Praveen Kumar D
College of Pharmacy
Madras Medical college
M Pharmacy 1st year
❖ Excipients play an important role in formulating a dosage
form. These are ingredients which along with active
pharmaceutical ingredients make up the dosage forms.
Excipients act as protective agents, bulking agents and
can also be used to improve bioavailability of drug.
❖Excipients as like other active pharmaceutical ingredients
need to be stabilized and standardized .
➢ An excipient is an inactive substance formulated alongside the active
ingredient of a medication, for the purpose of bulking-up formulations
that contain potent active ingredients .
➢ The resultant biological, chemical and physical properties of the drug
product are directly affected by the excipient chosen, their
concentration and interaction with the active pharmaceutical
➢ Consistency of drug release and bioavailability.
➢ Stability including protection from degradation.
➢ Ease of administration to the target patient populations by the intended
IDEAL PROPERTIES OF EXCIPIENT
❑No interaction with drug
❑Stable for handling
❑EXCIPIENT ARE INACTIVE
INGREDIENTS USED AS CARRIER FOR
THE ACTIVE INGREDIENTS IN A
THESE MAY BE CLASSIFIED INTO THE
1. Anti adherents
DRUG EXCIPIENT INTERACTION
IN PHARMACEUTICAL DOSAGE FORMS THE ACTIVE
PHARMACEUTICAL INGREDIENTS ARE INTIMATE
CONTACT WITH THE EXCIPIENT WHICH ARE GREATER
QUANTITY EXCIPIENT AND DRUGS MAY HAVE CERTAIN
INCOMPATIBILITY WHICH LEAD TO DRUG EXCIPIENT
TYPES OF DRUG EXCIPIENT INTERACTIONS
4.Excipient — excipient interactions.
Physical interactions alter the rate of
dissolution, dosage uniformity, etc. Physical
interactions do not involve chemical
changes thus permitting the components in
the formulation to retain their molecular
structure. Physical interactions are difficult
INTERACTION BENEFICAL EFFECT EXAMPLES DETRIMENTAL EFFECT
Complexation :- Cyclodextrin is often used to improve Tetracycline formed insoluble
Usually binds bioavailability of poorly water soluble complex with calcium
reversibly with drugs drugs. This increases bioavailability and carbonate leading to slower
to form complex, increases rate and extent of drug dissolution and decreased
sometimes insoluble dissolution by increasing mucosal and decreased absorption.
complexes are permeability or increasing stability of
formed which lead drug.
to slower dissolution
2. CHEMICAL INTERACTIONS
Active pharmaceutical ingredients and excipients react with each other to form
INTERACTION FACT OBSERVED EXAMPLE OF DRUG UNDERGOING SUCH
Hydrolysis Drugs with functional groups like esters, Anesthetics , Antibiotics , Vitamins , and
amides, lactones, undergoes Barbiturates.
hydrolysis, in presence of water, low or
high pH, in presence of alkaline
metals, acids i.e. anion and hydrogen
ion, alkali etc.
Oxidation Oxidative reactions are catalyzed by Steroids Vitamins , Antibiotics , Epinephrine ,
oxygen , light , heavy metal ions, Aldehydes , Alcohols , Phenols.
fumed metal oxides , fumed silica ,
fumed , zirconia etc.
3. BIOPHARMACEUTICAL INTERACTIONS
These are the interaction observed
after administration of the
medication. Interaction within the
body is between medicine and body
fluids which influence the rate of
absorption. All excipient
physiological way when they are
administered along with active
1. PREMATURE BREAKDOWN OF ENTERIC COAT
The enteric coating polymers like cellulose acetate
phthalate and hydroxyl propyl cellulose acetate phthalate.
Are soluble more at basic pH , antacids raise pH of stomach
resulting in breakdown of the enteric coat in stomach and
release of active pharmaceutical ingredient in stomach itself ,
which result in degradation of drug in stomach . In case of
NSAID’ s premature breakdown of enteric coat many cause
side effects like gastric bleeding.
2. INCREASE IN GASTROINTINAL MOTILITY
Many of the excipients like sorbitol , xylitol have
tendency to increase the gastrointestinal motility thus
reducing the time available for absorption of drugs like
4. EXCIPIENT – EXCIPIENT INTERACTIONS.
Excipient – excipient interaction though
observed very rarely. These are prime importance
in determining the stability of the dosage forms
excipient – excipient interactions can be
undesirable as well as some interactions are used
in the formulations to get the desired product
KINETIC OF STABILITY
1.Definition of drug kinetics
2.Importance of studying kinetics
3.Rate and order of reaction
4.Factors affecting rate of reaction
5.Kinetics of drug degradation
7.Scope of stability testing
8.Advantage of stability testing
9.Types of stability
10.Stability testing methods
11.Guidelines for stability testing
12.Climatic zone for stability testing
13.Estimation of shelf life
❖ DRUG KINETICS
Defined as how drug change with time
i.e. study of rate of change.
Many drugs are not chemically stable
and the principle of chemical kinetics are
used to predict the time span for which a
drug will maintain its therapeutic
effectiveness or efficacy at a specified
IMPORTANCE OF STUDING KINETICS
➢Stability of drug / half life of drug defined as time
necessary for a drug to decay to its half or 50%
➢ Shelf life- defined as the time required for a drug to
decay to 90% of its original conc.
RATE AND ORDER OF REACTION
➢ The velocity with which a reaction or process occurs is called its rate.
➢ The cone. Of drug which influences the rate of reaction or process is called its order of
Consider the following chemical reaction
DRUG A DRUG B
➢ The rate of forward reaction is expressed by-
➢ As the reaction proceeds , the conc. Of drug B increases & rate of reaction can be
o If C is the conc. of drug A as it is changed to B can be described by expression as a
function of time t;
dC/dt = – KCn
K = rate constant
n = order of reaction
if , n = 0 (Zero order kinetics )
n = 1 (first order kinetics )
The two commonly encountered rate processes are:
1.ZERO ORDER REACTION
2.FIRST ORDER REACTION
ZERO ORDER REACTION
✓ Also called as constants rate process.
✓ The rate of reaction is independent of conc. i.e rate of reaction cannot be increased
further by increasing the conc. Of reactant.
dC/dt = – 𝐾0𝐶0 = – 𝐾 ………………… 𝑒𝑞𝑛1
Where, 𝐾0 = 𝑧𝑒𝑟𝑜 𝑜𝑟𝑑𝑒𝑟 𝑟𝑎𝑡𝑒 𝑐𝑜𝑛𝑠𝑡𝑎𝑛𝑡𝑠 (𝑖𝑛 mg/ min)
Rearranging 𝑒𝑞𝑛 1:
dC = – 𝐾0 dt ………………. 𝑒𝑞𝑛2
Integrating the 𝑒𝑞𝑛 2:
න 𝑑𝑐 = න −𝑘𝑜𝑑𝑡
C – 𝐶0 = – 𝐾0𝑡
𝐶0= conc. Of drug at t = 0
C = conc. Of drug yet to undergo reaction at time t
Slope = -𝐾0
dC/dt Type equation here. C
Time (t) Time (t)
Graph of zero order kinetics showing relationship b/w
Rate of reacting and conc. Of drug
FIRST OREDER REACTION
❖ These are the reaction whose rate is directly proportional to conc. Of the drug
undergoing i.e. greater the conc., faster the reaction.
❖ It follows linear kinetics.
dC/dt = – KC ……………………𝑒𝑞𝑛 3
Where, K = first order rate constant (per hour)
Rearranging the above 𝑒𝑞𝑛 3,
dC/C = – Kdt
Integrating the above𝑒𝑞𝑛 4,
𝐶 = −𝐾𝑑𝑡
In C- In 𝐶0= – Kt
In C = In 𝐶0- Kt
In terms of log.
Iog C = log 𝐶0 – Kt/2.303
Slope = – K/2.303
Graph of first order kinetics showing linear relationship b/w rate of reaction and concentration. of drug
Factors affecting rate of reaction
4.Phase & Surface Area
KINETIC OF DRUG DECOMPOSITION
The drug decomposition follows the degradation pathway-
❑Many pharmaceuticals ester or amide hydrolysis of an
ester hydrolysis in solution. E. g. anesthetics, antibiotics, vitamins, & barbiturates.
❑ The hydrolysis of an ester in acid & alcohol rupture of a covalent
linkage b/w Carbon & oxygen atom. e.g. Aspirin.
❑ The hydrolysis of amide gives acid & amine. E.g. barbiturates,
❖ Type of solvent (ethanol, mannitol)
❖ Reduction to salts.
❖The oxidative decomposition instability of
preparation such as steroids, vitamins, antibiotic &
❖Reaction mediated either by free radicals or by molecular
❖Autoxidation involves a free radical chain process.
AB A* + B
❖These radicals are highly unstable & readily take electrons
from other substances, causing oxidation
FUNCTIONAL GROUP SUSCEPTIBLE TO OXIDATION
Functional Group Drugs/Excipients
Carboxylic acids Fatty acids
Conjugated dienes Vitamin A
Ethers Diethyl ether
Nitrites Amyl nitrite
Phenols Catecholamine, Morphine
❑ Low oxygen content
✓Photolytic degradation exposure to UV or visible light in
the wavelength range of approx. 300-800 nm.
✓Photo degradation rates directly dependent on the
amount of incident radiation & on the amount of radiation that is
absorbed by the compound.
✓Alcoholic solutions of hydrocortisone, prednisolone, &
methylprednisolone degrade by
photolytic reactions following first – order kinetics.
❑An optically active substance loses its optical activity
without changing its chemical composition.
❑Dextro form generally therapeutically less active that Ievo
from. E.g. Ievo of adrenaline is 20 times active than dextro.
Stability : defined as capability of a particular formulation in
specific Container/closure system to remain within its physical,
1 chemical, microbiological, toxicological, protective and
It is the extent to which a product retains, within the specified
2 limits, throughout its period of storage and use, the same
properties and characteristics possessed at the time of its
SCOPE OF STABILITY TESTING
➢Provide as to how the quality of drug product
varies with time.
➢Establish shelf life of drug product.
➢Determine recommended storage conditions.
➢Determine container closure system suitability.
IMPORTANCE OF STABILITY TESTING
❖Assurance to patient that drug is safe.
❖Legal requirement to provide data.
❖To protect the reputation of the manufacture.
❖To provide a database.
❖To determine shelf life and storage conditions.
❖To verify that no changes have been introduced in
the formulation or manufacturing process that can
adversely affect the stability of the product.
TYPE OF STABILITY
o Each active ingredient retain its chemical integrity and labeled
potency within specified limits.
o Includes appearance, palatability, uniformity, dissolution and
suspend ability are retained.
o Sterility or resistance to microbial growth is retained according to
Therapeutic o Activity remains unchanged.
Toxicological o No significant increase in toxicity
STABILITY TESTING METHODS
1. REAL TIME STABILITY TESTING
2. ACCELERAYED STABILITY TESTING
3. RETAINED SAMPLE STABILITY TESTING
4. CYCLIC TEMPERATURE STRESS TESTING
1. REAL TIME STABILITY TESTING
❖Performed for longer duration of the test period in order to all
significant product degradation under recommended
❖Depends upon the stability of the product which should be
long enough to indicate clearly that no measurable
Stability of reference
Date collected at To distinguish
material include the
appropriate Instability from
stability of reagent as well
frequency day to day
as consistency of
2. ACCELERATED STABILITY TESTING
❖ A product is stressed at several high temp. & the amount of heat input
required to cause product failure is determined.
❖ This is done to subject the product to a condition that accelerates
❖ This information is then projected to predicted to predict shelf life or
used to compare the relative stability of alternative formulations.
Samples subjected to Assayed
The concept of accelerated stability testing is based upon the Arrhenius
In K = In A +
K = degradation rate/s,
A = frequency factor/s,
E = activation energy (kJ/mo1),
R = universal gas constant (0.00831 kJ/mo1),
T = absolute temperature (K)
3.RETAINED SAMPLE STABILITY TESTING
❑ Usual practice for every marketed product for which stability data
❑ Only one batch a year are selected.
❑ If the number of batches marketed exceeds 50, stability sample from two batches are
recommended to be taken.
❑ Stability testing by evaluation of market samples is a modified method which involves
taking samples already in the market place and evaluating stability attributes
4. CYCLIC TEMPERATURE STRESS TESTING
➢ Is not a routine testing method for marketed products
➢ In this method, cyclic temp. stress tests are designed on knowledge of the product so as
to mimic likely condition in market place storage.
➢The period of cycle mostly considered is 24 hours.
➢The min. and max. temp. for the cyclic stress testing is recommended to be selected on
a product by – product basis and considering factors like recommended storage temp.
for the product and specific chemical and physical degradation properties of the
➢The test should normally have 20 cycles.
GUIDELINE FOR STABILITY TESTING
ICH CODE GUIDELINE TITLE
QIA Stability testing of New Drug Substances and Products
QIB Stability testing : Photo stability testing of New Drug
Substances and Products
QIC Stability testing of New Dosage Form
QID Bracketing and Matrixing Designs for stability testing of drug
substances and Products
QIE Evaluation of stability data
QIF Stability data package for Registration Applications in
Climatic Zones III and IV
Q5C Stability testing of Biotechnological/Biological Products
CLIMATIC ZONES FOR STABILITY TESTING
Zone I Zone III Zone IV
(TEMPERATE) (HOT & DRY) (HOT & HUMID)
❖ United ❖ Japan, Southern
❖ Iraq, India. ❖ Iran, Egypt.
❖ Long term
Northern ❖ Long term testing
❖ Long term testing
Europe, condition- testing conditions-
❖ Long term
Test storage condition
Intended storage Study Storage condition Minimum time
condition Period covered
Room temperature Long term 25°∁ ± 2°∁/60%𝑅𝐻 ± 5% 𝑅𝐻 12 Months
Intermediate 30°∁ ± 2°∁/65%𝑅𝐻 %± 5% 𝑅𝐻 6 Months
Accelerated 40°∁ ± 2°∁/75%𝑅𝐻 ± 5% 𝑅𝐻 6 Months
Long 5°∁ ± 3°∁ 12 Months
Refrigerated Accelerated 25°∁ ± 2°∁ 60% 𝑅𝐻 ± 5% 𝑅𝐻 6 Months
Freezer Long -20°∁ ± 5°∁ 12 Months
ESTIMATION OF SHELF LIFE
➢The time period during which a drug product is expected to
remain within the approved shelf life specification, provide that it
is stored under the conditions.
➢The time period during which the drug maintain its 90% potency
or loss not more than 10 % potency.
➢The shelf life is determined from the data obtained from the data
obtained from the long term storage studies.
EXPIRATION OF DATA
➢ An expiration data is defined as the time up to which the product will
remain stable when stored under recommended storage conditions.
➢ Thus, an expiration data is the date beyond which it is predicted that the
product may no longer retain fitness for use.
➢ If the product is not stored in accordance with the manufacture’s
instructions, then the product many be expected to degrade more
THEORIES OF DISPERSION AND
1. Theories of Emulsification
2. Method of preparation of Emulsion
3. Instability of Emulsion
1. Method of preparation of Suspension
2. Preparation techniques for suspension
3. Stability of suspension
❖A thermodynamically unstable system consisting of at least 2
immiscible liquid phases, 1 of which is dispersed as globules in the
other liquid phase.
❖The dispersed liquid is known as the internal or discontinuous
❖Where as the dispersed medium is known as the external or
Theories of Emulsification:
❖ Many theories have been advances to account for the way or means by which the
emulsion is stabilized by the emulsifier.
1. Electric double layer Theory.
2. Phase Volume Theory.
3. Hydration Theory of Emulsions.
4. Oriented wedge theory.
5. Adsorbed Film and Interfacial tension Theory.
1. ELECTRIC DOUBLE LAYER THEORY
➢ Layer of oppositely charged ions forms a layer in the oil globules in
a pure oil and pure water emulsion carry a negative charged. The
water ionizes so that both hydrogen and hydroxyl ions are present.
➢ The negative charge on the oil may come from adsorption of the
➢ These adsorbed hydroxyl ions form a layer around the oil globules.
A second liquid outside the layer of negative ions
➢ The electric charge is factor is a factor in all emulsions, even those
stabilized with emulsifying agents.
2. PHASE VOLUME THEORY:
✓ If spheres of same diameter are packed as closely as possible,
one sphere will touch 12 others and the volume the spheres
occupy is about 74 per cent of the total volume.
✓ Thus if the spheres or drops of the dispersed phase remain rigid it is
possible to disperse 74 parts of the dispersed phase in the
continuous phases; but if the dispersed phase is increased to more
than 74 parts of the total volume, a reversal of the emulsion will
✓However, the dispersed phase does not remain rigid in shape but
the drops flatten out where they come in contact with each other,
nor are all the dispersed particles the same.
3. HYDRATION THEORY OF EMULSIONS:
➢ Fischer and hooker state that hydrated colloids make the best
➢Fischer states the emulsifying agent, by which a permanent
emulsion is obtained, ‘ proves to be a hydrophilic colloid when
water and oil emulsions are concerned.
➢Fischer and hooker have found albumin, casein, and gelatin to be
good emulsifying agents.
4. ORIENTED WEDGE THEORY:
▪ This theory deals with formation of monomolecular layers of emulsifying
agent curved around a droplet of the internal phase of the emulsion.
▪ In a system containing 2 immiscible liquids, emulsifying agent would be
preferentially soluble in one of the phases and would be embedded in
▪ Hence an emulsifying agent having a greater hydrophilic character will
promote o/w emulsion and vice – versa.
▪ Sodium Oleate is dispersed in water and not oil. It forms a film which is
wetted by water than by oil. This leads the film to curve so that it
encloses globules of oil in water.
5.ADSORBED FILM & INTERFACIAL TENSION THERORY:
✓ Lowering interfacial tension is one way to decrease the free surface
energy associated with the formation off droplets. Assuming the droplets
∆F = 6 𝜸 𝑽Τ𝑫
✓ V = volume of the dispersed phase in ml,
✓ D = Mean diameter of the particles.
✓ Y = Interfacial tension
✓ It is desirable that the surface tension should be reduced below
10daynes / cm by the emulsifier and it should be absorbed quickly.
METHODS OF PREPARATION OF EMULSION;
❖Commercially, emulsions are prepared in large volume mixing tanks
and refined and stability by passage through colloid mill or
Extemporaneous production is more concerned with small scale
1. dry Gum Method
2. wet Gum Method
3. Bottle Method
4. Beaker Method
5. In situ Soap Method
1. DRY GUM METHOD:
o Dry gum Method is used to prepare the initial or primary emulsion from
oil, water, and a hydrocolloid or “ gum “ type emulsifier.
o Dry Gum Methodology (4 parts oil, 2 parts water, and 1 part Emulsifier).
o Take mortar, 1 part gum is levigated with the 4 parts oil until the powers is
thoroughly wetted; then the 2 parts water are added all at once, and the
mixture is vigorously
triturated until the primary emulsion formed is cream white and
produces a “ cliking “ sound as it is triturated.
o Active ingredients, preservatives, colour, flavor’s are added as a solution to
the primary emulsion.
o When all agents have been incorporated, the emulsion should be transferred to
a calibrated vessel, brought to final volume with water.
2. Wet gum method
❑(Oil 4 parts + water 2 Parts + emulsifier 1 parts)
❑In this method, the proportions of oil, water and emulsifier are the
same (4:2;1), but the order and techniques of mixing are different.
❑The 1 part gum is triturated with 2 parts water to from a mucilage;
them the 4 parts oil is added slowly, in portions, while trituration.
❑After all the oil is added mixture is triturated for several minutes to
form the primary emulsion.
❑Then other ingredients may be added as in the continental method.
3. BOTTLE METHOD:
❖This method may be used to prepare emulsions of
volatile oils, Oleaginous substances of very low
❖This method is a variation of the dry gum method.
❖One part powdered acacia (or other gum ) is
placed in a dry bottle and four parts oil are added.
❖The bottle is capped and thoroughly shaken.
❖To this, the required volume of water is added all
at once, and the mixture is shaker thoroughly until
the primary emulsion forms.
4. BEAKER METHOD:
➢Dividing components into water soluble and oil soluble
➢All oil soluble components are dissolved in the oily phase
in one beaker and all water soluble components are
dissolved in the water in separate beaker.
➢Oleaginous components are melted and both phases are
heated to approximately 70°𝑪 over a water bath.
➢The internal phase is then added to the external phase with
stirring until the product reaches room temperature.
5. IN SITU SOAP METHOD:
✓Two types of Soap developed by this Methods:
✓1) Calcium soap: W/O types emulsions
✓E.g. Oleic acid + Lime water. Prepared by simple
mixing of equal volumes f Oil and Lime water.
✓Emulsifying agent used is Calcium salt of free
✓E. g. Olive oil + oleic acid (FAA)
INSTABILITY IN EMULSION:
Instability Factors Prevention
Flocculation: 1) Uniform globule size 1) Uniform sized globules.
Globules come closes each distribution. 2) Use same charged ionic
other to form aggregates. 2) Opposite charge on globule electrolytes.
surface. 3) Viscosity improving agents
3) Low viscosity of external hydrocolloids.
Creaming; 1. Globule size. 1.Homogenization uniformed
Concentration of globules at 2. Viscosity of external medium. size globules.
top/bottom of emulsion. 3. Differences in density of oil- 2. Thickening agents to.
water (aq >oil). improve viscosity
3. Reducing density differences
Coalescence: 1. Insufficient amount of E.A NO this is permanent change
Few globules fuse to form bigger 2. Altered portioning of E.A
globules emulsifier film is 3. Incompatibility between E.A
destroyed. 4. Phase volume ration > than
INSTABILITY FACTORS PREVENTION
Breaking: Unnoticed coalescence No this is permanents change
Complete separation of oil &
Phase inversion: 1. Change in chemical nature
Change in emulsion from o/w of E.A → Sodium sterate
to w/o or vice versa (water soluble) →o/w
Sodium sterate + CaC𝐼2 →
Calcium sterate (oil soluble) →
1. Altering phase: volume
o/w emulsion + oil → w/o
Emulsion should + water → o/w
this method should be properly
controlled other wise lead to
the phase inversion.
❖A pharmaceutical suspension is a coarse dispersion in which internal
phase is dispersed uniformly through the external phase.
METHOD OF PREPARATION OF SUSPENSION:
Suspension can be prepared by 2 methods:
❖ Precipitation methods:
Three main methods
❖Organic solvent precipitation
❖Precipitation effected by changing pH of the medium
• ORGANIC SOLVENT PRECIPITION:
Water insoluble drug
Dissolve in organic solvents
Add organic phase to eater
organic solvents include ethanol,
Methanol, propylene glycol and
❑Precipitation effected by changing pH of the
Application to those drugs in which solubility is dependent on pH value.
Concentrated solution in favorable pH
Pour to other system to change pH
On agitation precipitate will form
e.g. estradiol suspension.
➢ Two water soluble reagent forms a water
➢E g white Lotion NF
Zinc sulphate solution
Solution of sulphureted potash
Precipitate of zinc polysulphide
Vehicle is formulated
Solid phase is wetted and dispersed
Use of surfactant to ensure wetting of hydrophobic
PREPARATION TECHNIQUES OF SUSPENSION:
❖Small scale preparation of suspensions
❖Large scale preparation of suspensions
SMALL SCALE PREPARATION OF SUPENSION:
Grinding insoluble materials with vehicle containing the
Soluble ingredients are dissolved in same portion of the vehicle
Added to the smooth paste to step to get slurry.
Make up the dispersion to the final volume.
LARGE SCALE PREPARATION OF SUSPENSION:
➢ If suspension is made by dispersion process it is best to achieve
pulverization of solid by micronization technique or spray drying
➢ If suspension is made by controlled crystallization, a
supersaturated solution should be formed and then quickly cooled
with rapid stirring.
STABILITY OF SUSPENSION:
1) Small particle size:
Reduce the size of the dispersed particle increase the total
surface area of the solid. The greater the degree the subdivision of
given solid the larger the surface area.
The increase in surface in surface area means also an liquids
leading to an increase in viscosity of a system.
Another factor which negatively affects the stability and
usefulness of pharmaceutical suspension is fluctuation of temp
Temperature fluctuations lead caking of claying.
3. INCREASING THE VISCOSITY
❖Increasing the viscosity of the continuous phase can lead to the
stability of suspension this is so because the rate of sedimentation
can be reduce by increase in viscosity.
❖Viscosity increase is brought about by addition of thickening
agents to the external phase. In water these must be either soluble
❖It is important to note that the rate of release of drug from a
suspension is also dependent on viscosity of a product.
❖The more viscous the preparation, the slower Is likely to the
release of a sometimes this property may be desirable for depot