FACTORS AFFECTING STABILITY OF

FORMULATIONS

Dr. Satish A. Patel

M. Pharm, Ph. D
S. K . Patel College of Pharmaceutical Education and Research
 INTRODUCTION
 Pharmaceutical stability is a critical quality attribute. Any
deviation from the established stability profile could affect the
 quality
 safety
 efficacy
 Stability testing is not done for only creating data for regulators,
but as an assurance to manufacturer itself on the quality of its
products.

 Structured, systemic, and documented stability testing based on

right principles can save manufacturers from lot of undue
hassels, faced when product is proved to be of inferior quality.
 Stability of Pharmaceutical Product is defined as Capacity of a
drug substance or drug product in a given packaging system to
remain within established specifications to maintain its Quality

(identity, strength, purity/impurity, potency) and deliver the

desired Performance throughout the retest or expiration period.

 It is also defined as capability of a particular formulation and

specific container to remain within its physical, chemical,
microbiological, therapeutic and toxicological specifications.

BUT…..
Developing global stability programs are challenging due to
climatic variations and differences in local regulatory requirements.
DRUG INSTABILITY COULD LEAD TO:

• Reduction of labeled quantity

• Sub-potent drug product
• Super-potent drug product
• Modification of Content uniformity
• Modification of Bioavailability
• Toxicity due to degradants
• Loss of container-closure integrity
• Loss of microbial integrity/sterility
• Loss of cosmetic aspects
• Loss of functional aspects (device)
OBJECTIVES OF STABILITY STUDY:

 To determine the shelf life , storage conditions, and labeling

specifications of products
 To select proper container- closure system and adequate
formulations for API
 To study how quality of drug substance or product varies with
the time under the influence of various factors
 To study possible degradation pathways and to get degradation
products
 To study changes introduced in the formulations due to
manufacturing process
 Development and validation of stability indicating analytical
methods
 To prevent great loss by recalling the batch due to instability
TYPES OF STABILITY STUDIES

1) Physical stability study

2) Chemical stability study

3) Microbiological stability study

CLASSIFICATION OF FACTORS AFFECTING STABILITY OF FORMULATIONS

1) Environmental factors 4) Chemical factors

• Light • Hydrolysis
• Oxygen • Dehydration
• Temperature • Isomerization and racemization
• Humidity • Ionic strength
• Decarboxylation
2) Physical factors • Oxidation
• Loss of volatile constituents • Photolysis
• Loss of water • Polymerization
• Absorption of water • Ultrasonic energy
• Color change • Ionizing radiation
• Crystal formation in pharmaceutical
preparations 5) Processing factors
• Blending
3) Factors affecting rate of • Milling
degradation • compression
• pH 6) Effect of Container-closure
• complexation
system
• surfactants
• presence of heavy metals 7) Microbial contamination
ENVIRONMENTAL
FACTORS
LIGHT: Responsible for the oxidation.
UV light is responsible for the photolysis
Remedy
 Use amber color bottle
 Appropriate secondary packaging material like cardboard

HUMIDITY: Higher humidity may lead to moisture adsorption.

• As relative humidity is increased stability is decreased
Specially for drugs which are highly sensitive to hydrolysis.

• Can affect the stability of pharmaceuticals by,

 Hydrolytic degradation
 Isomerization
 Crystallization
 Affecting flow and compaction properties etc
Remedy
 Maintenance of controlled humidity condition
 Moisture proof packaging.
OXYGEN: It enhance the oxidation degradation

Remedy : Air/oxygen replaced with inert gases such as nitrogen or

carbon- dioxide

TEMPERATURE: One of the primary factor affecting the drug stability. -

Study of decomposition of the product at elevated temperature
should be done to know the temperature dependency of reaction.
- It helps in predicting the stability of the product at ordinary shelf
temperature.
- It catalyses…….
 Hydrolysis
 Oxidation
 Thermal reaction follows just after initiation of photolytic reaction.
Remedy :
 stored within the temperature range in which they are stable.
 should not be exposed to extremes of temperature

HOWEVER, Sometimes……

 There are few drugs on which freezing has an adverse effect, so freezing
should be avoided unless until it is stable at such temperatures
PHYSICAL
FACTORS
LOSS OF VOLATILE CONSTITUENTS:

Agents such as iodine, camphor, menthol, ethyl alcohol, anesthetic ether,

chloroform have a tendency to evaporate from the product during storage.
Examples of products:
a. Aromatic waters
b. Elixirs
c. Spirits
d. Some types of tablets which contain aromatic water (Nitroglycerin
tablets).

Remedy

 Keeping the product in well-closed containers.

 Store in cool place.
 LOSS OF WATER

Loss of water (Vehicle) from the product decrease in weight

rises in conc. Of drug
increases potency.
Depends on temperature
humidity
Examples of dosage forms:
a. Saturated solution
b. Emulsions
c. Creams
d. Pastes
e. Ointments
Remedy
 Humectants e.g. Glycerin
 Preserving the product in well-closed container
 Store in a cool place.
ABSORPTION OF WATER : Increase weight of product, dilutes the dose
and decreases the potency.
Examples of dosage forms:
a. Powders
b. Suppositories
Remedy
 Store in well-closed containers.
COLOR CHANGE : Indicate some kind of chemical or photochemical
decomposition of the active ingredients, dyes or other
ingredients.
Remedy
 Protect the product from light and air.

CRYSTAL FORMATION IN PHARMACEUTICAL PREPARATIONS:

Causes:
a. Polymorphism phenomena: i.e. Chloramphenicol
b. Saturated solution
c. In suspension
CHEMICAL
FACTORS
HYDROLYSIS: means “splitting by water’’
Hydrolysis is often the main degradation pathway for drug substances
having …….. - ester
- amide
- lactam
- imides
- carbamates
as functional groups within their structure.
The rate of hydrolysis may vary depending on the pH of the solution

Examples: Procaine, Benzocaine, Aspirin, Atropine, Scopolamine, Meperidine

Chloramphenicol, Acetaminophine, Lincomycine etc.
Remedy
Solid drug formulations avoid contact with moisture such as packed in strip packs.
-Extra protection achieved by use of silica bags.
 In liquid drug formulation optimum pH should be selected.
 By changing the dielectric constant.
 By use of complexing agent. E.g. caffeine
-E.g. of drugs Benzocaine, Procaine
 By formulating in the form of Dry Powder.
-E.g. penicillin
DEHYDRATION:
 Sugars such as glucose and lactose are known to undergo dehydration to form
5-(hydroxymethyl) furfural.
 Erythromycin is susceptible to acid catalyzed dehydration
 Prostaglandins E1 and E2 undergo dehydration followed by isomerization.
 streptovitacin A exhibits two successive acid-catalyzed dehydration reactions.

ISOMERIZATION AND RACEMIZATION:

 Isomerization -Conversion of active drug into less active or inactive drug.

EX-Vitamin - A susceptible to isomerization in presence of light.
 Racemization- Conversion of optically active drug into its enantiomer.
Examples:
Pilocarpine ,Etoposide, Epinephrine, benzodiazepines, penicillins, Cephalosporins,
Oxazepam, Moxalactam etc.

Racemization of epinephrine
IONIC STRENGTH (PRIMARY SALT EFFECTS)

 Drug degradation involving reactions with or between ionic species, the rate is
affected by the presence of other ionic species such as salts like sodium
chloride.

DECARBOXYLATION AND ELIMINATION

 Drug substances having a carboxylic acid group are sometimes susceptible

to decarboxylation
 4-Aminosalicylic acid is a good example.
 Foscarnet also undergoes decarboxylation under strongly acidic
conditions.

Other examples are -etodolac

-Trimelamol
- Levothyroxine etc.
OXIDATION
 loss of electrons
 well-known chemical degradation pathway for pharmaceuticals
 The degradation may occur in both water- and oil- soluble drugs as well as in
volatile oils
 Two types of oxidation processes affect pharmaceuticals
• Those involving atmospheric oxygen, also referred to as autoxidation and
• Those involving the reversible loss of electrons.
 Oxidation mechanisms for drug substances depend on ……
- The chemical structure of the drug
- The presence of reactive oxygen species or other oxidants.
Catechols such as methyldopa and epinephrine are readily oxidized to quinones.
Other examples are 5-Aminosalicylic acid, Ethanolamines, thiols such as 6-
mercaptopurine etc.
Remedy

 Antioxidants
E.g. Sodium sulphite, Sodium metabisulphite,
Sodiumthiosulphite(water soluble), Tocopherol, Ascorbyl palmitate
(oil soluble)
 By use of Chelating agent e.g. EDTA
 Replacement of air from container by inert gases. E.g. nitrogen
PHOTOLYSIS:
 Means decomposition by light.
 Mechanisms are generally very complex.
 The shorter the wavelength the more potentially damaging is the light.
 Since the light energy may be converted to heat, photolysis may be
accompanied by a thermal reaction.
 Photolytic reactions include the decomposition of riboflavin and
chlorpromazine, the darkening of morphine and codeine, the fading of
tatrazine dye, sodium nitropruside etc.
Remedy
 suitable packing in amber colored bottles
 cardboard outers
 Aluminum foil over wraps.

IONIZING RADIATION
 Mainly gamma rays affect the drug molecule
 FACTORS AFFECTING
RATES OF DEGRADATION
PH:
 The acidity or the alkalinity of a solution has a profound influence on the
decomposition of drug compound.
e.g. Aspirin buffered solution is maximum stable at a pH of 2.4,
above a pH of 10 the decomposition rate rapidly increases.
 pH can also influence the rate of oxidation.

COMPLEXATION:
 Complex formation reduces the rate of hydrolysis and oxidation.
E.g. caffeine complexes with local anesthetics, such as benzocaine,
procaine and tetracaine to cause a reduction in their rate of
hydrolytic degradation.
 FACTORS AFFECTING RATES OF
DEGRADATION continue….
SURFACTANT:

 Nonionic, cationic and anionic surfactants when added to solutions containing

drugs form micelle and the drug particles become trapped in the micelle.

 The hydrolytic groups such as OH cannot penetrate this micelle cover and
reach the drug particles, hence hydrolysis rate is decreased.

PRESENCE OF HEAVY METALS:

 Heavy metals, such as….

copper, iron; cobalt and nickel
increase the rate of formation of free radicals and enhance oxidative
decomposition.
 MICROBIAL
CONTAMINATION
 Contamination from microorganisms is a big problem for all formulations
containing moisture
BUT…..

it can be a bother in solid dosage forms also if some natural polymers are
used because many natural polymers are fertile sources of microorganisms.

 Sources of Microbial Contamination:

1. Water
2. Air
3. Raw materials, containers and closures
4. Personnel
5. Instruments and apparatus
 Remedy
• Suitably designing the containers.
• Usually using single dose containers.
• Sticking to proper storage conditions.
• Adding antimicrobial substance as a preservative.
•e.g. Phenol
Cresol
Chlorocresol
Chlorhexidine acetate
Benzalkonium chloride
Benzoic acid
Methyl paraben
Alcohol
 PROCESSING FACTORS
BLENDING:-
 most important step for manufacturing of dosage form.
• High speed of mixing may introduce air into the product,
• slow mixing may not form a satisfactory product.

 Mixing might produce particle size reduction or polymorphic conversion

 During mixing some other factors like type of agitator, temperature or vaccum
etc. can affect the stability.

for example, if during mixing, vacuum is not applied than air bubble will present
into the product that might produce oxidation of product.

Ways for stabilization:-

 Use of optimum time and rate of mixing.
 Use of optimum and controlled temperature.
 Application of vacuum.
 Use of closed system
 PROCESSING FACTORS
continue….
FREEZE-DRYING PROCESS:
 Freeze-drying process also affects the stability of product
E.g.:-1) Freeze drying was found to have destructive effect on the ordered
structure of starch & this effect varied with respect to preparation
condition.
2) Surfactants & sugars possess synergistic effects on the lipoplex stability
during freeze drying.
MILLING:
 The formation of a high energy amorphous material is usually undesirable and
given the opportunity, will spontaneously transfer either to a crystalline hydrate
or anhydrate.
 These physical changes in the state of the drug substance can alter the
stability, dissolution characteristics and possibly even the bioavailability of the
drug.
Ways for stabilization:
- Use of moderate condition of milling.
- Optimum time of milling.
 PROCESSING FACTORS
continue….
40 min. (1%Form B)

16 min. 150 min.

Form A Form B Form C

30 min. (1% Form A)

The phase transformation of chloramphenicol palmitate associated with grinding

 PROCESSING FACTORS
continue….
EFFECT OF COMPRESSION:-
 It is generally assumed that overall amount of energy input into a formulation
during compression is not sufficient to induce a phase transformation and for
many substances this situation is certainly true.

BUT… There are numerous examples, for which changes in phase composition
do accompany a compression step.

 Carbamazepine is a drug which shows differences in the dissolution rates that

are associated with production of different polymorphs by tablet mfg process.
It has 3 different crystalline form – α, β and Dihydrate form.
Dihydrate - good compressibility but not stable
α - best stability but sticking
β - Best stability.

 The effects of compression on the solid-state Maillard reaction between

metoclopramide hydrochloride and lactose
 CONTAINER-
CLOSURE SYSTEM
The immediate container and closure are particularly important in affecting
product stability.
 Four types of containers commonly utilized for packing drug products.
- Glass
- Plastic
- Rubber (natural and synthetic)
- Metal

GLASS
 Problems:
a) Release of alkali
b) Release of Insoluble flake
 Remedy for prevention of release of alkali:-
 By decreasing soda content
 Siliconization of surface.
 By replacing sodium oxide with other oxides.
 Surface treatment by sulphur-di-oxide in presence of water-vapor & heat.
 Remedy for prevention of release of insoluble flake:-
 Flake formation can be prevented by using borosilicate glass.
 Pretreatment of the container with dilute acid.
PLASTIC
 high molecular weight polymers like polyethylene, polypropylene,
polystyrene, pvc etc
problems:
• Permeation of moisture
• Leaching
• adsorption or absorption
• Chemical/physical reaction of contents of containers with products.

Remedy
• Lining of the container with an epoxy resin
(Epoxy lining does not prevent sorption of phenyl mercuric nitrate).

METALS
Metals commonly used are tin, plastic coated tin, tin-coated lead, aluminum
and coated aluminum.
problems: Reactivity
1. Tin + chloride - errosion
2. Aluminum + fatty alcohol - white encrustation
Remedy
 Application of an epoxy lining to internal surfaces
RUBBER
problems: a) Sorption of API into rubber.
b) Extraction of one or more components of rubber into vial solution .
Leached extractive in the solution can cause:-
a. Interference with chemical analysis of drug.
b. Affects toxicity & pyrogenicity of injectables.
c. Can cause drug inactivation.
d. Can cause physical instability so, to prevent such intereferences.
Remedy

 Epoxy lining applied to rubber stoppers

 Use of Teflon – Coated rubber stoppers essentially prevents sorption and
leaching of the rubber stopper.
THE INSTABILITY POSSIBILITIES IN DIFFERENT FORMULATIONS
1. Oral solutions
Instability problems
1. Loss of flavour
2. Change in taste
3. Presence of off flavours due to interaction with plastic
bottle
4. Loss of dye
5. Precipitation
6. Discoloration
Effects
Change in smell or feel or taste
2. Parenteral solutions:
physical instability occurs due to:
- Interaction of the contents with the container.
- Changes in Chemical composition.
Instability problems
- Discoloration due to photo chemical reaction or oxidation.
Ex: thiamine hydrochloride
- Presence of precipitate due to interaction with container or stopper.
- Presence of “whiskers”
Effects
- Change in appearance and in bioavailability
3. Suspensions
This instability occurs due to:
a. Particle diameter
b. Concentration of resuspending agent
c. Viscosity of surrounded media
d. Temperature
e. pH
f. Presence of microbes
Instability problems
1. Settling
2. Caking
3. Crystal growth
Effects
Loss of drug content uniformity in different doses from the bottle and loss of
elegance.
4. Emulsions
This instability occurs due to:
a. Droplet diameter
b. Viscosity
c. Difference in Density
d. Temperature
e. pH
f. Presence of microbes
Instability problems
1. Creaming
2. Cracking
Effects
- Loss of drug content uniformity in different doses from the bottle and loss of
elegance
5. Semisolids (Ointments and suppositories)
Instability problems
1. Changes in:
a. Particle size
b. Polymorphic state, or hydration or
solvation state
c. Consistency
d. drug release rate
2. Caking or coalescence.
3. Bleeding
Effects
Loss of drug content uniformity, loss of elegance and change in drug release
rate.
6. Tablets
Instability problems Change in
a. Disintegration time
b. Dissolution profile
c. Hardness
d. Appearance
Effects
Change in drug release
7. Capsules
Instability problems Change in
a. Appearance
b. Dissolution
c. Strength
Effects
Change in drug release
 REFERENCE

http://rgmaisyah.files.wordpress.com/2009/02/stability_
of_drugs_and_dosage_forms.pdf

http://cst-kh.edu.ps/staff/mabujamee/wp-content/uploa
ds/2010/10/Unit-4-Drug-Stability.pdf

http://cst-kh.edu.ps/staff/mabujamee/wp-content/
uploads/2010/10/Unit-4-Drug-Stability.pdf