Unit III

Pharmaceutical Product Development

Dr Iti Chauhan
Professor
I.T.S College of Pharmacy
 Content
An advanced study of Pharmaceutical Excipients in pharmaceutical
product development with a special reference to the following categories:

Tablet and capsule excipients.

Directly compressible vehicles.
Coat materials.
Excipients in parenteral and aerosols products.
Excipients for formulation of NDDS.
 Tablet excipients
• Excipients are added to improve one or more of the three key functional properties of a dosage form:
(1) Bioavailability,
(2) Manufacturability,
(3) Stability,
(4) Patient acceptability
(5) Assist in product identification

• Excipients facilitate optimum bioavailability, the rate and extent of drug absorption from the dosage form, by
providing reproducible and optimum rate, extent, and site of drug release.

• Excipients facilitate manufacturability by converting the API powder into a powder blend that flows,
compresses, and can be manufactured on high-speed equipment.

• Excipients facilitate the stability of the API for the duration of time a product may be stored between the
manufacture and the consumption (called shelf life).
1. Diluents (bulking agent)- Diluents are fillers used to make required bulk of
the tablet when the drug dosage itself is inadequate to produce the bulk.
In addition, enabling the manufacturability of powder blends on high-speed
equipment requires adequate properties such as cohesion, flow and
compressibility, which are improved by the addition of diluents.
• Microcrystalline cellulose-Avicel (PH 101and PH 102),
• Lactose (spray dried/anhydrous),
• Mannitol,
• Sorbitol,
• Dicalcium phosphate,
• Calcium and magnesium salts ,
• Directly compressed starch-Sta Rx 1500
• Sucrose- Sugartab, DiPac, Nutab
2. Granulating fluid: Granulating fluids are liquids that are used
for wet granulation.
e.g. water, ethanol, or isopropanol—or the solution of a
hydrophilic polymer (binder) in one of these liquids.
The addition of granulating fluid while mixing a powder blend of
the API with excipients promotes the surface adhesion of particles.
3.Binders (Compression aids): These materials are added either in dry or wet form to
create granules or to form cohesive compacts for directly compressed tablets.
Hydrophilic polymers are added in either dry or liquid (solution in water) form to
promote the transformation of primary powder particles into cohesive agglomerates
(granules) during wet granulation or to promote cohesive compacts during direct
compression.
e.g. Cellulose derivatives such as hydroxypropyl cellulose (HPC), HPMC, MC
polyvinylpyrrolidone (PVP), and starch
Natural gums: Acacia, tragacanth
Gelatin-10-20%solution
Glucose- 50% solution
Ethylcellulose 5% solution (insoluble in water but dissolved in alcohol or as dry binder),
is widely used as a binder for moisture-sensitive materials.
4.Disintegrants: added to the tablets to facilitate the breakup or disintegration when
tablets come in contact with aqueous fluids in the GI tract. Disintegrants act by
(a) swelling in the presence of water and bursting tablet and granule open
(b) capillary action to promote rapid ingress of water into the centre of the tablet or
capsule
e.g. Starch (Potato maize & corn starch) & its derivative (sodium starch glycollate)
Cross-linked PVP,
Croscarmellose sodium (CCS),
Cellulose and its derivatives (MCC, Sod CMC and Croscaramelose)
Clays (Veegum, bentonite)
Alginates
Cation exchange resins
• Super-disintegrants- they can swell dramatically upon exposure
to water and thus quickly and effectively break the tablet.
• They are included in the formulation at relatively low
concentration 1-5% by weight.

• E.g. Croscarmellose sodium – Primellose®

• Crospovidone
• Sodium starch glycolate – Primojel®
5. Glidants: They are added to tablet formulations to improve the flow
properties of the granulations during transfer operations, such as from the
hopper to the roller compactor or tablet press. They improve flow by
reducing interparticulate friction.
• e.g. colloidal silica, starch, talc

6. Lubricants (antiadherent): Prevent adherence of the tablet material to

the stainless steel processing equipment surfaces under compression forces.
• They promote flow, reduce interparticle friction, and facilitate the smooth
ejection of compressed tablets from the die cavity.
• e.g. magnesium stearate, calcium stearate, stearic acid, sodium stearyl
fumarate, PEG
7. Tablet Coatings and Films: Protect tablet from the environment
(air, moisture, light); increases the mechanical strength, masks taste
and odour, aids swallowing, assists in product identification, can be
used to modify drug release, may contain flavouring and colourings.
• e.g. sugar, polymers

8. Co-processed Excipients: Coprocessed excipients are blends of

two or more individual excipients, which are processed together to
create a synergistic combination with improved functionality and
performance compared to their individual components.
Coprocessed excipients can improve the flow properties of powders during manufacturing
processes such as mixing, granulation, and tabletting; exhibit better compressibility, enhance
stability, improve organoleptic limitations, Enhance palatability and increased tongue feel.
9. Colouring agent: to impart a visual characteristic
• Reasons to colour a tablet- Identification, Flavour perception, to
increase aesthetics, to reduce the risk of counterfeiting.
• Pharmaceutical colourants can be classified as water-soluble
dyes or water-insoluble pigments, lakes – FD & C dyes, D & C
dyes
• e.g. Titanium dioxide, Ferric ferrocyanide, indigo carmine,
tartrazine, erythrosine, and brilliant blue
Miscellaneous excipients
 Capsule Excipients

The powder formulations for encapsulation into hard gelatin capsules require
careful consideration of the filling process requirements, such as lubricity,
compactibility, and flow.

Additives present in capsule formulations, such as the amount and choice of

fillers, lubricant, disintegrant, and surfactant, and the degree of plug compaction,
can influence drug release from the capsule.

The functional categories of formulation components are as follows:

1. Fillers (or diluents): The active ingredient is mixed with a sufficient volume
of a diluent, usually microcrystalline cellulose, lactose, mannitol, starch, or
dicalcium phosphate, to increase the bulk of the formulation.
Diluent is also chosen for its plug-forming properties.
2. Glidants:Glidants are finely divided dry powders added to the formulation in
small quantities to improve their flow rate from the hopper and into the body of
the capsule during the filling process.
Glidants, such as colloidal silicon dioxide, powdered silica gel, starch, talc,
improve flow by
• Reducing the roughness by filling surface irregularities.
• Reducing attractive forces.
• Reducing electrostatic repulsion.

The optimal concentration of the glidant used to improve the flow of a powder
mixture is generally less than 1% w/w.
3. Lubricants: Capsule formulations usually require a lubricant to reduce
powder adhesion to the machine parts, especially during plug formation.
Lubricants ease the ejection of plugs by reducing the adhesion of powder
to metal surfaces and friction between the sliding surfaces in contact with
the powder.
Common lubricants for capsule formulations are hydrophobic stearates,
such as magnesium stearate, calcium stearate, and stearic acid.

4. Surfactants and wetting agents: Surfactants may be included in capsule

formulations of poorly water-soluble drugs to reduce the contact angle, increase the
wettability of drug particles, and enhance drug dissolution.
e.g. sodium lauryl sulfate and sodium dioctyl sulfosuccinate.
In addition, a hydrophilic polymer, such as HPMC, is sometimes used as a wetting
agent in the formulations of poorly soluble drugs. The powder wettability and
dissolution rate of several drugs, such as hexobarbital and phenytoin, were enhanced
with the inclusion of methyl-cellulose or hydroxyethylcellulose in their capsule
formulations. Wetting agents improve water penetration.

5. Disintegrants: A disintegrant is included to aid rapid disintegration and

dissolution of the contents. Disrupts powder mass.
Common disintegrants used in hard gelatin capsule formulations include
croscarmellose sodium, crospovidone (act as wicks, attracting water into the plug)
and sodium starch glycolate (swell manyfold on absorbing water)
6. Absorbents: These are generally insoluble materials or material blends
used to recover liquids by soaking up through the process of adsorption or
absorption.
• Sorbents are used in the solid dosage form to soak oils, uniformly
distribute liquid colours, or increase the cohesiveness of the mass without
making the mixture soggy.
• They are used for capsules or tablets to limit fluid sorbing and make them
moisture-proof. The sorbents hold the excess moisture present in the
formulation and decrease the chances of hydrolysis and microbial attack.
• e.g.- Polyolefins such as polypropylene and polyethylene; Natural carbon-
containing materials .
7. Capsule Shell Material- Form the capsule body to fill the required
material. Gelatin A (acid-processed) and B (alkali- processed), HPMC,
Pullulan

8. Plasticizers- imparts softness, and elasticity hardness to capsule shell.

e.g. glycerin, sorbitol, and polyethylene glycol (PEG).
• Plasticizers are selected based on their compatibility with the fill
formulation, their ease of processing and the desired properties
9. Opacifiers- provide opacity or translucency to the capsule shell. These
opacifiers serve several purposes, including improving the appearance of
the capsule, protecting light-sensitive ingredients, and enhancing product
stability.
• e.g. Titanium di oxide, Iron oxides, Zinc oxide, silica
10. Fill matrix in Softgels:
• Lipophilic vehicles: Vegetable oils, Medium-chain triglycerides
• Hydrophilic vehicles: PEG 400, Propylene glycol
• Solubilizers: Polysorbate 80, Cremophor
• Antioxidants: BHT, BHA, Tocopherol (to stabilize oils)

11. Vegetarian Capsules- HPMC, Pullulan, carrageenan, Alginates,

modified starch
 12. Enteric-coated capsules
• Capsules that have an acid-resistant coating that prevents them
from dissolving when they pass through the stomach.
• The coating can be formulated with the appropriate polymers
(acrylic acid copolymer, HPMC acetate succinate or sodium
alginate, methacrylate polymer, Cellulose acetate phthalate).

13. Modified Release Capsules- Matrix polymers: HPMC,

Ethylcellulose, Xanthan gum, Carbopol
 Directly Compressible Vehicle
• Direct compression excipients/ direct compressible excipients / direct
compression filler/binders: are pharmacologically inactive, non-medicinal
substances which may be compacted with no difficulty and which may do so even
when mixed with active drug substances.
• These filler/ binders play significant role in improving flowability and
compressibility during the manufacture of tablets by direct compression method.
• The introduction of spray-dried lactose in 1960 as the first excipient specially
designed for direct compression initiated the “direct compression revolution”.
• Other direct compressible excipients
• Microcrystalline cellulose (the first effective dry filler and binder),
• Starch 1500 (a compressible starch which maintains its disintegrant properties),
• Emcompress (a free-flowing dicalcium phosphate)
 Properties of an ideal direct compression excipients

1. The excipient should have high fluidity or flowability. Flowability is required

in the case of high-speed rotary tablet machines, in order to ensure homogenous
and rapid flow of powder for uniform die-filling.
2. It should have sufficient cohesive properties to form a firm, strong tablet under
adequate compression force.
3. It should be physiologically safe and should not interfere with the
bioavailability of the active drug substance.
4. It should be compatible with all types of active ingredients & packaging
material(s).
5. Physically and chemically stable to air, heat and moisture; colourless and
tasteless.
6. It should accept colourants uniformly.
7. It should be relatively cheap and available preferably from multiple suppliers.
8. It should not contribute to the microbiological load of the formulation.

9. It should have a particle size range which should be equivalent to most active
ingredients.

10. It should have a good pressure hardness profile.

11. A direct compression blend should possess an optimum bulk density and it
should be acceptable. ‘Acceptability’ of an excipient is its ability to comply with
pharmacopoeial requirements, relating to purity, inertness and compatibility.
• A directly compressible adjuvant should have high dilution potential so that the final dosage
form has a minimum possible weight.

Dilution potential can be defined as the amount of an active ingredient that can be
satisfactorily compressed into tablets with the given directly compressible excipient.

•A directly compressible adjuvant should have a particle size equivalent to the active
ingredients present in the formulation. Reproducible particle size distribution is necessary to
achieve uniform blending with the active ingredient(s) in order to avoid segregation.
 Classification of Direct Compression Vehicles
Directly compressible vehicles may be classified based on their disintegration and flow
properties into:

1. Disintegration agents with poor flow e.g. Microcrystalline Cellulose (Avicel), Microfine
Cellulose, Directly Compressible Starch

2. Free-flowing materials that do not disintegrate e.g. Dibasic Calcium Phosphate

(Emcompress).

3. Free-flowing powders that disintegrate by dissolution e.g. Spray Dried Lactose

Anhydrous Lactose, Spray-Crystallized Maltose-Dextrose (Emdex), Sucrose, Dextrose,
Amylose, Mannitol.

4. Co-processed excipients- Ludipress 8

 Methods of Preparing Directly Compressible Excipients
• Alteration of excipient properties by subjecting them to cross-linking or carrying out
reactions like substitution, condensation, hydrolysis
Chemical
Modification
• Ethyl Cellulose, Methyl Cellulose, Hydroxypropyl Methylcellulose and Sodium
Carboxymethyl Cellulose prepared from cellulose, Cyclodextrin prepared from starch,
Lactitol from lactose
Physical • Optimizing the physical properties of materials for specific application.
Modification • dextrates , sorbitol
Grinding and/or • Used to control flow properties of excipients
Sieving • α-Lactose monohydrate (100 #), dibasic dicalcium phosphate

Crystallization
• Process of forming crystalline solid materials from aqueous solution or melt
• β-Lactose, Di-pac®.
• Method of producing a dry powder from an aqueous or non-aqueous dispersion of materials
Spray Drying by rapidly drying with a hot gas.
• Fast Flo lactose, Avicel PH
Granulation/
• Addition of an aqueous dispersion of granulating agent to a previously mixed excipient
blend, followed by drying and sieving.
Agglomeration
• granulated Lactitol ,Tablettose.
 Microcrystalline Cellulose

• A purified, partially depolymerized cellulose that occurs as a fine,

white, tasteless, odourless, hygroscopic crystalline powder which
consists of poor flowing non-fibrous particles.
• Highest compressibility potential, can be directly compressed
without the addition of binder.
• It promotes fast tablet disintegration and enhances rapid drug
availability of tablets.
• Microcrystalline cellulose is used in direct compression as a strong
dry binder, disintegrant, absorbent, lubricant, and anti-adherent.
• Available under the brand names Avicel, Emcocel, Vivacel
 Microfine cellulose (MFC)

• Also known as powdered cellulose or cellulose flocs

• A white, odourless, compressible, self-disintegrating, anti-adherent substance used
in direct compression.

• Available under the brand names Elcema in powder (P050, P100), fibrous (F150), and
granular form (G250)

• Because of the inferior binding properties of microfine cellulose when compared with
those of MCC, modified microfine cellulose with improved compaction properties have
been developed. e.g.- low crystalline powdered cellulose (LCPC)
 Lactose
• Produced from whey, as a by-product of cheese and casein production.
• most widely used filler-diluent in tablets.
• Cost-effective, ease in availability, bland taste, low hygroscopicity, excellent
physical and chemical stability and water solubility.
• Lactose from different suppliers exhibits different properties and therefore could
not be treated as interchangeable in direct compression formulations
• Crystalline lactose mainly consolidates by fragmentation and amorphous
lactose by plastic deformation.
• Tablets containing amorphous lactose show high crushing strength with increasing
water content
• E.g. FlowLac 90
 Spray-dried lactose
• produced by spray drying the slurry containing lactose crystals.
• The final product contains mixture of crystals of lactose monohydrate and
spherical agglomerates of small crystals held together by glass or amorphous
material.
• The former contributes fluidity and the latter gives the compressibility to the product.
• It has excellent flow properties and binding properties.
• Amorphous portion of the spray-dried lactose is responsible for the better binding
and plastic deformation.
• Disintegrant is required in the formulations containing spray-dried lactose.
• widely used as binder, filler-binder, and flow aid in direct compression tableting
 Sucrose
• widely used as filler in chewable tablets and as a binder in wet
granulation.
1. Directly compressible sugar: 95% icing sugar and 5% maltodextrin. It
confirms to British pharmacopoeia monograph for compressible sugar.
2. Di-Pac®: a free-flowing, sweet-tasting, directly compressible, co-
crystallized sugar consisting of 97% sucrose and 3% modified dextrin.
An agglomerated product consisting of hundreds of small sucrose crystals
“glued” together by the highly modified dextrin.
Tablets containing a high proportion of Di-pac tend to harden after
compression at higher relative humidity.
3. NuTab®-a roller compacted direct compression excipient composed of 95% sucrose, 4 %
invert sugar and small amounts of cornstarch and magnesium stearate (about 0.1 – 0.2%).
It has better flowability due to relatively larger particles but has poor colour stability
Primarily used for the preparation of chewable tablets by direct compression.

Dicalcium Phosphate Dihydrate

• The most common inorganic salt used in direct compression as a filler-binder.
• The advantage of using dicalcium phosphate in tablets for vitamin and mineral
supplements is the high calcium and phosphorous content.
• Dicalcium phosphate dihydrate is slightly alkaline which precludes its use with
active ingredients that are sensitive to even small amount of alkali (i.e. ascorbic
acid).
 Spray-Crystallized Maltose and Dextrose (Dextrates)

• This product is spray-crystallized and consists of dextrose microcrystals in the form of

free-flowing porous spheres, maltose and higher glucose saccharides.

• Used as a directly compressible tablet diluent in chewable, non-chewable, soluble,

dispersible, and effervescent tablets.

• It has good binding properties with a sweet taste

• Both anhydrous and hydrous possess excellent compressibility
• Spray-crystallized maltose-dextrose possesses the largest particle size of all the common
direct compression excipients. Blending problems can occur if blends of other excipients
are not used to fill in voids.
 Mannitol

• White, odourless, crystalline powder, or free-flowing granules

• Another type of water-soluble sugars - used in direct compression technology.
• Considered an ideal direct compressible excipient for chewable tablets largely because of its smooth mouth-feel
and cooling effect.

• Mannitol possesses fairly good fluidity and compressibility.

• It is non-hydroscopic and hence it is recommended for moisture-sensitive drugs. It is commonly a component
of direct compression vehicles for moisture-sensitive vitamins.

• Mannitol is present in different polymorphic forms and they have different compression characteristics.
• Drawback - problems of unblending as a result of relatively large particle size and relatively high cost.
 Coat Materials
The 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 are called coating agents.
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.

Types: Three types of coating agents are used pharmaceutically,

1. Film coating.
2. Sugar coating
3. Compression coating
 A good film former
• Lack of toxicity

• Suitable solubility profile for film application and upon ingestion

• Ability to produce a tough yet elastic film

• Film should be stable to heat, light, moisture

• Free from undesirable taste and odour

 Function of coating agents

1. To improve appearance: often where the core tablet is of poor colour or shows mottling.
2. Protection from environmental conditions: Some of the ingredients may not be stable in the
presence of moisture, light, oxygen etc. The product stability can be improved by coating.
3. Taste masking: Mask the bitter or unpleasant taste.
4. Odour masking: Mask the unpleasant odour of active ingredients like vitamins, and antibiotics. The
polymer coat creates a physical barrier between the taste buds and the API, which minimizes the
opportunity for the solubilized drug to interact with these buds.
5. Change in appearance: To impart colour for easy identification during manufacture, dispensing, in use by
patients and brand image building.
6. Helping elderly patients suffering from dysphagia since swallowing can be facilitated by the presence of a
film coat on the Dosage form (improve the surface characteristics)
7. To improve the integrity of the tablet itself. Uncoated tablets are often subject to being abraded or chipped,
causing a loss of active ingredients in the process
8. functional Film Coat is mainly used to add new added value to the produced products. These values may
include - improving the stability of the product and modifying its release pattern to produce drug-
targeting products. e.g. enteric coating
 Coating polymer selection criteria
1. Solubility - The polymer used should be soluble in an
aqueous medium.
• Polyethylene glycol (PEG), polyvinyl pyrrolidone (PVP),
methylcellulose, (MC), hydroxypropyl cellulose (HPC),
hydroxypropyl MC (HPMC) are excellent aqueous soluble
film-coating polymers used with common organic solvents.

2. Viscosity – The polymer within the solution to be sprayed

should be of low viscosity to provide a smooth coating
3. Permeability- A suitable polymer must provide an efficient barrier
against vapor permeation.

4. Polymers for enteric coating- used to resist the release of the API
in the acidic gastric fluid in the stomach but allows for release above
pH 5.0. They remain unionized at low pH and therefore remain
insoluble.

5. Mechanical properties- must be adequate to achieve pliability, to

avoid abrasion, chipping, cracking, and splitting of the film
Sucrose, other sugars, and sugar alcohols (used in sugar coating)

• Major ingredient used in the sugar-coating process is sugar (primarily sucrose),

• glucose,
may be substituted by other sugars and sugar alcohols (such as
lactose, maltitol, mannitol, isomalt, sorbitol, xylitol, and sugar
mixtures such as invert sugar and starch sugars) for low-calorie
diabetic products (typically in the candy industry) and for the fact that sucrose
cause dental caries.
 Modified release coating

• A coating may be applied to a tab to modify the release pattern of the API.
• Two types: enteric and controlled release
• Enteric is insoluble in low pH environment of the stomach but dissolve
readily in the small intestine at elevated pH. E.g. shellac, cellulose
acetate
• Controlled release: regulate the release of the active ingredient(s) over a
prolonged period. This type of coating is designed to provide a steady
and controlled release of the drug, maintaining therapeutic levels in the
body and minimizing fluctuations in drug concentration. e.g. HPMC,
acrylic polymers
 Materials for Edible Coating

Material Class Examples

Polysaccharide Films Starch, chitosan, Alginate, gellan gum,
pullulan, cellulose derivatives
Protein-based coatings Gelatin, corn zein, whey protein, wheat gluten
and soy protein
Lipid-Based coatings Waxes, Paraffins, acetoglyceride, shellac
resins.
 Excipients in Parenteral

• To provide efficacious and safe parenteral dosage forms, added substances must be
frequently incorporated into the formula to maintain stability, control product
attributes, ensure sterility or aid in parenteral administration.

• The excipient should be of GRAS (Generally Recognized as Safe) status or

accepted by regulatory agencies.

• Excipients used in the parenteral formulations are also expected to have low
bioburden, sterile or unaffected by the sterilization or manufacturing process.

• In parenteral preparation, every additive must justify a purpose or function.

 EXCIPIENT USED In LYOPHILIZATION
Bulking Agents and Lyoprotectants
• Bulking agents form the bulk of the lyophilized product and provide an adequate
structure to the cake.
üThese are generally used for low-dose (high potency) drugs that do not have the
necessary bulk to support their structure.
• The structure of the lyophilized cake is important since proper cake formation
leads to proper pore formation that provides the means for vapour to escape from
the product during the drying cycle.
• Lyoprotection is defined as the stabilization and prevention of the degradation of
a molecule both during freeze-drying and afterwards, during storage.
• E.g.-Lactose, Sucrose, Trehalose, Mannitol, Sorbitol, Glucose, Raffinose,
Glycine Histidine, PVP (K40)
 Buffering agents

• Control of pH is critical to avoid degradation of the drug during processing,

storage and reconstitution, thereby necessitating the addition of a buffering agent
in the lyophilized formulation.
• The stability and solubility of the drug is dependent on pH.
• Parenteral products should be formulated to possess sufficient buffer capacity to
maintain proper product pH.
• The choice of the buffer depends on the pH stability profile of the active
ingredient as the drug needs to be reconstituted and stored for some time before it
can be administered to the patient.
• Commonly used buffers in the parenteral formulations are Acetate, Citrate,
Tartrate, Phosphate, and Triethanolamine (TRIS).
 EXCIPIENTS USED IN LIQUID INJECTION
Tonicity adjusting agents
Parenteral formulations should be isotonic with human plasma to avoid damage to the
tissues.
However, not all drugs at their recommended dosage are isotonic with blood, thus requiring
the addition of a tonicity adjusting agent to the formulation.
e.g. dextrose (5%), potassium chloride (1%), sodium chloride (0.9%),
Mannitol (5%), propylene glycol
Antioxidants
used to prevent the oxidation reaction of the drug or excipients over the shelf life of the
product
The most commonly used antioxidants in the sterile formulations are Ascorbic acid,
Acetylcysteine, salts of sulphur di oxide (bisulfite, metabisulfite),
Monothioglyercol
• These antioxidants maintain stability by being preferentially oxidised and
gradually consumed over the shelf life of the product.
• Sulfite levels are determined by the reactivity of the drug, type of container,
single or multiple dose use, container headspace, and expiration dating period.

Antimicrobial agents: A suitable preservative system is required in all multiple-

dose parenteral products to prevent the growth of microorganisms accidentally
introduced during the withdrawal of individual doses.
Preservatives may be added to single-dose parenteral products that are not
terminally sterilised as a sterility assurance measure.
Commonly used antimicrobial agents : Phenol, metacresol, Benzyl
alcohol, Parabens (methyl, propyl, butyl), Benzalkonium chloride,
Chlorobutanol, Thimerosal, Phenylmercuric salts (acetate, borate,
nitrate)
Chelating agent
These agents bind to metal ions, preventing them from catalyzing the
degradation of the active ingredient.
They are added to form complex and thereby inactivate metals such as
copper, iron and zinc that generally catalyse oxidative degradation of
drug molecules.
Sources of metal contamination- raw material impurities, solvent, rubber
stoppers, containers or equipment.
e.g. Calcium disodium EDTA, Disodium EDTA, Sodium EDTA
Solubilizing agents
The agents that help in dissolving or increasing the drug solubility into
the formulation are known as solubilizing agents,
The solubilising agents can be broadly classified into surfactants and co-
solvents.
When using solubilisers, the formulator must consider their effect on the
safety and stability of the drug.

Surfactants are used for wetting and to prevent crystal growth in

suspension.
They are used extensively in parenteral suspensions for wetting powders
and to provide acceptable syringability. Also used in emulsions.
Examples of surfactants- Polyoxyethylene sorbitan monooleate (Tween 80), Sorbitan
monooleate Polyoxyethylene sorbitan monolaurate (Tween 20), Lecithin, Pluronics
Examples of co-solvents -Propylene glycol, Glycerin, Ethanol, Polyethylene glycol (300 and
400), Sorbitol, Dimethylacetamide and Cremophor EL etc.

Complexing and Dispersing Agents

Complexation is sometimes used to improve the solubility of drugs in the solvent, especially
water.
Cyclodextrins have emerged as very effective additive compounds for solubilizing
hydrophobic drugs.
In the parenteral dosage form, modified cyclodextrins, such as hydroxypropyl-b-
cyclodextrin and sulfobutylether- b -cyclodextrin have been reported to solubilize and
stabilize many injectable drugs, including dexamethasone, estradiol, interleukin-2.
Flocculating/suspending agents
The controlled flocculation approach uses a flocculating agent(s) to form loosely bound
aggregate or flocs in a controlled manner that settles rapidly but redisperses easily upon
agitation.
Electrolytes, surfactants and hydrophilic colloids are used as flocculating agents.
• Electrolytes & surfactants reduce the electrical forces of repulsion between particles &
allow the flocs to form, which in turn is influenced by the surface charge on the particles.
E.g. Potassium/sodium chloride, Potassium/sodium citrate, Potassium/sodium acetate
• Hydrophilic colloids (generally negatively charged) not only affect the repulsive force but
also provide a mechanical barrier to the particles. e.g. PVP solution
• Viscosity-building agents used in the formulation of injectable suspension are:
Sodium carboxymethyl cellulose, Acacia, Gelatin, Methylcellulose, Polyvinyl pyrrolidone
Wetting Agents
• Various nonionic surfactants-Lecithin, Polysorbate 20, Polysorbate 80,
Pluronic F-68, Sorbitan trioleate (span 85)
• Non-aqueous solvents like glycerin, alcohol & propylene glycol are types of
wetting agents commonly used in injectable suspensions.
 VEHICLES

• AQUEOUS VEHICLE - WATER FOR INJECTION (WFI) USP

• Highly purified water is used as a vehicle for injective preparations which will be
subsequently sterilized.

• USP requirements include not more than 10 parts per million of total solids.

• pH of 5.0 – 7.0 .

• WFI may be prepared by either distillation or reverse osmosis.

• Stored in a chemically resistant tank.

BACTERIOSTATIC WATER FOR INJECTION
• This type of water used for making parenteral solutions prepared
under aseptic conditions and not terminally sterilized.
• Need to meet USP sterility test.
• It can contain an added bacteriostatic agent when in containers of
30 ml or less.
STERILE WATER FOR INJECTION
• SWFI contains one or more suitable bacteriostatic agents.
• multiple-dose containers not exceeding 30 ml.
• They are permitted to contain higher levels of solid than WFI
because of possible leaching.
• Used for washing wounds, surgical incisions, or body tissues.
WATER MISCIBLE VEHICLES

• The number of solvents that are miscible with water has been used
as a portion of a vehicle.
• Primarily to affect the solubility of drugs and to reduce hydrolysis.
• Example:
– Ethyl alcohol
– Liquid propylene glycol
– Glycerine
• NON – AQUEOUS VEHICLES
– Fixed oils
– E.g., (vegetable origin, liquid, and rancid resistance,
unsaturated, free fatty acid content )
– Peanut oil
– Corn oil , Cottonseed oil (depo-testosterone) Sesame oil,
Soyabean oil, Ethyl oleate, and Isopropyl myristate.
EXCIPIENTS IN AEROSOLS
• Pharmaceutical aerosols are dosage forms that contain therapeutically active
ingredients dissolved, suspended, or emulsified in a propellant or a
mixture of solvent and propellant and intended for administration as a fine mist,
spray, or foam.
• Aerosol products depend on the power of compressed or liquefied gas to expel
the contents from the container
• Pharmaceutical aerosols are packaged under pressure and contain therapeutically
active ingredients that are released upon activation of an appropriate valve
system.
• Intended for topical application to the skin as well as local application into the
nose (nasal aerosols), mouth (lingual aerosols), or lungs (inhalation aerosols).
 Solvents/Co-Solvents

•Solvents may be added to the aerosol formulation to reduce the evaporation rate
of the propellant and to assist in dissolving the active ingredient or other
excipients.
•Solution aerosols can be challenging to formulate because many propellants or
propellant-solvent mixtures are non-polar and are poor solvents for the product
concentrate.
•Water is the most widely used vehicle because of its inert nature, lack of toxicity,
physiological compatibility, and good solubilizing power due to its high
dielectric constant, but it is likely to cause hydrolytic instability to polar drugs
and support microbial growth.
•Other Solvents used in aerosols: ethyl alcohol, propylene glycol, dipropylene
glycol, ethyl acetate, hexylene glycol, acetone, etc.
 Co-solvents

•Co-solvents are employed in aerosol formulations to increase the

solubility of poorly water-soluble substances and/or to enhance the
chemical stability of drugs.
•The polar co-solvents help to enhance solubility, mask taste as well as
smell and as an antimicrobial agent.
•Examples, of co-solvents- propylene glycol, glycerol, ethanol, low
molecular weight PEGs and non-polar co-solvent such as fractionated
coconut oils
•Sorbitol and dextrose can often be incorporated as solubilizers as well as
base sweeteners, as an alternative to water.
 Propellant

Propellant is added to produce pressure, which is needed to expel the medicament from the container.

Liquefied Gas Propellants

• Fluorinated hydrocarbons are widely used in oral and inhalation aerosol as propellants.
• Chlorofluorocarbons (CFCs): CFC propellants such as trichloromonofluoromethane (P-11),
dichlorodifluoromethane (P-12), and dichloro tetrafluoromethane (114) are used in aerosol products.
• But since they deplete the ozone layer, are now used at low strength in the products used to treat asthma and
chronic obstructive pulmonary disease. They are relatively low toxic and are inflammable.

For the application of Topical aerosol, commonly used propellants are:

1. Hydrocarbons: Propane, butane, isobutene

2. Compressed gas: Nitrous oxide, nitrogen, carbon dioxide

 Buffering agents

• Buffering agents help to maintain a stable pH

• The maintenance of desired pH of the formulation is necessary, to ensure physiological
compatibility, maintain stability of the drugs and excipients and for the
antimicrobial effectiveness as well as solubility of formulation components.
• Commonly used buffering agents include sodium bicarbonate, magnesium
carbonate and sodium citrate.

Anti-oxidants
added to inhibit oxidation of the drug substance and to extend the life of the marketed product
from self-decomposition due to oxidation.
e.g. Vitamin C & E, beta carotene, Butylated hydroxytoluene (BHT), Butylated
hydroxyanisole (BHA)
Surfactants are added to reduce interfacial tension and surface tension making it easier to aerosolize & To control
particle size

Non-ionic surfactants are more preferred in aerosol preparations. Other

Surfactants used in emulsion aerosols have included fatty acids saponified with triethanolamine, anionic
surfactants, polyoxyethylene fatty esters, polyoxyethylene sorbitan esters, alkyl phenoxyethanols,
and alkanolamides, sorbitan trioleate

Preservatives

Preservatives prevent an increased risk of contamination and proliferation by opportunistic microbes. Ideal properties of
these types of excipients are mostly targeted to microbial cells and have no toxicity towards mammalian cells.

Examples of preservatives - benzalkonium chloride, cetrimonium bromide benzoic acid, sorbic acid, paraben
derivatives
Wetting agents
used in liquid aerosols to reduce surface tension and make them more effective in spreading over and
penetrating surfaces.
They are also used as suspending agents to encourage deflocculation at low levels.
Examples of wetting agents include Tweens, Spans, poloxamers, lecithin, SLS. Hydrophilic
colloids such as bentonite, tragacanth, alginates, and cellulose derivatives

Anti-foaming agents (Defoamer)

An antifoaming agent is used to reduce foam formation in liquid dosage formulation.
Foaming is encountered during processing or at reconstitution.
Antifoaming agents are effective in reducing foams by lowering surface tension and cohesive binding
of the liquid phase.
E.g. Insoluble oils, polydimethylsiloxanes and other silicones, certain alcohols, stearates
and glycols
Humectants
• Humectants are used to prevent loss of moisture thereby retaining the skin's natural
moisture.
• Hygroscopic humectants are used at about 5% strength in aqueous suspensions and
emulsions for external application.
• are used to prevent drying of the product after application to/on the skin and prevent cap-
locking caused by condensation onto the neck of aerosol container after first opening.
• Examples of humectants used in aerosol include propylene glycol, glycerol, PEG.

• Lubricants such as isopropyl myristate and light mineral oil have been used to control
particle size agglomeration and growth, which in turn can lead to aerosol valve clogging
problems.
• Viscosity modifiers are used in nasal spray formulations to
reduce the rate of settling of suspended active ingredients,
thereby improving the stability profile of the product.
• Viscosity modifiers can also act as mucoadhesives,
increasing the residence time of the spray in the nasal cavity.
• A longer residence time within the nasal cavity will improve
the chance of drug absorption through the nasal mucosa.
• Cellulose derivatives, carbomers, PVP, Clays, silica