DRUG EXCIPIENT INTERACTION

INTRODUCTION
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.

EXCIPIENT
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 ingredients.
Consistency of drug release and bioavailability.
Stability including protection from degradation.
Ease of administration to the target patient populations by the intended route.

IDEAL PROPERTIES OF EXCIPIENT

 No interaction with drug

 Cost effective
 Pharmacological inert
 Stable for handling

EXCIPIENT ARE INACTIVE

Ingredients used as carrier for the active ingredients in a pharmaceutical product. These may be
classified into the following categories,

1. Anti adherents
2. Binders
3. Disintegrants
4. Preservatives
5. Sweeteners

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DRUG EXCIPIENT INTERACTION

In pharmaceutical dosage forms the active pharmaceutical ingrtedients are intimate contact with
the excipient which are greater quantity excipient and drugs may have certain incompatibility
which lead to drug excipient interaction.

TYPES OF DRUG EXCIPIENT INTERACTIONS

1) Physical interactions.
2) Chemical interactions.
3) Biopharmaceutical interactions.
4) Excipient - Excipient interactions.

1) PHYSICAL 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 to detect.

INTERACTION BENEFICAL EFFECT DETRIMENTAL EFFECT

Complexation :-
Usually binds reversibly with
drugs form complex,
sometimes insoluble
complexes are formed which
lead to slower dissolution and
decreased absorption drug.
EXAMPLES
Cyclodextrin is often used to
improve bioavailability of
poorly water soluble drugs.
This increases bioavailability
and increases rate and extent
of drug dissolution by
increasing mucosal
permeability or increasing
stability of drug.
EXAMPLES
Tetracycline formed insoluble
complex with calcium
carbonate leading to slower
dissolution and decreased and
decreased absorption.

2) CHEMICAL INTERACTIONS

Active pharmaceutical ingredients and excipients react with each other to form unstable
compounds.

INTERACTION FACT OBSERVED EXAMPLE OF DRUG

UNDERGOING SUCH
INTERACTIONS
Hdrolysis Drugs with functional groups like Anesthetics, Antibiotics,
esters, Anesthetics, Antibiotics, Vitamins, and Barbiturares.
Vitamins, and amides, lactones,

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 undergoes
hydrolysis, in presence of water, low
or high pH, in presence of alkaline
metals, acids i.e. anion and hydrogen
ion, alkali etc.
Oidation Oxidative reactions are catalyzed by Steroids Vitamins,
oxygen, light, heavy metal ions, fumed Antibiotics, Epinephrine
metal oxides, fumed silica, fumed, Aldehydes, Alcohols,
zirconia etc. Phenols.

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 pharmaceutical ingredients.
EXAMPLES;

 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.

 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
metoprolol.

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
attributes.

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 KINETIC OF STABILITY & STABILITY TESTING

CONTENTS
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
6) Stability testing
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
14) Expiration date

1) 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 temperature.

2) IMPORTANCE OF STUDING KINETICS

It determine:
Stability of drug / half life of drug defined as time necessary for a drug to decay to its half or
50% Conc.
Shelf life- defined as the time required for a drug to decay to 90% of its original conc.

3) 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 reaction.
Consider the following chemical reaction
DRUG A DRUG B

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The rate of forward reaction is expressed by-
-dA/dt
As the reaction proceeds, the conc. Of drug B increases & rate of reaction can be expressed by-
dB/dt
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
Where,
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:

a. ZERO ORDER REACTION
b. FIRST ORDER REACTION

a. 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 = - KoCo = - Ko
Where,
Ko = zero order rate constants (in mg/ min)
Rearranging equation;
dC = - Ko dt
Integrating equation;

c t
co
dc    kodt
o

Where,
Co= conc. Of drug at t = 0
C = conc. Of drug yet to undergo reaction at time t.

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b. 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
Where, K = first order rate constant (per hour)
Rearranging the above equation
dC/C = - Kdt
Integrating the above equation
c t
∫ dC/C=∫ =−kdt
co o
In C – In Co = -kt

4) FACTORS AFFECTING RATE OF REACTION

 Temperature
 Light
 Solvent
 Phase & Surface Area
 Catalysis
 Concentration

5) KINETIC OF DRUG DECOMPOSITION

The drug decomposition follows the degradation pathway
a. Hydrolysis
b. Oxidation
c. Photolysis
d. Racemization

a. HYDROLYSIS
Many pharmaceuticals Ester of amide Hydrolysis of an ester hydrolysis in solution.
E.g. Anesthetics, antibiotics, vitamins & barbiturates.
The hydrolysis of an ester acid & alcohol rupture of a covalent linkage b/w carbon
& oxygen atom. E.g. Aspirin.
The hydrolysis of amide acid & amine. E.g. barbiturates.
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 Prevention
pH
Type of solvent (ethanol, mannitol)
Reduction to salts.

b. OXIDATION
The oxidative decomposition Instability of Preparation such as steroids, vitamins, antibiotic
& Epinephrine.
Reaction mediated either by free radicals or by molecular Oxygen.
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

Aldehydes Paraldehyde
Amines Clozapine
Carboxylic acids Fatty acids
Conjugated dienes Vitamin A
Ethers Diethyl ether
Nitrites Amyl nitrite
Phenols Catecholamine, Morphine

Prevention:
Low oxygen content
Antioxidants
PH

c. PHOTOLYSIS
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.

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d. RACEMIZATION
An optically active substance loses its optical activity without changing its chemical
composition.
Dextro form generally therapeutically less active that levo from. E.g. levo of adrenaline is 20
times active than dextro.

6) STABILITY TESTING
Stability: defined as capability of a particular formulation in specific Container/closure system to
remain within its physical, chemical, microbiological, toxicological, protective and informal
specifications.
It is the extent to which a product retains, within the specified limits, throughout its period of
storage and use, the same properties and characteristics possessed at the time of its packaging.

7) 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.

8) 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.

9) TYPE OF STABILITY
Chemical - Each active ingredient retain its chemical integrity and labeled potency within
specified limits.
Physical - Includes appearance, palatability, uniformity, dissolution and suspend ability are
retained.
Microbiological - Sterility or resistance to microbial growth is retained according to specific
requirement.

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Therapeutic - Activity remains unchanged.
Toxicological - No significant increase in toxicity.

10) STABILITY TESTING METHODS

a. Real time stability testing
b. Accelerated stability testing
c. Retained sample stability testing
d. Cyclic temperature stress testing

a. REAL TIME STABILITY TESTING

Performed for longer duration of the test period in order to all significant product degradation
under recommended storage conditions.
Depends upon the stability of the product which should be long enough to indicate clearly that no
measurable degradation occurs.

b. 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 degradation.
This information is then projected to predicted to predict shelf life or used to compare the
relative stability of alternative formulations.
The concept of accelerated stability testing is based upon the Arrhenius equation
In K = In A + ΔE/RT
Where,
K = degradation rate/s,
A = frequency factor/s,
E = activation energy (kJ/mol),
R = universal gas constant (0.00831 kJ/mol),
T = absolute temperature (K)

c. RETAINED SAMPLE STABILITY TESTING

Usual practice for every marketed product for which stability data are required.
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.

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Stability testing by evaluation of market samples is a modified method which involves taking
samples already in the market place and evaluating stability attributes.

d. 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 products.
The test should normally have 20 cycles.

11) GUIDELINE FOR STABILITY TESTING

Q1A - Stability testing of New Drug Substances and Products (Second Revision)
Q1B - Stability testing : Photo stability testing of New Drug Substances and Products
Q1C - Stability testing of New Dosage Form
Q1D - Bracketing and Matrixing Designs for stability testing of drug substances and Products
Q1E - Evaluation of stability data
Q1F - Stability data package for Registration Applications in Climatic Zones III and IV
Q5C - Stability testing of Biotechnological/Biological Products

12) CLIMATIC ZONES FOR STABILITY TESTING

Zone I (TEMPERATE) – United Kingdom, Northern Europe, Russia, United states.
Long term testing conditions (21℃/45% RH).

Zone II (SUBTROPICAL & MEDITERRANEAN) – Japan, Southern Europe. Long term

conditions (25℃/60% RH).

Zone III (HOT & DRY) – Iraq, India. Long term testing conditions (30℃/35% RH).

Zone IV (HOT & HUMID) – Iran, Egypt. Long term testing conditions (30℃/65% RH).

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

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 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

13) 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.

14) 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 rapidly.

THEORIES OF DISPERSION AND PHARMACEUTICAL DISPERSION

CONTENTS
 Emulsion Definition
Theories of Emulsification
Method of preparation of Emulsion
Instability of Emulsion

 Suspension Definition
Method of preparation of Suspension
Preparation techniques for suspension
Stability of suspension

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EMULSION
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 phase.
Where as the dispersed medium is known as the external or continuous phase.

THEORIES OF EMULSIFICATION
Many theories have been advances to account for the way or means by which the emulsion is
stabilized by the emulsifier.
a) Electric double layer Theory.
b) Phase Volume Theory.
c) Hydration Theory of Emulsions.
d) Oriented wedge theory.
e) Adsorbed Film and Interfacial tension Theory.

a) 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 OH ions.
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.

b) 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 occur.
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.

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c) HYDRATION THEORY OF EMULSIONS
Fischer and hooker state that hydrated colloids make the best emulsifiers.
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.

d) 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.
EXAMPLE:
In a system containing 2 immiscible liquids, emulsifying agent would be preferentially soluble in
one of the phases and would be embedded in that phase.
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.

e) 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 spherical,
ΔF = 6 γ V/D
Where,
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 homogenizer.
Extemporaneous production is more concerned with small scale methods.

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METHODS
a. Dry Gum Method
b. Wet Gum Method
c. Bottle Method
d. Beaker Method
e. In situ Soap Method

a. DRY GUM METHOD

Dry gum Method is used to prepare the initial or primary emulsion from oil, water, and a
hydrocolloid or “gum” type emulsifier.
Dry Gum Methodology (4 parts oil, 2 parts water, and 1 part Emulsifier).
PROCEDURE:
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.
Active ingredients, preservatives, colour, flavor’s are added as a solution to the primary
emulsion.
When all agents have been incorporated, the emulsion should be transferred to a calibrated
vessel, brought to final volume with water.

b. WET GUM METHOD

Methodology
(Oil 4 parts + water 2 Parts + emulsifier 1 parts)
PROCEDURE:
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.

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c. BOTTLE METHOD
This method may be used to prepare emulsions of volatile oils, Oleaginous substances of very
low viscosities.
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.

d. BEAKER METHOD
Dividing components into water soluble and oil soluble components.
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.

e. IN SITU SOAP METHOD

Two types of soap developed by this methods.
Calcium soaps.
Soft soaps.
Calcium soap: W/O types emulsions.
E.g. Oleic acid + lime water. Prepared by simple mixing of equal volumes foil and lime water.
Emulsification agent used is calcium salt of free fatty acids.
E.g. Olive oil + oleic acid (FAA).

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SUSPENSION
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 for as,
 Precipitation methods
 Dispersion method

PREPARATION METHODS
Three main methods
a. Organic solvent precipitation
b. Precipitation effected by changing pH of the medium
c. Double decomposition

a. ORGANIC SOLVENT PRECIPITION

Water insoluble drug

Dissolve in organic solvents

Add organic phase to eater organic solvents include ethanol, Methanol, propylene glycol and
polyethylene glycol.

b. PRECIPITATION EFFECTED BY CHANGING PH OF THE MEDIUM

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.

c. DOUBLE DECOMPOSITION
Two water soluble reagent forms a water Insoluble product.

Eg. white Lotion NF

Zinc sulphate solution

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 Solution of sulphureted potash

Precipitate of zinc polysulphide

DISPERSION METHOD
Vehicle is formulated

Solid phase is wetted and dispersed

Use of surfactant to ensure wetting of hydrophobic solids

PREPARATION TECHNIQUES OF SUSPENSION

a. Small scale preparation of suspensions
b. Large scale preparation of suspensions

a. SMALL SCALE PREPARATION OF SUPENSION

Grinding insoluble materials with vehicle containing the wetting agent.

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.

b. 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
a. 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.

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The increase in surface in surface area means also an liquids leading to an increase in viscosity
of a system.
b. Temperature
Another factor which negatively affects the stability and usefulness of pharmaceutical suspension
is fluctuation of temp Temperature fluctuations lead caking of claying.
c. 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 or swell.
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 preparations.

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