Formulation Additives

Formulation Additives
Drugs are rarely administered as pure chemical
substances alone and are almost always given as
formulated preparations or medicines. These can
vary from relatively simple solutions to complex
drug delivery systems through the use of
appropriate additives or excipients in the
formulations. The excipients provide varied and
specialized pharmaceutical functions. It is the
formulation additives that, among other things,
solubilize, suspend, thicken, preserve, emulsify,
modify dissolution, improve the compressibility
and flavour drug substances to form various
preparations or dosage forms.

Different Types of Formulations
Dosage Forms
Solid
Tablets
Capsules
Semi Solid
Cream
Suppositories
Liquid
Monophasic
Syrup
Solution
Biphasic
Emulsion
Suspension
Gas
Aerosols

Additives Used in Tablets
According to the USP, tablets are compressed solid dosage forms,
containing medicinal substances with or without suitable diluents.
In addition to the active or therapeutic ingredient, tablets contain a
number of inert materials. The latter are known as additives or
excipients. They may be classified according to the part they play in
the finished tablet. Different additives used in tablets are as follows:-
 Diluents
 Binders
 Lubricants
 Glidants
 Disintegrents
 Colouring Agents
 Flavouring Agents

Additives of Capsules
Capsules are solid dosage forms in which the drug substance is
enclosed in either a hard or soft, soluble container or shell of
gelatin or other suitable material. Gelatin capsules are made from
gelatin and other materials used either to enable capsule formation
or to improve their performance additives are as follows:-
 Coloring Agent
 Process Aids (Surfactants)
 Performance Aids (Flavoring agent)
 Preservative
 Protective Coating
Additives of powder filled capsules are:-
 Diluent
 Lubricant
 Glidants
 Wetting Agents

Additives of Semisolid Formulations
Ointments, creams, and gels are semisolid dosage forms intended
for topical application. They may be applied to the skin, placed on
the surface of the eye, or used nasally, vaginally, or rectally. Some
additives used in semisolid preparations are:-
Vehicles
Emulsifiers
Emollients
Permeation Enhancers
Preservatives

Additives of Monophasic Liquids
solutions are liquid preparations that contain one or more chemical
substances dissolved in a suitable solvent or mixture of mutually
miscible solvents. Additives used for solutions are:-
Vehicle
Buffers
Density Modifiers
Isotonicity Modifiers
Preservatives
Antioxidants
Sweetening Agents
Colouring and Flavouring Agents

Additives of Biphasic Liquids
Emulsion is a two-phase system prepared by
combining two immiscible liquids, in which
small globules of one liquid are dispersed uniformly throughout the
other liquid. Apart from solution additives following are used:-
 Emulsifiers
A coarse suspension is a dispersion of finely divided, insoluble solid
particles (the disperse phase) in a Fluid additives of Suspension
are:-
 Suspending agents
 Protective Colloids
Additives of Aerosols
Aerosols are system that depends on the power of
compressed or liquefied gas to expel the content from
the container. Additives mainly used in aerosol are:-
 Propellants

Antioxidants
Such materials, when added to a product, prevent the active from
degrading in the presence of oxygen or peroxides.
 Butylated Hydroxyanisole (BHA)
 Butylated Hydroxytoluene (BHT)
 Citric acid
 Sodium Metabisulfite
Three Types:
 True (Water Insoluble): BHA
 Reducing Agents (Water Soluble): Ascorbic Acid
 Synergist (Chelating Agent): EDTA
 BHA and BHT: Butylated hydroxyanisole is an antioxidant with
some antimicrobial properties. Butylated hydroxytoluene has
some antiviral activity. Butylated hydroxyanisole is frequently
used in combination with other antioxidants, particularly
butylated hydroxytoluene and alkyl gallates, and with
sequestrants or synergists such as citric acid.

USDA regulations require that the total content of antioxidant
shall not exceed 0.01% w/w (100 ppm) of anyone antioxidant or
0.02% w/w combined total of any antioxidant combination in
animal fats.
 Citric Acid: Citric acid monohydrate is used as a sequestering
agent and antioxidant synergist. Concentration of 0.3–2.0% is
used as sequestering agent
 Sodium Metabisulfite: Sodium metabisulfite is used as an
antioxidant in oral, parenteral, and topical pharmaceutical
formulations, at concentrations of 0.01–1.0% w/v. Primarily,
sodium metabisulfite is used in acidic preparations; for alkaline
preparations, sodium sulfite is usually preferred;

Binders and Adhesives
A binder (also sometimes called adhesive) is added to a drug-filler
mixture to ensure that granules and tablets can be formed with the
required mechanical strength. Binders can be added to a powder in
different ways:-
 As a solution which is used as agglomeration liquid during wet
agglomeration. The binder is here often referred to as a
solution binder.
 As a dry powder which is mixed with the other ingredients
before compaction (slugging or tabletting). The binder is here
often referred to as a dry binder.
 Alginic Acid, Sodium alginate, Carboxymethyl cellulose sodium
(CMC), Microcrystalline cellulose (MCC), Powdered cellulose,
Confectioner’s sugar, Dextrin, Dextrose, Ethylcellulose, Guar
gum, Hydroxypropyl cellulose (HPC), Hypromellose (HPMC),
Lactose, Maltodextrin, Methylcellulose, Povidone, Starch,
Tragacanth, Zein are examples of Binders.

 Starch Paste: Cornstarch is used widely as a binder. The
concentration may vary from 10% to 20%. It is usually prepared
as it is to be used, by dispersing cornstarch in sufficient cold
purified water to make a 5–10% w/w suspension and warming
in a water bath with continuous stirring until a translucent paste
forms. It has been observed that, during paste formation, not all
of the starch is hydrolyzed. Starch paste then is not only useful as
a binder, but also as a method to incorporate some disintegrant
inside the granules.
 Gelatin: Gelatin is used as a 10–20% solution; gelatin solutions
should be prepared freshly as needed and used while warm, or
they will solidify.
 Cellulosic Solutions: Various cellulosics have been used as
binders in solution form. Hydroxypropyl methylcellulose (HPMC)
has been used widely in this regard. Typically a number of
cellulosics, HPMC is more soluble in cold water than hot. Other
water-soluble cellulosics, such as hydroxyethylcellulose (HEC)
and hydroxypropylcellulose (HPC), have been used successfully
in solution as binders.

Ethylcellulose can be used effectively, when dissolved in alcohol
or as a dry binder that then is wetted with alcohol. It is used as a
binder for materials that are moisture-sensitive.
 Polyvinylpyrrolidone(PVP): PVP is a synthetic polymer and can
be used as an aqueous or alcoholic solution, and this versatility
has increased its popularity. Concentrations range from 2% and
vary considerably.
 Important examples of dry binders are microcrystalline cellulose
and crosslinked polyvinylpyrrolidone. Solution binders are
generally considered the most effective, and this is therefore the
most common way of incorporating a binder into granules.

Coating Agents
Similar to taste masking technology, the first coatings were
solutions of sucrose (12–20%). Once polymers were discovered
and understood, they were applied in low concentrations (1–3%)
using organic solvents. Current technology uses polymers
manufactured as latex or pseudo-latex dispersions to avoid the use
of organic solvents. Depending on the application, aesthetic or
functional coating, the use levels can range from 2 to 20% of the
weight of the material being coated.
 Carboxymethyl cellulose sodium (CMC), Carnauba Wax,
Cellulose acetate phthalate (CAP), Ethylcellulose, Gelatin,
Hydroxypropyl cellulose (HPC), Hypromellose (HPMC),
Maltodextrin, Methylcellulose, Starch, Sucrose, Zein
 Cellulose Acetate Phthalate (CAP): Cellulose acetate phthalate
(CAP) is used as an enteric film coating material, or as a matrix
binder for tablets and capsules. Such coatings resist prolonged
contact with the strongly acidic gastric fluid, but dissolve in the
mildly acidic or neutral intestinal environment. Concentrations
generally used are 0.5–9.0% of the core weight.

 Shellac: Shellac has been used in pharmaceutical formulations
for the enteric coating of tablets and beads, the material
usually being applied as a 35% w/v alcoholic solution
 Zein: Zein is used as a tablet binder in wet-granulation
processes or as a tablet-coating agent mainly as a replacement
for shellac. It is used primarily as an enteric-coating agent or in
extended release oral tablet formulations.

Colors and Pigments
The use of colourants in pharmaceutical dosage forms produces no
direct therapeutic benefits but colouring of pharmaceuticals is
extremely useful for product identification during manufacturing
and distribution. There are two basic types of coloring agents for
pharmaceutical products: dyes and lakes. Dyes are soluble forms of
a particular color. They go into solution and can result in very deep,
vibrant colors. Lakes are dyes that undergo a processing step that
adheres them onto insoluble substrates, such as aluminum or
calcium salts. Dyes are usually used in liquid products, whereas
lakes are used in chewable products and coating solutions for
tablets. The colourants that can be used to colour medicines are
governed by legislation, which varies from country to country

Frequently, the single dose of the active ingredient is small, and an
inert substance is added to increase the bulk to make the tablet a
practical size for compression. Ideal Properties of diluents are :-
 Chemically Inert
 Economic
 Non Hygroscopic
 Biocompatible
 Good Biopharmaceutical Property
 Acceptable Taste
 Examples of diluents Calcium carbonate, Calcium sulfate,
Microcrystalline cellulose (MCC), Powdered cellulose, Dextrates,
Dextrin, Dextrose, Kaolin, Lactose, Maltodextrin, Mannitol,
Starch, Sucrose
Diluents/Fillers

 Dibasic calcium phosphate and calcium sulfate have the
advantages of possessing low concentrations of unbound
moisture and having a low affinity for atmospheric moisture.
These are requires feature of excipient material to be combined
with a water. The bound water of calcium sulfate is not released
until a temperature of approximately 80°C is reached. Such
bound water is usually unavailable for chemical reactions.
 Lactose is the most common filler in tablets. It possesses a
series of good filler properties, e.g. dissolves readily in water,
has a pleasant taste, is non hygroscopic and fairly non-reactive
and shows good compactability. Its main limitation is that some
people have an intolerance to lactose.
Lactose exists in both crystalline and amorphous form.
Amorphous lactose dissolves more rapidly than crystalline and
shows better compactability. Its main use is therefore in the
production of tablets by direct compaction. The amorphous
lactose is, however, hygroscopic and physically unstable, i.e. it
will spontaneously crystallize if crystallization conditions are
met as a result of elevated temperature or high relative
humidity.

Anhydrous Lactose does not undergo Maillard reaction. Spray
dried lactose is one of several diluents now available for direct
compression following mixing with the active ingredient, and
possibly, a disintegrant and a lubricant. If this form of lactose is
allowed to dry out and the moisture content fails below the
usual 3% level, the material loses some of its direct
compressional characteristics. In addition to its direct
compression properties, spray dried lactose also has good flow
characteristics. It can usually be combined with as much as 20
to 25% of active ingredient without losing these advantageous
features.
 Starch: Starch which may come from corn, wheat or potatoes,
is occasionally used as a tablet diluent. The USP grade of starch,
however, has four flow and compression characteristics and
possesses a high typical moisture content of between 11 and
14%.
 Dextrose is also used as a tablet diluent. Dextrose is
sometimes combined in formulation to replace some of the
spray-dried lactose, which may reduce the tendency of the
resulting tablets to darken.

 Mannitol is perhaps the most expensive sugar used as a
tablet diluent, but because of its negative heat of solution, its
slow solubility, and its pleasant feeling in the mouth, it is
widely used in chewable tablets. It is relatively
nonhygroscopic and can be used in vitamin formulation, in
which moisture sensitivity may be a problem. Mannitol
formulations typically have poor flow characteristics and
usually require fairly high lubricant levels.
 Sucrose, or sugar, and various sucrose-based diluents are
employed in tablet making. Some manufacturers avoid their
use in products that would subject a diabetic to multiple gram
quantities of sugar. All have a tendency to pick up moisture
when exposed to elevated humidity.
 Microcrystalline cellulose, The flow properties of the
material are generally good, and the direct compression
characteristics are excellent. This is a somewhat unique
diluent in that while producing cohesive compacts, the
material also acts as a disintegrating agent. It is, however, a
relatively expensive material when used as a diluent in high
concentration and is thus typically combined with other
materials.

Disintegrants
A disintegrant is added to most tablet formulations to facilitate a
breakup or disintegration of the tablet when it contacts water in the
gastrointestinal tract. Disintegrents may function by drawing water
into the tablet, swelling, and causing the tablet to burst apart. Such
tablet fragmentation may be critical to the subsequent dissolution
of the drug and to the attainment of satisfactory drug
bioavailability.
 Alginic Acid, Sodium alginate, Microcrystalline cellulose (MCC),
Croscarmellose sodium, Crospovidone, Guar gum, Polyacrilin
Potassium, Sodium Starch Glycolate are examples of
disintegrants
 Starch USP and various starch derivatives are the most common
disintegrating agents. They also have the lowest cost. Starch is
typically used in a concentration range of 5 to 20% of tablet
weight Various pre gelatinized starches are also employed as
disintegrants, usually in a 5% concentration.

 Polyvinylpyrrolidone: Cross linked polymer that is available
as a disintegrant.
 Clays: Veegum HV and bentonite have been used as
disintegrants at about a 10% concentration.
 Super Disintegrant: Sodium Starch Glycolate, crospovidone,
croscarmellose and prolacrilin potassium

Emollients
These materials are usually used in conjunction with emulsifying
agents in the preparation of topical products. An emollient is
intended to impart a soft, supple feeling to the skin, helping the skin
to retain moisture and natural flexibility.
 Glycerin
 Glyceryl monostearate
 Isopropyl Myristate
 Petrolatum
 Polyethylene Glycols
 Glycerin: In topical pharmaceutical formulations and cosmetics,
glycerin is used primarily for its humectant and emollient
properties.
 Isopropyl myristate: It is a nongreasy emollient that is
absorbed readily by the skin. It is used as a component of
semisolid bases and as a solvent for many substances applied
topically.

Emulsifiers
An emulsifier functions and is operationally defined as a stabilizer
of the droplet form (globules) of the internal phase. On the basis of
their structure, emulsifiers (wetting agents or surfactan(s) may be
described as molecules comprising both hydrophilic (oleophobic)
and hydrophobic (oleophilic) portions. For this reason, this group
of compounds is frequently called amphiphilic (i.e., water- and oil-
loving).
 Surface Active Agents or Surfactants
 Hydrophilic Colloids
 Finely Divided Solids
o Reduction of Interfacial
Tension
o Interfacial Film Formation
o Electrical Repulsion

 Surfactants:
Anionic Surfactants: Sodium Oleate, Sodium Palmitate, Sodium
lauryl sulfate, Lauryl sarcosinate, Cetrimide
Cationic Surfactants: Benzalkonium Chloride, Tetradecyl
methyl amine
Nonionic Surfactants: Tridecanol, Polysorbate 20, tween 20,
Glycerol Trimer
Ampholytic Surfactants: Lecithin (P), Betain
 Hydrophilic Colloids:
 Natural: Acacia, Tragacanth, Karaya, Agar, Carrageenan,
Alginate
 Synthetic: Methyl-, hydroxyethyl-, hydroxypropyl ether,
Gelatin, carboxyvinyl Polymer

Flavors
Flavouring agents are incorporated into a formulation to give the
tablet a more pleasant taste or to mask an unpleasant one. The
latter can be achieved also by coating the tablet or the drug
particles. Flavouring agents are often thermolabile and so cannot
be added prior to an operation involving heat. They are often mixed
with the granules as an alcohol solution.
 A combination of flavoring agents is usually required to mask
these- taste sensations effectively. Menthol, chloroform, and
various salts frequently are used as flavor adjuncts. Menthol and
chloroform are sometimes referred to as desensitizing agents.
They impart a flavor and odor of their own to the product and
have a mild an esthetic effect on the sensory receptor organs
associated with taste.

Taste Sensation Recommended Flavor
Salt Butterscotch, maple, apricot, peach,
vanilla, wintergreen mint
Bitter
Wild cherry, walnut, chocolate, mint
combinations, passion fruit, mint spice,
anise
Sweet Fruit and berry, vanilla
Sour Citrus flavors, licorice, root beer,
raspberry

Glidants / Antiadherents
These products facilitate the movement of the powder or
granulation prior to compaction, compression, or encapsulation.
Some of these materials possess moisture scavenging capabilities
similar to desiccants. By facilitating flow of the material, there is
less weight variability of the dosage form, resulting in more
consistent dosing of the active ingredient(s). Additionally, by
controlling the amount of moisture available to interact with the
active ingredient(s) and other excipients, the product’s stability is
enhanced.
 Colloidal silicon dioxide
 Talc
 Colloidal silicon dioxide: small particle size and large specific
surface area give it desirable flow characteristics that are
exploited to improve the flow properties of dry powders in a
number of processes such as tableting.
 Materials used as glidants, or flow promoters, are typically talc
at a 5% concentration, corn starch at a 5 to 10% concentration,
or colloidal silicas such as Cab-O-Sil, Syloid, or Aerosil in 0.25 to
3% concentrations.

Humectants
These materials promote the retention of moisture. They are
necessary in some semi-solid products (creams and gels) to
prevent the dosage form from drying out. They also help prevent a
phenomenon known as cap-locking. Cap-locking involves liquid
products that recrystallized at the bottle-cap interface and makes
opening the bottle difficult after prolonged periods of non-use.
These materials are hygroscopic and should be stored in well
closed containers prior to use.
 Glycerin
 Propylene Glycol
 Sorbitol
 Triethanolamine
 Sorbitol: In liquid preparations sorbitol is used as a vehicle in
sugarfree formulations and as a stabilizer for drug, vitamin, and
antacid suspensions. In syrups it is effective in preventing
crystallization around the cap of bottles.

Lubricants
These materials facilitate compression/compaction of tablets and
consolidation of capsule plugs. Lubricants are used in small
quantities in the formulation. One could think of a particle of
lubricant as a deck of cards. When the deck is undisturbed, it has a
very small coverage area; however, when the individual cards are
randomly tossed on a table the coverage area is greatly increased.
That is how lubricants, like Magnesium, stearate function. Other
lubricants, such as Stearic acid, melt during
compaction/compression and exert their lubricant effects in that
manner. Many lubricants are hydrophobic—water repellent. If used
at too high a concentration or blended for too long, tablet hardness
and/or dissolution could be negatively affected.
 Calcium stearate, Glyceryl monostearate, Isopropyl Myristate,
Magnesium stearate, Polyvinyl Alcohol, Sodium Stearyl
Fumarate, Stearic Acid, Talc

 Calcium stearate is primarily used in pharmaceutical
formulations as a lubricant in tablet and capsule
manufacture at concentrations up to 1.0% w/w. Although
it has good antiadherent and lubricant properties,
calcium stearate has poor glidant properties.
 Magnesium stearate is primarily used as a lubricant in
capsule and tablet manufacture at concentrations
between 0.25% and 5.0% w/w.

Plasticizers
Plasticizers lower the glass transition temperature of polymers,
specifically polymers used for coatings. By lowering the glass
transition temperature, the polymers can partially melt, and the
droplets can coalesce to form a completely sealed coating on a
tablet or spheroid at a lower temperature, thus, preventing the
active from being exposed to elevated processing temperatures.
This affords better, more consistent release of the active.
 Glycerin
 Propylene Glycol
 Triacetin
 Triethanolamine
 Glycerin is used as a plasticizer of gelatin in the production
of soft-gelatin capsules and gelatin suppositories.
 Propylene glycol is commonly used as a plasticizer in
aqueous film-coating formulations.

Preservatives
If these materials prevent the initiation and growth of
microorganisms in products, they are known as bactericidal
preservatives. Some preservatives, either by concentration or
activity, may only maintain the bacteria level in the product at the
time of manufacture and are referred to as bacteriostatic
preservatives.
 Alcohol
 Benzalkonium chloride
 Boric acid
 Butylated Hydroxyanisole (BHA)
 Butylated Hydroxytoluene (BHT)
 Butylparaben
 Methylparaen
 Phenol
 Phenethyl Alcohol
 Potassium Sorbate

 In ophthalmic preparations, benzalkonium chloride is one of
the most widely used preservatives, at a concentration of 0.01–
0.02% w/v. Often it is used in combination with other
preservatives or excipients, particularly 0.1% w/v disodium
edetate, to enhance its antimicrobial activity against strains of
Pseudomonas. In nasal, and otic formulations a concentration of
0.002–0.02% w/v is used. Benzalkonium chloride 0.01% w/v is
also employed as a preservative in small-volume parenteral
products.
 As a group, the Parabens are effective over a wide pH range
and have a broad spectrum of antimicrobial activity, although
they are most effective against yeasts and molds. Owing to the
poor solubility of the parabens, paraben salts, particularly the
sodium salt, are frequently used in formulations. However, this
may raise the pH of poorly buffered formulations.
 Concentraion in oral suspensions is 0.006–0.05% and 0.02–
0.4% in topical preparations
 Methylparaben (0.18%) together with propylparaben (0.02%)
has been used for the preservation of various parenteral
pharmaceutical formulations

Surfactants
Surfactants function by decreasing the surface tension of a material,
coating agent, and a substrate, a tablet. By reducing the surface
tension, the coating can more uniformly cover the tablet surface,
resulting in a more aesthetically pleasing product. When used in
suspension, the surfactant facilitates the wetting of the drug
particle, facilitating its ability to go into solution.
 Polyethylene Glycols
 Polyoxyethylene Sorbitan Fatty Acid Esters
 Sodium Lauryl Sulfate
 Sorbitan Esters
 Sorbitan esters are widely used in cosmetics, food products,
and pharmaceutical formulations as lipophilic nonionic
surfactants. They are mainly used in pharmaceutical
formulations as emulsifying agents in the preparation of creams,
emulsions, and ointments for topical application. It is used in
concentration range of 1-15%.
 Sodium lauryl sulfate is an anionic surfactant employed in a
wide range of nonparenteral pharmaceutical formulations and
cosmetics. It is a detergent and wetting agent effective in both
alkaline and acidic conditions

Thickening Agent
Viscosifiers (thickening agents) are similar in function to
suspending agents; both impart thickness to liquid products. Some
viscosifiers go into solution, such as certain cellulose based
polymers, resulting in a Newtonian-type viscosity. Other materials
increase viscosity, while imparting a yield stress to the suspension.
This type of product is known as thixotrope.
 Acacia, Agar, Sodium alginate, Bentonite, Carbomer,
Carboxymethyl cellulose sodium (CMC), Guar gum,
Hydroxypropyl cellulose (HPC), Hypromellose (HPMC),
Methylcellulose, Pectin
 Acacia is mainly used in oral and topical pharmaceutical
formulations as a suspending and emulsifying agent, often in
combination with tragacanth.

Marketed Excipients Products
o Directly compressible starches Sta-Rx 1500 is one such free-
flowing, directly compressible starch; it may be used as a
diluent, binder, and/or disintegrating agent. Since it is self-
lubricating, it may be compressed alone upto 5 to 10% of drug.
Sta-Rx 1500 contains about 10% moisture and is reportedly
prone to softening when combined with excessive amounts
(more than 0.5%) of magnesium stearate.
o Two hydrolyzed starches are Emdex and Celutab, which are
basically 9O to 92% dextrose and about 3 to 5% maltose. They
are free-flowing and directly compressible. These materials may
be used in place of mannitol in chewable tablets because of their
sweetness and smooth feeling in mouth.
o Such modified Primogel and Explotab, which are low
substituted carboxymethyl starches, are used in lower
concentrations (1 to 8%, with 4% usually reported as
optimum).

o Dextrose is available from one supplier under the name
Cerelose and comes in two forms: as a hydrate, and in
anhydrous form for when low moisture contents are required.
o Sucrose-based diluents have such tradenames as Sugartab (90
to 93% sucrose plus 7 to 10% invert sugar), DiPac (97%
sucrose pIus 3% modified dextrins)and Nu Tab (95% sucrose
and 4% invert sugar with a small amount of corn starch and
magnesium stearate). All of these diluents are available for
direct compression, and some are also employed, with or
without mannitol, in chewable tablets.
o A new material known as Ac-Di-Sol is now available and is
effective in low concentration levels. It is an internally cross
linked form of sodium carboxymethylcellulose.
o Micro Crystalline Celluose: Avicel, is a direct compression
material. Two tablet grades exist: PH 101 (powder) and PH 102
(granules).

 Ludipress: Lactose monohydrate (93%), Kollidon 30 (3.5%) and
Kollidon CL (3.5%): Low Hygroscopicity, good flow property
 Cellactose 80: -Lactose monohydrate (75%) and cellluslose
powder (25%): Highly Compressible, low cost
 StarLac: -Lactose monohydrate (85%) and maize starch (15%):
Good flow, optimized disintegration
 Pharmatose DCL14: Anhydrous -Lactose(95%) and
lactitol(5%): High Compactibility, low lubricant sensitivity
 Avicel CE15: MCC and Guar Gum: less grittiness, imroved
palatibility
 Advantose FS 95: Fructose (95%) and Starch (5%): Excellent
flow, good compressibility
 Captisol: Modified Cyclodextrin
 Kollidon CL, CL-F, CL-M: Crosslinked water-insoluble polyvinyl
pyrrolidone
 Xylitab 100: Xylitol and polydextrose: Directly compressed
sugar
 Eudragit RL and RS: Methacrylic acid plymers
 Tablettose: Crystalline lactose monohydrate

The ideal excipients must be able to fulfill the important functions
i.e. dose, stability and release of API from the formulation. Although
considered pharmacologically inert, excipients can initiate,
propagate or participate in chemical or physical interactions with
drug compounds, which may compromise the effectiveness of a
medication.
Exicipients are not exquisitely pure. In common with virtually all
materials of minerals, synthetic, Excipients may have functional
groups that interact directly with active pharmaceutical
ingredients. Alternatively, they may contain impurities or residues,
or form degradation products in turn cause decomposition of the
drug substance.
Interactions classified simply as:
 physical,
 chemical, and
 physiological/biopharmaceutical
Interactions and Incompatibilities

 Physical interaction: it is the most common form, but due to a
lack of any chemical changes, it is challenging to detect.
Components retain chemical structure.
 Physical interactions are frequently used in manufacturing of
dosage form, for example to modify drug dissolution. However
many of the physical interactions are unintended which usually
causes the problems. Physical interaction can either be
beneficial or detrimental to product performance.
 The techniques usually adopted to detect such physical
interactions between drug excipient/excipient excipient involve
DSC, isothermal microcalorimetry, differential thermal analysis,
or by using thermogravimetric analysis, HPLC, or TLC.
 Chemical interactions: Chemical interaction involves chemical
reaction between drugs and excipients or drugs and impurities/
residues present in the excipients to form different molecules.
Chemical interactions are almost detrimental to the product
because they produce degradation products.

 One notable exception to the detrimental nature of most
chemical interactions is the beneficial interaction of the
effervescent couple whereby sodium bicarbonate reacts with an
organic acid, typically citric acid, in the presence of water to
generate carbon dioxide.
 All of these reactions can involve excipients, either as reactants
or as catalysts.
 For almost all chemical interactions, a key component is
presence of ‘‘free’’ (unbound) water.
 Physiological/Biopharmaceutical Interactions: By this we
mean interactions that occur after the medicine has been
administered to the patient. For the most part, they are physical
interactions. However, the major distinctions are that the
interaction is between the medicine (including excipients) and
the body fluids, primarily comprising aqueous solutions, and
that they have the potential to influence the rate of absorption
of the drug. They will vary depending on the route of
administration.
 Examples, Enteric Coating and Antacids, Tetracyclines, etc.

 Antioxidants:
◦ Iron salts cause discoloration with loss of activity in BHA and
BHT
◦ use with peroxides and permanganates; contact with oxidizing
agents may result in spontaneous combustion of BHT and BHA
◦ Citric Acid is potentially explosive in combination with metal
nitrates. On storage, sucrose may crystallize from syrups in the
presence of citric acid.
◦ Sodium metabisulfite reacts with sympathomimetics and other
drugs that are ortho- or para-hydroxybenzyl alcohol derivatives
to form sulfonic acid derivatives possessing little or no
pharmacological activity.
◦ In addition, sodium metabisulfite is incompatible with
chloramphenicol owing to a more complex reaction; it also
inactivates cisplatin in solution.
Examples

 Binders:
◦ Microbial Growth may result in natural binders
◦ Disintegration an Dissolution time may extend in wet
granulation of ethylcellulose as binder.
 Coating Agents:
◦ Cellulose acetate phthalate is incompatible with ferrous
sulfate, ferric chloride, silver nitrate, sodium citrate,
aluminum sulfate, calcium chloride, mercuric chloride,
barium nitrate, basic lead acetate, and strong oxidizing agents
such as strong alkalis and acids.
◦ Zein is incompatible with oxidizing agents.
◦ Shellac is chemically reactive with aqueous alkalis, organic
bases, alcohols, and agents that esterify hydroxyl groups.
◦ Shellac is effective sealant, but tablet disintegration and
dissolution time tend to lengthen on aging because of
polymerization of shellac.

 Diluents:
◦ In the presence of moisture, calcium salts may be incompatible
with amines, amino acids, peptides, and proteins, which may
form complexes.
◦ Lactose show Maillard reaction with amine containing
compounds; amino acids, aminophylline and amphetamines in
presence of metal stearate lubricants
◦ Lactose anhydrous is incompatible with strong oxidizers.
◦ In the presence of dilute or concentrated acids, sucrose is
hydrolyzed or inverted to dextrose and fructose (invert sugar).
◦ Microcrystalline cellulose is incompatible with strong oxidizing
agents.
◦ Calcium salts will interfere with the bioavailability of
tetracycline antibiotics.
◦ It is also anticipated that calcium sulfate would be
incompatible with indomethacin, aspirin, aspartame,
ampicillin, cephalexin, and erythromycin since these materials
are incompatible with other calcium salts.

 Emollients/Humectants:
◦ Glycerin may explode if mixed with strong oxidizing agents
such as chromium trioxide, potassium chlorate, or potassium
permanganate.
◦ Black discoloration of glycerin occurs in the presence of light,
or on contact with zinc oxide or basic bismuth nitrate.
◦ Isopropyl myristate is incompatible with hard paraffin,
producing a granular mixture. It is also incompatible with
strong oxidizing agents.
◦ Propylene glycol is incompatible with oxidizing reagents such
as potassium permanganate.
◦ Sorbitol will form water-soluble chelates with many divalent
and trivalent metal ions in strongly acidic and alkaline
conditions.
◦ Sorbitol increases the degradation rate of penicillins in
neutral and aqueous solutions.

 Glidants:
◦ Incompatible with diethylstilbestrol preparations.
 Lubricants:
◦ If lubricants used at too high a concentration or blended for
too long, tablet hardness and/or dissolution could be
negatively affected.
◦ Magnesium stearate cannot be used in products containing
aspirin, some vitamins, and most alkaloidal salts.
 Preservatives:
◦ Ethanol solutions are also incompatible with aluminum
containers and may interact with some drugs.
◦ Bezalkonium Chloride is incompatible with aluminum,
anionic surfactants, citrates, cotton, fluorescein, hydrogen
peroxide, hypromellose, iodides, kaolin, lanolin, nitrates,
nonionic surfactants in high concentration, permanganates,
protein, salicylates, silver salts, soaps, sulfonamides, tartrates,
zinc oxide, zinc sulfate, some rubber mixes, and some plastic
mixes.
◦ Butylparaben is discolored in the presence of iron and is
subject to hydrolysis by weak alkalis and strong acids.

◦ The antimicrobial activity of butylparaben is considerably
reduced in the presence of nonionic surfactants as a result
of micellization.
 Surfactants:
◦ Sodium lauryl sulfate reacts with cationic surfactants,
causing loss of activity even in concentrations too low to
cause precipitation.
◦ The antibacterial activity of certain antibiotics is reduced in
polyethylene glycol bases, particularly that of penicillin and
bacitracin.
 Thickening Agent:
◦ Acacia is incompatible with a number of substances
including amidopyrine, apomorphine, cresol, ethanol
(95%), ferric salts, morphine, phenol, physostigmine,
tannins, thymol, and vanillin.
◦ Xanthan gum and locust bean gum (carob gum or ceratonia)
in the presence of water creates a much more viscous gel
system than can be created using either component alone.

Formulation Additives

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