength,
purity and quality of the drug on an extended period of
time on the condition of normal storage.
Pharmacopial protocol (USP)acceptable levels of stability

Stability Type of Conditions maintained during shelf -

life of the product
1 Chemical Retains its chemical integrity and labelled
potency

2 Physical Maintains appearance, color, palatability,

uniformity; dissolution , dispersability,
3 Microbiological Sterility, pyrogens-free,effectiveness of
preservatives
4 Therapeutic Efficacy Drug action remains unchanged
5 Toxicological No significant increase in toxicity
Physical instability of the pharmaceutical products

• Physical instability in pharmaceutical products

refers to changes in the physical properties of a
drug product that can lead to a reduction in its
quality, efficacy, or safety.
• These changes do not affect the chemical structure
of the active ingredient but can still affect the
product's appearance, dosage form, or
performance.
• Physical instability can occur in various forms,
including changes in the shape, color, size, or
texture of the product, and may lead to issues like
sedimentation, crystallization, or phase separation.
 Types of Physical Instability:
1. Precipitation or Crystallization:
This occurs when a substance (APIor excipient) that was
previously dissolved in a formulation (becomes insoluble and
forms solid particles.
• Example: Crystallization of poorly soluble drugs from a solution
or suspension.
• Causes: Changes in temperature, pH, or the concentration of
excipients can lead to supersaturation, promoting crystallization.
2. Phase Separation:
This is when different phases (solid, liquid, or gas) separate
from each other in a formulation, often observed in emulsions or
suspensions.
• Example: The separation of oil and water phases in emulsions or
suspensions.
• Causes: Inadequate emulsifying agents or changes in
temperature or pH.
3. Aggregation or Clumping:
The active ingredient or excipients in a suspension or
colloidal system can aggregate or clump together, leading
to a loss of uniformity.
Example: Aggregation of protein molecules in a protein-
based injectable drug.
Causes: Alterations in pH, temperature, or the presence of
certain excipients may cause molecules to aggregate.
4. Sedimentation:
This occurs when solid particles in a suspension settle at the
bottom of the container due to gravity, leading to non-
uniformity in the product.
Example: Sediment formation in a suspension formulation.
Causes: The size, density, and concentration of particles in
suspension can lead to sedimentation if the system is not
properly stabilized.
5. Vaporization or Loss of Volatile Components:
The loss of volatile solvents or other volatile components
from the formulation, which can alter the composition and
performance of the product.
Example: Loss of alcohol or water from a topical
formulation.
Causes: Exposure to high temperatures, improper storage,
or packaging.
6. Color Change:
A change in color can be an indication of physical
instability, especially when the color change is due to a
change in the formulation or interaction between
components.
Example: Discoloration of an oral solution or tablet.
Causes: Exposure to light, heat, or moisture, or chemical
reactions that can affect the color of the product.
7. Caking or Sticking:
This happens when powder formulations, such as granules
or tablets, form lumps or cakes due to the attraction of
particles to each other or moisture absorption.
Example: Moisture-induced caking in tablets or powders.
Causes: Humidity, temperature fluctuations, or improper
storage.
 Preventing and Managing Physical Instability:

1. Proper Formulation Design: Use of stabilizers, surfactants, or

emulsifiers can help prevent phase separation or precipitation.
2. Storage Conditions: Controlling temperature, humidity, and
light exposure is critical to maintaining product stability.
3. Packaging: Using appropriate packaging materials that protect
from moisture, light, or air can reduce instability.
4. Excipients Selection: Careful choice of excipients that do not
interact negatively with the active ingredient is essential.
5. Quality Control: Regular testing for physical stability during
manufacturing, packaging, and storage can help detect and
address issues early.
 Chemical decomposition of drugs

• All medicinal agents are to be investigated for

their decomposition before being marketed.
• Most drugs contain different functional groups
therefore, under goes different chemical reactions.
• APIs are affected by different factors of
environmental, moisture, radiation, light.
There are many chemical degradation pathways for
drugs such as :
• Hydrolysis
• oxidation,
• dehydration,
• isomerization and racemization,
• photodegradation,
• complexation.
 1. Hydrolysis:
• Hydrolysis is the breaking of a colavent bond in the
drug molecule due to the reaction of water.
• Hydrolysis is often the main degradation pathway for
drug substances that are derivative of carboxylic acid or
contains functional groups based on this moiety, for
example esters, amides, lactone, lactams , imides.
• Many drugs are decomposed by oxidation e.g esters
( Aspirin , physostigmine , Atropine , procaine) ,amides
(penicillins , cephalosporin , Chloramphenicol ,).
• The factors that promote hydrolysis include water
content , enzymes levels ,temperature,PH.
 Protection against hydrolysis:

• hydrolysis reactions are known to occur in

presence of moisture, catalytic species H+ and
(OH)-. Protective measures should aim at
eliminating the influence of these factors on the
drug.
1.Alteration of the dielectric constant by the addition
of nonaqueous solvents with lower dielectric
constant than water such as alcohol, glycerin or
propylene glycol.
2. Formulation design:
• Use of Prodrugs: Are designed to prevent
premature drug hydrolysis by modifying the
hydrolysable groups such as ester and amide ,
then the drug is converted to the active form in
the liver or target tissues e.g. Enalapril ,
clopedigrel.
• Encapsulation: Drugs can be encapsulated in
polymers or liposomes to shield them from
water or moisture
• PH-Sensitive formulations: Hydrolysis rates are
often pH-dependent, and some drugs may be
more prone to hydrolysis under acidic or basic
conditions. By adjusting the pH of the
formulation to a more neutral or suitable range,
the rate of hydrolysis can be minimized.
3. Environmental Control during storage:
• Moisture Control: by Using desiccants (silica gel)
• Sealed packaging: packaged in air-tight containers
or blister packs that prevent moisture and air from
reaching the drug.
• Temperature and light control.
 2.Oxidation:
• Oxidation involves the removal of electrons from a
molecule.
• It is particularly important for drugs that contains
reactive groups such as alcohols , aldehydes or
unsaturated bonds.
• Many drugs are decomposed by oxidation e.g.
Morphine , Epinephrine Riboflavin , B12 ,
Prednisolone , Promethazine
• The reaction between the compounds and atmospheric
ox oxygen is called auto oxidation ,e.g. auto-oxidation
of unsaturated fats and oils which forms peroxides.
• The factors that promote oxidation are light ,
temperature , heavy metals, PH
 Protection against oxidation:
• Oxidation reactions are known to occur in presence of
oxygen, trace heavy metals, H+and (OH)-ions.
• Protective measures should aim at eliminating the
influence of these factors on the drug.
o Environmental control measures.
o The use of antioxidants and reducing agents
o Chelating agents.
1.Environmental control measures
1. Protection from light ; e.g. morphine sulfate
ampoules in amber container
2. Oxygen- free environment ;the oxygen in
pharmaceutical containers should be replaced
with nitrogen or carbon dioxide.
3. Low temperature storage.
2.Antioxidants and reducing agents
• They act by breaking the free radical chain
reactions at the step of chain propagation
• examples Tocopherols( vit E) , butylated hydroxy
anisole (BHA), butylated hydroxy toluene (BHT),
propyl gallate etc , these are oil-soluble
antioxidants used to stabilize oily preparations.
• Water-soluble antioxidants act by preferentially
undergoing oxidations instead of the drug itself.
Examples Ascorbic acid
• Compounds having -SH groups consume
molecular oxygen present in solution. Examples
are cysteine , acetylcysteine
• Addition reducing agents : They are more readily
oxidized than the drug and so protect it from
oxidation. e.g. sodium metabisulfite
3.Chelating agents:
• Addition of a chelating agent to a product well be
useful when traces of heavy metals catalyse the
oxidation.
• Substances such as EDTA (Ethylene Diamine
Tetra acetic acid) , citric acid and tartaric acid,
form complexes with heavy metals e.g.
prednisolone.
4.Isomerisation and Racimization :
• Isomerization is a chemical process that converts a
compound into its optical or geometric isomer. The
therapeutic activity of chemical compounds vary with their
isomeric forms, for example, the Levo (L) form of
adrenaline has 15–20 times greater effect than the Dextro
(D) form. Similarly, tetracycline, vitamin A, etc. also
undergo chemical conversion to form their isomeric forms
• Racemization is the conversion of the therapeutically
active form , into its less active isomer.
• Protective measures protect from heat light control pH