Pharmaceutical

Formulation and
Biopharmaceutics

Aniruddha Roy
Components of a dosage form

Pharmaceutical Excipients
 API (Active Pharmaceutical
Active PharmaceuticalIngredients)
Ingredients (API) (or) Drugs (meant for oral
administration) are classified into two types based on their
absorption:
• a) Non-absorbable drugs.
• b) Absorbable drugs.
a) Non-absorbable : The therapeutic action of non-absorbable
drugs (seen locally in GI tract, Eg: Antacids and adsorbents)
depends on the surface properties of the drug particles i.e.,
fine particle size and larger surface area.

b) Absorbable drugs : The therapeutic action of

absorbable drugs is seen systemically. Solubility of the
drug should be considered at or above the absorption
site (i.e., upper GIT or the intestinal tract).
The physical and chemical properties of the drugs must be
studied extensively before finalizing the formulation so
as to obtain better characteristics.
How Excipients May Impact
Absorption?
Release rate/amount of drug in
solution
• Altered disintegration time
• Altered dissolution rate
• Altered local pH
• Complexation (excipient-drug
complexes)
Transit and luminal volumes
• Faster gastric emptying
• Increased luminal volume (osmotic
effect)
• Altered small intestinal transit time

Altered effective permeability

Uptak
Activ

• Damage to intestinal surface/ tight

junction modulation
e

• Inhibition of efflux
• Inhibition or enhancement of active
uptake

Altered metabolism
• Inhibition of gut wall metabolism

*Area of
Impact
 Excipient
o An excipient is an inactive substance formulated alongside
the active ingredient of a medication.
o Formulation of API with excipients is primarily to ensure an
efficacious drug product with desired properties and a
robust manufacturing process.
o The resultant biological, chemical and physical
properties of the drug product are directly affected by
the excipients chosen, their concentration and interactions
with the API:
o Consistency of drug release and bioavailability
o Stability including protection from degradation
o Ease of administration to the target patient
population(s) by the intended route
o Excipients are sub-divided into various functional
classifications, depending on the role that they are intended
to play in the resultant formulation.
Ideal properties of excipient
• Chemically stable
• Non reactive
• Low equipment and process sensitive
• Inert to human body
• Acceptable organoleptic properties
• Economical
Excipients may be classified into the
following categories:

• Fillers and Diluents

• Binders
• Disintegrants
• Lubricant and Glidants
• Antiadherents
• Coatings
• Coloring Agents
• Preservatives
• Sorbents
• Sweeteners
• Solvents and co-solvents
 Diluents
• Diluents increase the volume of a formulation to
prepare tablets of the desired size. Widely used
fillers are lactose, dextrin, microcrystalline
cellulose, starch, pre-gelatinized starch, powdered
sucrose, and calcium phosphate.
• The diluent is selected based on various factors,
such as the experience of the manufacturer in the
preparation of other tablets, its cost, and
compatibility with other formulation ingredients.
For example, in the preparation of tablets or
capsules of tetracycline antibiotics, a calcium
salt should not be used as a diluent since
calcium interferes with absorption of the
antibiotics from the GI tract.
Classification :
Diluents

Chemical nature Solubility

Organic Inorganic materials Soluble Insoluble

materials
• Dextros • Calcium
• Calcium phosphate (II)
• Dextrose e phosphate (II)
• Calcium phosphate (III)
• Lactose • Lactose • Calcium
• Calcium sulphate
• Mannitol • Mannitol phosphate (III)
• Calcium carbonate
• Sorbitol • Sorbitol • Calcium sulphate
• Starch • Sucrose • Calcium
• Sucrose carbonate
 Lactose :
• most widely used diluent
• solubility – water soluble

Hydrous used in wet granulation

Forms
Anhydrou shows fast disintegration, good
s friability, practically no sticking,
binding and capping

• Lactose is an excellent choice of filler in many respects but can exhibit

poor flow characteristics, so is often combined with free-flowing
microcrystalline cellulose in wet granulation formulations.

Hydrous form undergoes maillard reaction discoloration of certain drugs

( amine drug )
 Binders
• Binders promote the adhesion of particles of the
formulation. Such adhesion enables preparation of granules
and maintains the integrity of the final tablet. Commonly
used binding agents include: starch, gelatin and sugars
(sucrose, glucose, dextrose, and lactose). Binders add
mechanical strength to the tablet or granules.

• Most commonly in wet granulation, the binder is added

already dissolved in the granulating fluid to enable a more
effective and controllable granule formation.

 Examples:
Dry binders: Microcrystalline cellulose, cross-
linked PVP
Solution binders: HPMC, PVP
Soluble in water/ethanol PVP
mix:
 Binders

Starch Cellulose
(1,4-alpha-glycosidic (1,4-beta-glycosidic
linkages) linkages)

Gellatin Polyethylene glycol (PEG)

Binders add mechanical strength to the

tablet or granules.
Starch Linear Cellulose
coil
 Disintegrants
• Added to a tablet formulation to facilitate its
breaking or disintegration when it contact in water
in the GIT.

• Example: Starch- 5-20% of tablet weight.

• Starch derivative – Primogel and Explotab (1-8%)
• Clays- Veegum HV, bentonite 10% level in colored tablet
only
• Cellulose
• Cellulose derivatives- Na- CMC (sodium carboxy methyl
cellulose)
• Alginate
• PVP (Polyvinylpyrrolidone), cross-linked
• Mode of action:
– In many cases water uptake alone will cause
disintegration, by rupturing the intra-particle
cohesive forces that hold the tablet together
and resulting in subsequent disintegration.
– If swelling occurs simultaneously with water
uptake, the channels for penetration are
widened by physical rupture and the
penetration rate of water into the dosage
form increased.
 Super-disintegrants
• Swells upto ten fold within 30 seconds when contact
water.

• Example: Croscarmellose- cross-linked cellulose, Crospovidone-

cross-linked povidone (polymer), Sodium starch glycolate- cross-
linked starch.

• A portion of disintegrant is added before granulation and a

portion before compression, which serve as glidants or
lubricant. Generation of carbon dioxide in effervescent
tablets is also one way of disintegration.

• Crosscarmellose Sodium-Hygroscopic excipients like

Sorbitol - Efficacy as disintegrant reduced.
 Lubricant and Glidants
• Lubricants are intended to prevent adhesion of the tablet
materials to the surface of dies and punches, reduce inter
particle friction and may improve the rate of flow of the
tablet granulation.
• Glidants are intended to promote flow of granules or powder
material by reducing the friction between the particles.
• Example: Lubricants- Stearic acid, Stearic acid salt - Stearic
acid, Magnesium stearate, Talc, PEG (Polyethylene glycols),
Surfactants
• Glidants- Corn Starch – 5-10% conc., Talc-5% conc., Silica
derivative - Colloidal silicas such as Cab-O-Sil, Syloid, Aerosil
in 0.25-3% conc.
Compression lubricants prevent adherence of granule/powder to
punch die/faces and promote smooth ejection from the die after
compaction:
– Magnesium stearate is by far the most extensively used
tableting lubricant
– Lubricants tend to be hydrophobic, so their levels (typically 0.3
– 2%) need to be optimised:
• Under-lubricated blends tend to flow poorly and show
compression sticking problems
• Over-lubricated blends can adversely affect tablet hardness
and dissolution rate
• Lubricants can also be used when compression isn’t
involved, e.g.
• In powder blends for filling into capsules to prevent
adherence of granule/powder to equipment surfaces and
dosator mechanisms
• Coating the surface of multi-particulate dosage forms
(including intermediate product) to inhibit agglomeration of
In general, there are four lubrication mechanisms:
hydrodynamic lubrication, elastohydrodynamic lubrication, mixed
lubrication, and boundary lubrication. In the pharmaceutical
industry, boundary lubrication is the most common mechanism
functioning in unit operations.

For boundary lubrication, a lubricant typically forms layers/film

between surfaces or at interfaces to reduce friction.
Structurally, the lubricants commonly used for boundary
lubrication are long chain molecules with active end-groups such
as stearic acid and its metallic salts. The typical end-groups
include: (1) –OH (long chain alcohol); (2) –NH2 (long chain amine);
(3) –COOH (long chain fatty acids); and (4) metal ions such as
Mg2+.

The molecules with these end-groups can be readily adsorbed on

the surfaces of metals or other particles to form an oriented
monolayer or multilayers. The layers formed prevent further
contact between the intended surfaces and powder particles. The
efficiency of a boundary lubricant is measured by the extent to
which these films can mask the field of force of the underlying
 Glidants
• Glidants promote flow of the tablet
granulation or powder materials by
reducing friction between particles.
• The commonly used glidants are talcum,
colloidal silica, silicates, stearates,
calcium phosphate etc.
• The effect of glidants on the flow of the
granules depends on the shape and size of
the particles of the glidants and the
granules
• As a general rule hydrophilic materials act
better on hydrophilic granules and
lipophilic ones on the lipophilic granules.
• The glidants in a particular formulation
ensure increasing flow of granules up to a
certain optimum concentration. If the
concentration of the glidant is taken
beyond this, a drag action may come into
operation bringing down the rate of flow.
Most commonly; colloidal silicon dioxide (traditionally,
talc was used)
• Good bulk powder flowability is especially important
during high speed processing
• Glidants improve flow by adhering to particles and so
reducing
inter-particulate friction
– Most common in dry powder formulations, e.g. direct
compression tablets
– Can also be added to granules to improve flow prior to
compression
– NB: can get undesirable “flooding” if flow is too good
• Very low levels required (ca. <0.2%)
– Control can be challenging with blends sensitive to levels
• Very low bulk density (0.03 – 0.04g/cm3)
– Difficult to work with (very voluminous) – not a standard
excipient, only added if needed
– Issues with dust exposure
Coating Agent:
Coating is a process by which an essentially dry, outer layer of
coating material is applied to the surface of a dosage form and
agents which are used in this coating process is called coating
agents.
Types:
Three types of coating agents are used pharmaceutically,
Film coating.
Sugar coating.
Compression coating.
Function of coating agents:
Protection, masking, elegance, ease of swallowing,
identification etc..
Examples:
HPMC, MC, HPC etc..
 Enteric Coatings

Free carboxylic acid

remains in polymer.
This is an acidic
functionality and is
Cellulose Acetate deprotonated
Phthalate (CAP) (ionized) at basic pH.
Tablets coated with enteric coatings will release
their contents in the small intestine, not the
stomach.
Such coatings are frequently used on products
that my irritate the stomach, such as aspirin.
A commonly used coating material is cellulose
Preservatives:
Preservatives are substances that commonly added to various
foods and pharmaceutical products in order to prolong their shelf
life.
Ideal properties of preservatives:
In concept, the preservative system protects the product against
microbial proliferation but does not compromise product
performance. In practice, this means that it must:
• Exert a wide spectrum of antimicrobial activity at low
inclusion levels.
• Maintain activity throughout product manufacture, shelf life
and usage.
• Not compromise the quality or performance of product, pack
or delivery system.
• Not adversely affect patient safety or tolerance of the product.

Examples:
Methyl & Ethyl parabens, Propyl paraben, Benzoic acid and its
 Ideally targeted for microbial cells - showing no
toxicity/irritancy towards mammalian cells
– Challenge is that the active groups involved are usually
harmful to all living tissue

 There are a limited number of approved

preservatives available for multi-use oral products,
and options are even more limited for other routes
of administration
– Should not use in parenteral infusions
– Must avoid access to cerebrospinal fluid and retro-ocular
administration

 This restricted number can be further reduced by

consideration of factors such as levels required
(dose), pH-solubility profiles, API & excipient
incompatibilities, adsorption, irritancy and toxicity.
MODE OF ACTION FOR PRESERVATIVES
Preservatives interfere with microbial growth,
multiplication, and metabolism through one or more of the
following mechanisms
1. Modification of cell membrane and leakage of cell
constituents (partial lysis)
2. Lysis and cytoplasmic leakage
3. Irreversible coagulation of cytoplasmic constituents
(protein precipitation)
4. Inhibition of cellular metabolism through interference with
enzymes systems or inhibition of cell synthesis
5. Oxidation of cellular constituents
6. Hydrolysis
Probable Modes Of Action Of Some
Preservatives

1. Benzoic acid, boric acid, p-hydroxybenzoates:

Denaturation of proteins

2. Phenols, chlorinated phenolic cmpds: lytic,

denaturation action on cytoplasmic membranes and for
chlorinated preservatives, also by oxidation of enzymes

3. Alcohols and Quaternary compounds: lytic and

denaturation action on membranes

4. Mercurials: Denaturation of enzymes by combining

with thiol (-SH) groups
Examples:
Benzoic acid (0.1 to 0.2%),
Sodium benzoate (0.1 to 0.2%),
Alcohol (15 to 20%),
Phenol (0.1 to 0.5%),
Cresol (0.1 to 0.5%),
Chlorobutanol (0.5%),
Benzalkonium Chloride (0.002 to 0.01%),
combination of methylparaben and
propylparaben (0.1 to 0.2%)
Antioxidant:
An antioxidant is a molecule that inhibits the oxidation of other
molecules. Oxidation is a chemical reaction that transfers electrons or
hydrogen from a substance to an oxidizing agent.
Ideal Properties of Antioxidants:
• Effective at a low, nontoxic concentration
• Stable and effective under normal conditions of use, over a wide pH
and temperature range
• Soluble at the required concentration
• Compatible with a wide variety of drugs and pharmaceutical
excipients
• Free from objectionable odor, objectionable taste
• Colorless in both the original and oxidized form
• Nontoxic both internally and externally at the required concentration
• Reasonable cost
• Unreactive (does not adsorb, penetrate, or interact) with containers
or closures
Examples:
BHT( Butylated Hydroxy Toluene), BHA( Butylated Hydroxy Anisol),
Sodium sulfite, Ascorbic acid etc..
 Antioxidants

Ascorbic acid Ascorbyl Palmitate

Butylated Alpha-tocopherol
hydroxyanisole
The phenolic antioxidants are frequently employed in smaller
amounts, together with a larger amount of an ascorbic acid
derivative, which serves to provide a hydrogen atom to the phenolic
radical, thus regenerating the antioxidant species.
Solvent
A solvent is a substance that can dissolve a solute (a
chemically different liquid , solid or gas) resulting in
solution. A solvent is usually a liquid but it can also be solid
or a gas. A solvent never changes its state forming a
solution.

Solvent classification

Solvents can be broadly classified into two groups ; They are

• Polar
• Non polar

Normally solvation of a solvent depends upon its

classification. Generally polar solvent dissolves polar
compound best and non polar solvent dissolves non polar
compound best.
Example and uses of solvent
• The first choice for a solvent is water in which a drug is
freely soluble.
• Oils are used as emulsion, intramuscular injections and
liquid fill oral preparation.
• Other acceptable non-aqueous solvents are
glycerol ,propylene glycol, ethanol are used generally for a
lipophilic drug.
Co-solvent
Co-solvents are defined as water-miscible organic
solvents that are used in liquid drug formulations to
increase the solubility of poorly water soluble substances
or to enhance the chemical stability of a drug.

Properties of co-solvent
• Co-solvent increases the solubility of a drug.
• An ideal co-solvent should possess values of dielectric
constant between 25 and 80.
• The most widely used system that will cover this range is
a water/ethanol blend.
• It should not cause toxicity or irritancy when
administrated for oral or parental use
• Other co-solvents are sorbitol, glycerol, propylene glycol.
Viscosity enhancing agents
●The viscosity of the formulation must be sufficiently
controlled in order to ensure the accurate measurement of
the volume to be dispensed.
●Increasing the viscosity may also increase the palatability
●The viscosity of solutions may be easily increased and
controlled by the addition of non-ionic or ionic hydrophilic
polymers.
E.g. ■ Non-ionic (neutral) polymers
– cellulose derivatives
Methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose
– polyvinylpyrrolidone
■ Ionic polymers
– sodium carboxymethylcellulose (anionic)
– sodium alginate (anionic).
Chelating agent
Chelating agents are molecules that are capable of forming
complexes with the drug involving more than one bond it’s a
complex compound contains one or more ring in its structure .
For example; ethylene diamine is bi-dentate and ethylene
diamine tetraacetic acid is hexa-dentate.

Example and uses of chelating agent

• EDTA: ethylene diamine tetraacetate is used for the chelation
of metals ions .
• EDTAH4: ethylene diamin tetraacetic acid is used for
softening water.
• Calcium Disodium Edetate: it is used in the treatment of heavy
metal poisoning mostly caused by lead.
Buffering agent
These are materials which, when dissolved in solvent will
enable the solution to resist any change in pH should an
acid or an alkali be added. The choice of suitable buffer
depends on the pH and buffering capacity required.

Features of buffering agent

It should have a low toxicity, it should be buffered at the
range of 7.4 as the pH of the body is 7.4, it should be
non-irritant.

Examples of buffering agent

Most of the buffering system are based on carbonate,
citrates, gluconates ,lactates, phosphates, or tartrates etc.
Viscosity imparting agents : These agents are used when it is
desirable to increase or decrease the viscosity of a liquid either to
serve as adjacent for palatability or to improve pour ability. They
are also called thickening agents.

Viscosity imparting agents are of two types:

a) Viscosity modifier-Viscosity modifiers decrease the viscosity of
a liquid to improve pour ability and make it more palatable.

b) Viscosity enhancer- Viscosity enhancers increase the viscosity

of a liquid to improve pour ability and make it more palatable.

Most commonly used viscosity imparting agents are :

Hydroxyethylcellulose
Hydroxypropylmethylcellulose
Methylcellulose
Polyvinyl alcohol
Polyvinylpyrrolidone
Humectant : A humectant attracts and retains the moisture in
the nearby air via absorption, drawing the water vapor into
and/or beneath the organism/object's surface.
Humectants absorb water vapors from atmosphere till a certain
degree of dilution is attained. Aqueous solutions of humectants
can reduce the rate of loss of moisture.

Ideal properties of humectants :

• It must absorb moisture from atmosphere and retain the same
under the normal conditions of atmospheric humidity.
• It should be colorless or not of too intense color.
• It should have good odor and taste.
• It should be nontoxic and nonirritant.
• It should be noncorrosive to packaging materials
• It should not solidify under normal conditions.
• It should not be too costly.
Classification of humectants with examples :
There are three types of humectants such as inorganic
humectants, metal organic humectants and organic
humectants.

Inorganic humectants:
These are limited used in cosmetics. Calcium chloride is an
example. It has compatibility problems and corrosive in
nature. Hence it is not frequently used in cosmetics.

Metal organic humectants:

These are limited used in cosmetics because of compatibility
problems, corrosive nature and pronounced taste. The
example of this class is sodium lactate.

Organic humectants:
These are widely used in cosmetics. They include polyhydric
alcohols, their esters and ethers. The most commonly used
organic humectants are glycerol, ethylene
glycol, polyethylene glycol (PEG), diethylene glycol, tri
ethylene glycol, propylene glycol, dipropylene glycol, glycerin,
Surfactants : Surfactants are compounds that lower
the surface tension (or interfacial tension) between two
liquids or between a liquid and a solid and increase the
solubility. They are also known as surface active agents.

Properties of surfactants : A surfactant must fulfill two

structural requirements:
a) A surfactant must contain a lipophilic region.
b) A surfactant must contain a hydrophilic region.

In a surfactant both hydrophilic and lipophilic region must

be balanced because then both the regions will be
concentrated at an interface and therefore surface tension
will be lowered.
Types of surfactants :
There are of four types of surfactants based on the charge of
the hydrophilic region :

1. Anionic surfactant ( here the hydrophilic region is

negatively charged i.e. an anion)
Sodium lauryl sulphate - It is used as an excipient on some
2. Cationic surfactant (here hydrophilic region is positively
charged i.e. a cation)

Cetyl trimethyl ammonium bromide ( cetrimide ) - is an

effective antiseptic agent against bacteria and fungi.

3. Non-ionic surfactants :

Tween 80 ( polyoxyethylene sorbitol monooleate)- Polysorbate

80 is an excipient that is used to stabilize aqueous
formulations of medications for parenteral administration
Span ( sorbitan ester of lauric acid )

4. Amphoteric surfactant :

Lecithin- it acts as a wetting, stabilizing agent and a choline

enrichment carrier, helps in emulsifications and encapsulation,
and is a good dispersing agent.
N-dodecyl alanine.
Sweetening agents:
Sweetening agents are employed in liquid formulations
designed for oral administration specifically to increase the
palatability of the therapeutic agent.

Example:
Sucrouse, Saccarine, Aspertame, Sorbitol etc.

Uses of sweetening agent:

The main sweetening agents employed in oral preparations are

sucrose, liquid glucose, glycerol, sorbitol, saccharin sodium
and aspartame. Aspartame is an artificial sweetening agent.
The use of artificial sweetening agents in formulations is
increasing . The use of sugars in oral formulations for children
and patients with diabetes mellitus is to be avoided.
Comparison of Sweetening agents

Sucrose Saccharin Aspartame

Source sugar chemical chemical synthesis;
cane; synthesis; phthalic methyl ester, dipeptide
sugar beet anhydride, of phenylalanine and
petroleum product aspartic acid
Relative 1 300 180-200
Sweetness
Bitterness none Moderate strong none
Aftertaste none moderate strong; none
sometimes
metallic or bitter
Calories 4/g 0 4/g
Acid good excellent fair
Stability
Heat good excellent poor
Stability
Sweetening Agents
Saccharin = metabolized and excreted by the kidneys virtually unchanged
Cyclamate = metabolised or processed in the digestive tract, and its
byproducts are excreted by the kidneys
Aspartame = breaks down in the body into three basic components: the
amino acids phenylalanine and aspartic acid, and
methanol
@ because of its metabolism to phenylalanine, the use of
aspartame by persons with phenylketonuria (PKU) is discouraged,
and diet foods and drinks must bear appropriate label warning.
@ saccharin and cyclamate were “generally recognized as safe” or
what is known as GRAS
Acesulfame = is more stable than aspartame at elevated temperatures; it
is used in candy, chewing gum, confectionery, and instant coffees
and teas
Stevia powder = Stevia rebaudiana bertoni. It is natural, nontoxic, safe,
and about 30 times as sweet as cane sugar, or sucrose
Flavoring agents:

Flavouring agents are added to increase patient

acceptance. The four basic taste sensations are
salty, sweet, bitter and sour. It has been proposed
that certain flavours should be used to mask these
specific taste sensations.

Example:
Clove oil, citric and syrup, glycerin, rose oil, orange
oil, menthol etc..
Flavor/Odor Correlations with Chemical
Structure
• Sour taste H+
• Saltiness Anions & cations
• Bitter High-MW salts
• Sweet Polyhydroxyl cmpds,
polyhalogenated cmpds,
alpha amino acids
• Sharp, biting Unsaturation
• Camphoraceous odor Tertiary “C” atom
• Pleasant odor Ketones
• Methylparaben Floral, gauze-pad
• Propyl/butyl paraben Numbing mouthfeel
 Flavoring Techniques
• Blending
– Fruit===========Sour
– Salty/Sweet/Sour===Bitter
– Salty===========Decreases sourness
– Salty===========Increases sweetness
 Flavoring Techniques (cont’d)
• Physical
– Formation of insoluble compounds
– Emulsification of oils
– Effervescence
– High-viscosity fluids
– Coating tablets
• Chemical
– Adsorption-silica gel
– Complexation
• Physiological
– Anesthetic effect====Menthol (mint)
Coloring agents:
Coloring agents are pharmaceutical ingredients that impart
the preferred color to the formulation.

There are two types of coloring agents

1.Natural and

2.synthetic

Example:
1.White: Titanium dioxide 2. Blue :Brilliant blue ,Indigo
carmine

3. Red :Amaranth Carmine 4.Yellow: saffron 5.Green 6.Brown:

caramel
 Physical interactions
Interaction Beneficial effect examples Detrimental effect examples
Complexation:- Cyclodextrin is often used to Tetracycline formed
Usually binds reversibly with improve bioavailability of insoluble complex with
drugs to form complex, poorly water soluble drugs. calcium carbonate leading to
sometimes insoluble This increases slower dissolution and
complexes are formed which bioavailability and increases decreased absorption.
lead to slower dissolution rate and extent of drug
and decreased absorption of dissolution by increasing Formulation of
drug. mucosal permeability or chlorpromazine with
increasing stability of drug. polysorbate 80 and sodium
Result observed in such cases lauryl sulphate decreased
is detrimental Complexation of membrane permeability of
Cyclodextrin with drug.
Complexing agents can also ursodeoxycholic acid
be used to increase increased bioavailability
bioavailability of poorly caused by increased
water soluble drugs dissolution.
Result observed in such case
is beneficial
Adsorption:- Formulation of Cetyl Pyridinium chloride
Adsorption of drug by Indomethacin cations get adsorbed on the
excipient can lead to (NSAID) using kaolin surface of magnesium stearate
reduced bioavailability as as adsorbent increased which acts as a lubricant in
the drug is not available its dissolution rate tablet containing Cetyl
for dissolution. which leads to increase Pyridini8um chloride. This leads
in bioavailability of to marked reduction in the
Adsorption of drug on drug. antibacterial activity of the drug.
excipient surface can assist
in increasing surface area Decrease in absorption of
of drug available for dicumarol in the formulations
dissolution which containing excipients like
eventually increases Aluminum hydroxide, Starch,
bioavailability. Talc, owing to the adsorbing
properties of excipients
Solid dispersion:- Improved dissolution Solid dispersion product
This kind of interactions rates of drugs like formed due to interaction
improves the dissolution and Piroxicam, Norfloxacin, between Povidone and
bioavailability of Nifedipine and Stearic acid in a capsule
hydrophobic drugs. Ibuprofen were observed showed slow dissolution of
when these drugs were drugs.
Sometimes solid dispersion formulated into solid
interactions can result in dispersions using
slow dissolution of drugs. Polyethylene glycol of
different molecular
weights.
 Chemical interactions
Interaction Effect observed Examples of drugs
undergoing such
interactions

Hydrolysis Drugs with functional groups like esters, amides, Anesthet ,

lactones, undergo hydrolysis, in presence of water, barbiturates,
low or high pH, in presence of alkaline metals, Antibiotics,
acids, acids i.e. anion and vitamins, and
hydrogen ion, alkali etc. barbiturates
Oxidation Oxidative reactions are catalyzed by oxygen, light, Steroids, Vitamins,
heavy metal ions, fumed metal oxides, fumed silica, Antibiotics,
fumed, zirconia etc. Epinephrine,
Oxidation process involves removal of an Aldehydes,
electropositive atom or electron or radical, or addition Alcohols, Phenols.
of oxygen atom, generally the interactions of the
active pharmaceutical ingredients are with oxidizing
impurities in excipients or oxidative degradation
products of excipients. ugs with substructures like
Benzilic carbons, Allylic carbons,
Tertiary carbons, and α position of heteroatoms
undergo oxidation.
Racemization Conversion of a chemical into its optical Adrenaline has optical 15-
or geometric isomer, having different 20 times greater biological
pharmacological or toxicological activity. activity then D –
(here optically active substance looses its Adrenaline.
optical activity without change in
chemical composition) .biological
activity of the formulations is hampered
as for e.g. biological effect of a drug in
dextro form can be less than that in levo
form.
Polymerization The polymorphic forms possess higher Amorphous forms of
potential energy with respect to the sodium and potassium
thermodynamically stable or lowest Penicillin-G were
energy forms. This potential energy is unstable to dry heat,
given out during mixing with the solvent, whereas crystalline forms
in some cases potential energy of were stable for several
compound is sufficient to exhibit an hours.
apparent solubility greater than more
stable form which may eventually
result into reversion of drug into less
soluble form
Maillard Carbonyl group of sugar reacts with Primary amines undergo
reactions amino acid, producing N- substituted maillard reactions, causes
Glycosylamine and water, unstable yellow brown coloration of
Glycosylamine undergoes amidroid drugs like chlorpromazine,
rearrangement forming ketosamine etc.
which reacts to produce water and Maillard reaction products
reductones or produce short chain found in capsule containing
hydrolytic fission products etc, rate of lactose and antidepressant
Maillard reactions increases as the water Fluoxetine.
activity increases.
Photolysis Decomposition resulting from Such interactions are
absorption of radiant energy in the form observed in Riboflavin,
of light. Folic acids, Nifedipine,
containing formulations.
Reactions like ring alterations,
oxidation- reduction, polymerization etc Prednisolone and Methyl-
are catalyzed or accelerated by exposure prednisolone degradation
to sunlight. Exposure to light is observed in alcoholic
may lead to discoloration or even preparations.
decomposition of product
 Excipient –Excipient Interactions
Excipients Incompatible with excipients like, Effect observed

Acacia Ethanol (95%) Ferric and Precipitate organic salts of Acacia

other salts Mucilage of acacia becomes gelatinous.
Trivalent salts initiate coagulation
Aqueous solutions (having negative charge) Form coacervates
react with gelatin.
Soaps in case of emulsions and suspensions.
Alcohol Acidic solution. Alkali React vigorously with oxidizing agents.
mixtures Darken color of preparation owing to reaction with
residual amount of aldehyde.
Bentonite Acids. Alcohol. Aqueous suspensions precipitated, acid washed
Cationic antimicrobial preservatives bentonite does not have suspending properties.
Precipitation of bentonite primarily due to
dehydration by lattic structure.
Antimicrobial efficacy reduced.
Oxidizing agents like Peroxides and Cause spontaneous combustion.
Butylated
Permanganates. Ion salts Discoloration with loss of activity.
Hydroxy
Acids Heating with catalytic amount of acids causes
Toluene
rapid decomposition with release of flammable gas
(BHT)
Isobutane
Crosscarmellose Hygroscopic excipients like Sorbitol Lower efficacy as disintegrant reduced.
Sodium
Gelatin Aldehyde. Gelatin film hardens resulting in hard gelatin
Cationic and anionic polymers. capsule shell. Viscosity is altered.
Isopropyl Hard paraffin Produces granular mixture.
Myristicate
 Excipient –container Interactions
Materials Interactions observed Effect observed
1) leaching of alkali Change in pH of the formulation
1) Glass 2) adsorption/absorption of Inactivation of formulation resulting in instability.
excipients:-
3) Glass containers possess oxides Alter physical and chemical stability of the formulation. E.g.:-
of l Boron, Sodium, Potassium, sulphate salts react with barium and calcium to form inorganic
Calcium, Iron and Magnesium insoluble salts.
which interact with formulation.
4) Oxidative reactions. Iron and Manganese oxide cations catalyze oxidative reactions, these
ions are extracted from glass and cause decomposition.
1. Moisture uptake associated with disintegrants in tablet form
2) Plastic 1) Moisture uptake micro- cracks due to disintegrant swelling.
2. Capsule becomes soft and sticky and undergoes chemical
reactions that affect dissolution behavior.
3. Change in the hardness of tablets is observed.
4. Strength change in lactose-corn starch tablets’ observed in strip
packaging.
5. Discoloration of sugar coated tablets of Ascorbic acid.
1) Water in oil type of emulsions have tendency to migrate and diffuse
2) Migration. into hydrophobic plastic containers.
2) Tocopherols may be absorbed into plastic.
1. Dyes migrate into parentrals and cause toxic effects.
3) Leaching. 2. Release of a constituent from plastic results in contamination.
3. Leaching of antioxidants from polyolefinic plastics into oleginious
containers anti-oxidants like Pentaerythrityl tetrakis (3, 5-di-tert-
butyl-4-hydroxyphenyl) propionate (Irganox) and tris (2, 4- di-
tert- butylphenyl) phosphate (Igrafos) showed release into oily
vehicles
4. which affects content quality.
4) sorption Preservatives are sorbed into the containers leading to the loss of
preservative activity.
 1) Tin tubes can be corroded by chlorides or acidic conditions.
3) metals 1) corrosion 2) Sodium lauryl suphates are mildly corrosive to steel,
copper, brass, bronze, and aluminium
2) reactivity Aluminium reacts with fatty alcohol emulsions to form a white
encrustation, unstable for mercury containing compounds.
Antimicrobial preservatives like phenyl mercuric acetate are
4) rubber 1) sorption known to partition into rubber during storage reducing
formulation concentration below effective antimicrobial levels
2 Water permeability Permeation of water through closures affects the overall
stability of formulation.
Presence of rubber closure extractives in the vial solutions
3) Leaching could affect toxicity pyrogeneticity of injectable preparations,
interaction with preservatives to cause inactivation or loss of
stability and causes physical instability of preparation.
1)Ethyl oleate dissolves certain types of rubber and causes
4) dissolution others to swell.
2)When Isopropyl myristicate comes in contact with rubber
there is drop in viscosity with concomitant swelling and
partial dissolution of the rubber.