PHARMACEUTICAL BIOTECHNOLOGY

UNIT-III

Materials and formulations:

Dosage form is a drug delivery system designed to deliver the active ingredient to the body and,
upon administration should deliver the drug at a rate and amount that assures the desired
pharmacological effect. Such dosage forms are manufactured under current good manufacturing
procedures (cGMP), using equipment and packaging to ensure product stability. The dosage form
must produce the same therapeutic response each time it is administered. To maintain this
reproducibility between and within batches, manufacturing procedures are validated under a
specific quality assurance program. Non-parenteral dosage forms can be categorized based on the
route of administration or physical form. Based on physical form they can be classified as solids,
liquids (homogenous and heterogeneous systems), semisolids, and aerosols. Dosage forms can
also be categorized based on the route of administration. Solid dosage forms include different
types of compressed tablets, granules, troches, lozenges, coated dosage forms, and hard and soft
gelatin capsules. Liquid dosage forms include solutions, suspensions, emulsions, and buccal and
sublingual sprays. Topical dosage forms are applied to the skin and include ointments, pastes,
creams, lotions, liniments, and transdermal patches. Some dosage forms are formulated for
application to body cavities, viz. rectal and urethral suppositories and vaginal pessaries.
Inhalation aerosols, using metered dose inhalers (MDIs), dry powder inhalers (DPIs) and
nebulizers, are used to deliver drugs to the respiratory tract. Nasal route uses solution and
suspension dosage forms. Occular route is used to administer solutions and suspensions to the
eye for local and systemic effects.

Tablets
Flowability and compressibility are two important parameters essential for successful
manufacture of tablets. Flowability determines ease of material flow from tablet hopper to the
press. Inadequate flow gives rise to arching, bridging, or rat-holing in hoppers. Powder flow can
be improved mechanically by use of force feeders. Flowability can also be increased by
incorporation of glidants like fumed silica and talc. Another method involves the conversion of
powder to spherical particles by spray drying or spheronization. Tablets are manufactured by dry
and wet methods. Dry methods consist of direct compression, slugging, and roller compaction of
drug-excipient blends. Directly compressible excipients may be disintegrants with poor flow,
e.g., microcrystalline cellulose (Avicel PH102); free-flowing materials which do not disintegrate,
e.g., dibasic calcium phosphate (DiPacw); or free-flowing powders which disintegrate by
dissolution (e.g., spraydried lactose, anhydrous lactose, dextrose, sucrose, amylose, etc.). The
drug is mixed with excipients in a blender and then compressed directly on a tablet press. Dry
granulation by compression or slugging is used for moisture or heat sensitive actives. The powder
blends are compressed into compacts or slugs. An alternative method is to squeeze the powder
blends into solid cake between rollers called roller compacts. These slugs or compacts are milled
and screened in order to produce granules with improved flow. Granulation is the process of
particle size enlargement of homogeneously mixed powder ingredients and simultaneously
increasing bulk density, flowability,and compressibility of the system. Wet granulation process
involves the massing of the powder mix, using a binder and solvent. The solvent should be
volatile, nontoxic, and removed by drying. This process is not suitable for hydrolysable and
thermolabile drugs. The binder is added in the form of a solution, or added dry or its mucilage
incorporated with the powder blend. The choice of liquid depends on the properties of the
material being granulated. Water is widely used alone or along with a binding agent. Commonly
used nonaqueous liquids are isopropanol and ethanol. Massing process is usually performed in a
low or high shear granulator where the liquid is poured or sprayed onto a moving powder bed
until a moist mass of finely divided material is formed. This is passed through an oscillating
granulator with the appropriate screen size to obtain the required granule particle size.
Sometimes both intra- and extra-granular portions are divided to prevent incompatibility between
excipient material hiding or better distribution, tableting or dissolution. Tablets require different
functional excipients for their manufacture. Diluents are inert bulking agents added to actives to
make a reasonably sized tablet. Generally, a tablet should weigh about 50–60 mg and therefore
very low dose drugs will require these diluents to make at least a 50 mg tablet. Adsorbents such
as fumed silica and kaolin are sometimes used for holding large amounts of fluids in an
apparently dry state. Binders are used as adhesives to bind powder in wet granulation and give
strength to compacts during compression. Binders may be incorporated into the dry blend or
added as a solution to the mixed powder during wet granulation. Disintegrants are usually added
to promote rapid breakup of tablets to increase surface area and aid drug dissolution.
Disintegrants can act by different mechanisms such as like swelling and capillary action. Glidants
are materials that are added to tablet formulations to improve flow properties of the granulation.
They act by reducing inter-particulate friction (e.g., fumed silica). Lubricants are added to
prevent the adherence of granules to the punch and die faces of the tablet press. Many lubricants
also facilitate flow of granules. Talc and magnesium stearate are more effective as punch
lubricants. Stearic acid works better as a die lubricant.

Specific Types of Tablets

Lozenges: These are compressed tablets formulated, without a disintegrant and must be allowed
to dissolve in the mouth. They are used for local activity (throat lozenges) or for systemic effect
(vitamins).
Effervescent tablets: These tablets undergo quick dissolution of actives in water due to internal
liberation of carbon dioxide. By combining alkali metal carbonates or bicarbonates with tartaric
or citric acid, carbon dioxide is liberated when placed in water. They are prepared by the heat
fusion technique. Usually a water-soluble lubricant is used to prevent scum formation at the water
surface.Sweetness is achieved by the addition of saccharin, since sucrose is hygroscopic and
increases the bulk of the tablet, e.g., Rochelle Saltw.
Chewable tablets: These tablets are preferred for pediatric and geriatric patients who have
difficulty swallowing whole tablets. Another advantage is that they do not need water for
administration. Mannitol is normally used as the base diluent because of its pleasant taste and
texture, and because it can effectively mask the taste of objectionable actives. They are usually
prepared by wet granulation and are not compressed very hard. High amounts of flavor are added
to increase palatability. Antacids are typically formulated as chewable tablets. Sublingual and
buccal tablets: These tablets are placed under the tongue (sublingual) or the cheek (buccal) and
can produce immediate systemic effects by enabling the drug to be directly absorbed through the
mucosa by preventing the first pass effect (e.g., isoprenaline sulphate and glyceryl trinitrate).
Tablets are small, flat, without a disintegrant, and are compressed lightly to produce soft tablets.
Molded tablets: These are prepared from mixtures of medicinal substances and a diluent usually
consisting of lactose and powdered sucrose in varying quantities. The powders are dampened
with solutions containing high proportions of alcohol depending on the solubility of the active
and filler. The dampened powders are pressed under low pressure in die cavities. Solidification
depends upon crystal bridging during the subsequent drying process, and not upon the
compaction forces.
Formulation requirements for enteric coated tablets
Most enteric coated tablets are good examples of Extended Release dosage forms. These dosage
forms can be classified by their mechanism of release and/or type of formulation. Coated beads,
granules microspheres, and other particulate systems are pellet type controlled release dosage
forms, where the drug is usually coated onto nonpareil beads (low dose) or made from granules
composed of the drug (high dose). These pellets are further coated with functional coating agents
(Eudragitsw, HPMCs, Sureleasew, etc.) to provide various release characteristics. These pellets
can be used to fill capsules (e.g., Ornade Spansulesw) or compressed at low pressure into tablets
(e.g., Theo-Durw). In some cases small mini-tablets of about 3–4 mm diameter can be
compressed. These tablets function like pellets and can be used to fill capsules.
Microencapsulation is a process of encapsulating microscopic drug particles with a thin wall of
coating material. Several coating materials have been used including gelatin, ethylcellulose, and
polyvinyl
alcohol, e.g., Micro-K-Extencapsw (Wyeth–Ayerst Research). Matrix systems are dosage forms
where drug substance is combined with hydrophilic cellulose polymers (excipient material),
which slowly erode in the presence of body fluids. On hydration, the polymers behave like a gel
and prevent the fast disintegration of the tablet. Diffusion from the gel controls the drug release
(e.g., Oramorph SRw tablets). A multi-layered tablet consists of several different granulations
compressed on top of each other to form a single tablet composed of two or more layers. Each
layer is fed from a separate feed frame with individual weight control. Precompression tamping
helps in good binding of layers. Also, reduced pressures prevent intermixing of granules during
compression. They may be bilayer where IR/ER combination are used or mainly when
incompatible drug substances is used. Sometimes the release from individual layers is controlled
to give a drug delivery system, such as, Geomatrixw system (1). In some cases if the bulk density
of the tablet is less than one, it floats in the gastric fluids thus extending the residence time in the
gastrointestinal tract (GIT). Such dosage forms are called Hydrodynamically Balanced Systems
(HBS), an example being Valreleasew (Roche). In some cases the drug is embedded inside inert
polymeric matrices with materials such as polyethylene, polyvinyl acetate, and
polymethacrylates. The granulations are then compressed into tablets. These inert matrices are
excreted in the feces unchanged (e.g., Ferro-Gradumetw (Abbott). Some drugs form complexes
resulting in slower dissolution and behave as extended release dosage forms, e.g., Rynatanw
(Carter- Wallace). A slowly eroding tablet may be granulated with hydrophobic excipients (waxy
lipophilic material) so that the drug leaches out over an extended period with an outer shell
containing the IR dose (buffered aspirin). In some cases a cationic or anionic drug solution can
react with an insoluble resin to form a complex. This complex can be tableted, encapsulated or
suspended in a vehicle, e.g., Tussionex Pennkineticw Extended Release Suspension (Medeva).
Osmotic pump drug delivery systems consist of a core tablet coated with a semi-permeable
membrane with a fine orifice made by laser beams. The core usually forms two layers containing
the active and osmotic agents. In the gastric fluids water is imbibed by the osmotic agent (pull)
and then exerts pressure on the drug (push) in solution, out through the orifice. Such dosage
forms are independent of pH of the gastric fluids and are termed as gastrointestinal therapeutic
systems (GITS), e.g., Procardia XLw (Pfizer). Repeat action tablets consist of slow release inner
core and a immediate release (IR) as in Repetabsw (Schering) or as bilayer IR/ER tablets.
Delayed release dosage forms are used for drugs that are destroyed in the gastric fluids, or cause
gastric irritation, or are absorbed preferentially in the intestine. Such dosage forms are enterically
coated using materials such as cellulose acetate pthalate, shellac, and waxes. The coating allows
the drug to release at higher pH (pH dependent) or by enzyme catalyzed reactions, e.g.,
Erythromycin or Aspirin delayed release dosage forms. Several forms of oral controlled release
systems are available in the market; however, most of them are dependent on the rate at which
the system passes along the gastro-intestinal tract. This can be overcome by regulating the release
of the drug by physical chemical means, or by a process related to the environment in which the
delivery system is present at the specific time.
Capsules
The word “capsule” is derived from the Latin word capsula meaning a small box. Gelatin, a
substance of natural origin with unique properties, is the major component of capsules. Gelatin is
used because it is nontoxic and readily soluble in biological fluids at body temperature. It has
good film forming properties and, as a in water and water–gylcerol systems, undergoes reversible
phase change from a solution to gel at only a few degrees above ambient temperature. There are
two forms of gelatin (A and B) based on the method of manufacture from animal bone and skin.
The properties important for capsule shell manufacture are viscosity and bloom strength. Hard
gelatin capsules are firm and rigid while soft gelatin capsules are soft and flexible. This is
because soft capsules contain a larger proportion of plasticizers like glycerol, sorbitol, propylene
glycol, acacia, and sucrose. Varying proportions of plasticizers are added depending on the
intended use of soft gelatin capsules. The colorants used consist of soluble and insoluble dyes.
Titanium dioxide and iron oxide pigments are common, although recently aluminum lakes are
being used. Preservatives are added to capsules to prevent microbial contamination. Moisture
levels are also maintained at low levels to prevent bacterial growth on storage.
Hard gelatin capsules (HGCs)
Hard gelatin capsules are available in sizes ranging from size 000, (the largest) to size 5 (the
smallest). The fill weight of capsule and tapped bulk density of the powder blend determines the
selection of capsule size. Recently, better techniques for capsule sealing, like, self-locking and
have made it possible for a range of materials. The filler material should not react with gelatin.
Aldehydes lead to gelatin cross-linking affecting the integrity of the shell and water in the
formula can act as a plasticizer. On the other hand, hygroscopic agents can make the capsule shell
brittle. Powders filled into hard gelatin capsules should have good flow properties to maintain
uniform fill weights during filling operations. Granules and pellets of spherical shape making
them free-flowing and nonfriable are good candidates for capsule filling using gravitational
systems or specialized dosing chambers to maintain uniform fill weight. In some instances,
minitablets (filmcoated, nonfriable) can be filled into capsules to produce specialized dosage
forms or to separate incompatible ingredients. A recent innovation in hard gelatin capsule filling
is a revival of the old practice of filling liquids or semisolids. The main problem encounted is
product leakage. This difficulty was overcome by using selflocking capsules and formulation
techniques. The use of mixtures of material which are either thermosoftening or thixotropic in
nature has become prevalent. These materials are liquefied by heat or shearing force, and revert
to solid state within the capsule shell after filling. Filling machines have been developed to
handle such formulations with existing powder filling equipment. This system works with solid,
liquid, semisolids, and potent drugs. The application of semisolids filling is also getting
prevalent. A more recent innovation in HGCs to fill liquid dosage forms with the use of new
machines which heatseal the caps permanently to prevent leakage as observed with liquid filled
HGCs in the past. A good example is the introduction of Licapsw (Capsugel) for liquid fills.
Capsules made of nongelatin ingredients for materials not compatible with gelatin are also
available, e.g., cellulose (Vegecapsw).
Soft gelatin capsules (SGCs)
SGCs or softgels are continuous gelatin shells surrounding a liquid or semi-solid fill. These
capsules are formed, filled, and sealed, all in one operation. These capsules are available in
different shapes and sizes. SGCs are preferred for drugs with poor compressibility, poor powder
flow, mixing problem, unstable or poor solubility in gastric pH, and bioavailability problems.
Such drugs can be solubilized or dispersed in a liquid, where dosage uniformity is more accurate.
Some drugs that are liquid or that melt during compression are good candidates, if other means of
tabletting are expensive. Gelatin used in SGCs has lower bloom strength than HGCs. The
plasticizer type and concentration controls the mechanical strength of the shell. In general,
plasticizer amounts are larger, making them more flexible than HGC shells. Preservatives,
colorants, and opacifiers are used in the same manner as in HGCs. Sometimes softgel capsules
are enteric coated for drugs which are absorbed in the small intestine. Once the capsule shells
dissolve in vivo, the drug is available in a liquid or semi-solid form that dissolves or disperses
into fine particles with enhanced bioavailability. SGCs can be filled with several materials such
as aqueous solutions, nonaqueous solutions, suspensions, pastes, oily solutions of drug, self-
emulsifying system, and watermiscible liquids. Materials that cause migration of water or
plasticizer from the shell cannot be filled. Surfactants and systems with extreme pH should be
avoided.
Sustained released dosage forms:
Many prolonged- or sustained-release dosage forms are made using melt-congealing processes.
The dosage forms can be melt-congealed matrix granules in the form of capsules or compressed
into tablets or melt-congealed coatings on drug-loaded substrates (particles or pellets in capsules).
Wax matrices are often prepared by melt-granulation or melt-extrusion processes, whereas
microspheres or microparticles are usually produced by spray-congealing processes, and coated
particles or pellets can be made by hot melt-coating processes. The formation of drug containing
wax-coated microspheres can be considered a coating process, although it is more correct to
describe it as an encapsulation process involving a phase-inversion technique. Giannola et al.
demonstrated this technique by producing carnauba wax microspheres loaded with valproic acid
(VA). These microspheres were between 200 and 425 mm in diameter, with an average drug
content of 26% w/w. The process used to manufacture this product consisted of melting carnauba
wax in an oil bath at 1108C and then adding a sample of the VA. To this homogeneous melt was
added an acidic aqueous solution (pH 4.5), which minimized the solubility of the VA, combined
with glycerine, which increased the melting point. A small amount of surfactant (Tween or
Spansw) was added, and then the mixture was stirred at a predetermined rate. On dispersion in
the aqueous medium, the molten mass formed spherical particles. The mixture was then quenched
by the addition of iced water, with the result that the carnauba wax solidified and enveloped the
drug. Miyagawa and coworkers used a twin-screw extruder to prepare wax matrix granules
(WMG) consisting of diclofenac sodium (DS) as model drug; carnauba wax as the matrix
material; and hydroxypropylcellulose (HPC–SL), methacrylic acid and copolymer L (Eudragit L-
100), and sodium chloride as rate-controlling agents. The dissolution behavior of DS from WMG
was strongly influenced by granule formulation. The release rate can be manipulated by the
addition of other ratecontrolling agents. Emori et al. formulated wax matrix tablets for prolonged
drug release using a melt-congealing process. They studied the addition of acrylic acid polymer
on the release of drug from a wax matrix consisting of carnauba wax and stearyl alcohol in a 1:1
ratio. Perez and colleagues prepared sustained-release phenypropanolamine HCl tablets and
investigated the effects of varying wax levels and methods of matrix formulation on drug release.
Two methods were used for the preparation of a drug–wax system: physical mixtures and solid
dispersions. In the first method, the drug, wax, and diluent were blended in a Turbula mixer by
geometric dilution for a total of 20 min. Then the mixture was compressed into tablets. For the
solid-dispersion method, the wax was melted in a water bath at a temperature of 80–85oC. The
drug was incorporated into the melted wax using constant stirring over a 5-min period, and then
the mixture was allowed to cool until it solidified. The solidified mass was granulated using a
Stokes oscillating granulator equipped with a no. 12 screen. Blending of milled material (wax and
active ingredient) and diluent was done in the Turbula mixer for 20 min. The tablets that were
prepared as a physical mixture gave higher drug release than did tablets prepared by the solid-
dispersion process. The formation of a barrier coat on drug-laden substrates, to protect the drug
from gastric fluid or to provide sustained release of the drug, can be achieved by the hot-melt
fluid-bed coating process. Processing conditions must be chosen to prevent solidification of the
coating material in the feed lines and to obtain smooth, uniform coats without excessive spray-
drying and agglomeration. Kennedy and Niebergal coated chlorpheniramine maleate (CPM)-
loaded nonpareils with hydrophobic coating agents such as beeswax, paraffin, etc. in a hot-melt
fluid-bed coating process. They demonstrated the ability to extend the release profile of a highly
watersoluble drug, CPM.
Parenteral Dosage forms:
Parenteral is derived from the two words “para” and “enteron” meaning to avoid the intestine.
Parenteral articles are defined according to the USP 24/NF19 “as those preparations intended for
injection through the skin or other external boundary tissue, rather than through the alimentary
canal, so that the active substances they contain are administered using gravity or force directly
into a blood vessel, organ, tissue, or lesion. Parenteral products are prepared scrupulously by
methods designed to ensure that they meet pharmacopeial requirements for sterility, pyrogens,
particulate matter, and other contaminants, and, where appropriate, contain inhibitors of growth
of microorganisms. An injection is a preparation intended for parenteral administration and/or for
constituting or diluting a parenteral article prior to administration”. Parenteral drug
administration is an attractive route of administration when oral administration is contraindicated,
and it has been traditionally used in institutional settings. With an increasing interest in reducing
overall health care costs and with the development of new biotechnologically derived compounds
and improved and novel infusionrelated technologies, parenteral products have become an
important component in the care of patients in hospitals and the home health care setting. In the
present article, information will be presented on history and the following: the use of parenterals
in health care, the advantages and disadvantages of using parenterals, routes of administration,
vascular access devices and infusion sets, types of parenteral products, components of parenteral
products, parenteral packaging, convenience and needleless systems, needleless injection,
extemporaneous compounding of parenteral products, infusion.
ADVANTAGES AND DISADVANTAGES OF PARENTERAL PRODUCTS
Generally, parenterally administered drugs are advantageous because they can provide rapid and
reliable drug systemic effects, long-term drug delivery, and targeted drug delivery. The
disadvantages of parenteral products are predominately associated with safety issues related to
infection and thrombosis, tissue damage and/or pain upon injection, and the use of requirements
for specific equipment, devices, and techniques.

ROUTES OF ADMINISTRATION
The most commonly used routes are intravenous, intramuscular, subcutaneous, and intradermal.
Formulations intended for administration into the central nervous system should not include
preservatives. For intramuscular, intradermal, and subcutaneous, a single needle and syringe is
generally used to administer the drugs. For intravenous and intra-arterial, drugs are administered
using vascular access or port devices. Other parenteral routes of administration (e.g., epidural,
intraarticular, and intrathecal) usually require specialized delivery sets. In some cases, the
specific drug requires a specialized delivery set be utilized due to the dose of the drug or the
physicochemical properties of the drug (e.g., nitroglycerin).
LIQUID DOSAGE FORMS
Solution
A solution is a homogenous single-phase system consisting of two or more components.
Solutions are easier to swallow and are acceptable dosage forms for pediatric and geriatric use.
The drug in solution is readily available for absorption and therapeutic response is faster.
Solutions, however, are bulky and inconvenient to transport. The stability of actives is poorer
than in solids and they provide suitable media for microbial growth. Aqueous solutions are
preparations made with water as solvent. Purified Water USP is widely used for most
preparations. Some drugs are unstable in water or sensitive to the presence of carbon dioxide or
oxygen. Not all substances are completely soluble in water and may lead to precipitation. Several
other techniques are used to increase solubility of drugs in solution. Cosolvency is a process of
increasing solubility of a drug by using a combination of solvents. Some suitable cosolvents are
ethanol, isopropyl alcohol, sorbitol, glycerol, and propylene glycol. If a drug is a weak acid or
base, then its solubility in water is influenced by pH. The pH for optimum solubility may not give
a stable product. Thus, a compromise must be reached to ensure proper formulation and
bioavailability. Suitable buffer systems may be used if necessary. Solubility of insoluble or
poorly soluble drugs can also be increased by addition of surface-active agents. Most surfactants
are miscible with solvent system and compatible with other ingredients. Hydrophilic surfactants
with HLB values are generally preferred. In some cases complexation of a drug with a material
may result in formation of soluble molecular complex. However, such complexation needs to be
reversible for the active to cross the biological barrier. Chemical modifications of the drug can
also result in more water-soluble derivatives. However, these modified drugs are regarded as new
chemical entities. Nonaqueous solutions are used when complete solution is not possible in water
or if the drug is unstable. Ethyl alcohol is the most widely used water-miscible solvent for
external preparations. Ethyl ether is occasionally used as a co-solvent, in combination with
alcohol in the preparation of some colloidons. Other solvents such as isopropyl myristate and
isopropyl palmitate are solvents with low viscosity and are ideally used in cosmetics
preparations. Xylene is present in ear drops for human use to dissolve ear wax. Liquid
formulation additives used include buffers, colorants, flavoring agents, and preservatives. Buffers
are dissolved in solvents to resist pH changes. The choice of buffers depends on the pH and the
buffering capacity. Most pharmaceutically acceptable buffer systems include carbonates,
phosphates, citrates, gluconates, and lactates. Colors are added for attractiveness and product
identification. Flavors are added to solutions to increase their palatability, particularly for drugs
with unpleasant taste. This is especially useful in pediatric formulations. Flavors also help in
product identification and are of natural or synthetic sources. Fruit juices, peppermint oil, and
menthol are some examples of flavors. Some flavors are preferred for specific products, e.g., mint
is associated with antacid formulas. Similarly, flavors are preferred by specific patient groups,
e.g., children prefer fruity tastes and smell, while adults prefer flowery and acid flavors.
Preservatives help prevent microbial growth. The choice of preservatives should be based on
their performance from a microbial challenge test. Care should be taken to ensure there is no
adsorption of preservatives onto product containers or packaging material. Antioxidants are
added to prevent degradation of the drug in solution; the amount and type can be determined after
careful determination of the degradation pathway and stability testing with different agents.
Sucrose is widely used as sweetening agent, because it is water soluble, and stable at a wide
range of pH. It has a pleasant texture and soothing effect on the throat. There are several other
sweeteners that are less widely used. Artificial sweeteners like sugar alcohols and aspartame are
used by diabetic patients.
Emulsions
These are dispersions of one liquid (dispersed phase) in the form of uniformly divided droplets in
another liquid (dispersion medium). Depending on which liquid is the dispersed phase oil-in-
water (o/w) or water-in-oil (w/o) systems are obtained. To test the identity, emulsion miscibility,
staining and conductivity tests are performed. The choice of emulsion depends on the route of
administration and the end use. For oral administration, o/w emulsions are used while for external
use, both o/w and w/o systems can be employed. Semisolid o/w emulsions are termed as
“creams,” and are easily washable after application. Water-in-oil emulsions have an occlusive
effect and are therefore preferred as moisturizing lotions and cleansing agents. The choice of oil
depends on the application with some oils like castor and cod liver oil having a therapeutic value.
Thus, w/o preparations are greasy, with high apparent viscosity while o/w emulsions are less
greasy and readily absorbed and washable. Ideally emulsions should exhibit pseudoplasticity and
thixotropy, that is, high viscosity at low shear rates and vice versa. They should be dispensable
from containers, bottles, and tubes but at the same time should spread on the skin with light
pressure. The rheological properties of emulsions are controlled by the concentration, particle
size, and viscosity of dispersed phase, concentration of dispersion phase, and the nature and
concentration of the emulsifier. The choice of emulsifying system depends on the route of
administration, its HLB value and its toxicity. There is no approved list of emulsifiers but
pharmaceutical companies employ emulsifiers approved for use in the food industry. Emulsifiers
with surface activity reduce the interfacial tension between the phases, thereby decreasing the
need for energy to disperse the internal phase. The surfactants used can be anionic like sodium,
potassium, and ammonium salts of long chain fatty acids (e.g., sodium stearate), soaps of di- and
tri-valents metal ions (e.g., calcium oleate and amine soaps, sulphated and sulphonated
compounds (e.g., SLS). Cationic surfactant, amphoteric surfactants like lecithin, and non-ionic
surfactants, like glycol and glycerol esters (e.g., glycerol monostearate), sorbitan esters,
polysorbates, fatty alcohol olyglycol ethers (e.g., cetyl or cetostearyl alcohol), fatty cid
polyglycol esters are also used. Sometimes naturally occurring materials and their derivatives,
such as acacia, semi-synthetic polysaccharides (e.g., methylcellulose), sterol containing
substances (e.g., beeswax), and wool fat (anhydrous lanolin), can also be employed as
emulsifiers. Other ingredients used in emulsions are finely divided olids, antioxidants, such as
butylated hydroxy toluene (BHT) and butylated hydroxyanisole (BHA), humectants and
preservatives like benzoic acid, parahydroxybenzoic acid esters, chlorocresol, and
phenoxyethanol. Emulsions can be used orally (o/w) with the therapeutic agent included in the
internal phase (as for taste masking bad tasting medicaments). Externally, they can be used as
lotions either with therapeutic agents or without (as in cosmetics). Emulsions are made using a
variety of equipment depending on the stability requirement and the kind of process used. Both
batch and continuous processes can be used. Colloid mills have been used traditionally. However,
high-pressure homogenizers, microfluidizers, and ultrasonic homogenizers are being used for
manufacturing emulsions.
Emulsifying agents
Emulsifying agents are used both to promote emulsification at the time of manufacture and to
control stability during a shelf life that can very from days for extemporaneously prepared
emulsions to months or years for commercial preparations. In practice, combinations of
emulsifiers rather than single agents are used. The emulsifier also influences the in vivo fate of
lipid parenteral emulsions by its influence on the surface properties of the droplets and on the
droplet size distributions. For convenience, most pharmacy texts classify emulsifiers into three
groups: i) surface active agents, ii) natural (macromolecular) polymers, and iii) finely divided
solids.
AEROSOL DOSAGE FORMS
Aerosols are pressurized dosage forms containing one or more active drug dissolved, suspended,
or mulsified in a propellant or a mixture of solvent and propellant, which is released on actuation
of the valve as a fine dispersion of liquid or solid in a gaseous medium. Aerosols are intended for
topical administration; for administration into body cavities; for administration orally or nasally
as fine solid particles or liquid mists through the pulmonary airways, nasal passages, or oral
cavity (buccal or sublinual). Those that provide an airborne mist are called space sprays; those
intended for carrying actives to surface are termed as surface sprays and other are termed foam
aerosols. Aerosol consists of product concentrate and the liquefied propellant. The pressure
depends on the types and amounts of propellants and the nature and amount of active present.
Propellant is a liquefied gas or mixture of liquefied gas, which serves as the solvent, or vehicle.
In some cases nonliquefied gases like nitrogen, and carbon dioxide are used. Space aerosols (85%
propellant) operate at 30–40 psig at 708F. Surface aerosols (30–70% propellant) operate between
22–55 psig at 708F. Foam aerosols operate at a slightly higher pressure. Foam aerosols are
emulsions of the propellant and product concentrate. Aerosols can be two-phase systems
comprising of a solution of drug in liquefied propellant and a vapor phase of propellant/gas.
Some of them are present as three-phase systems, comprising of water-immiscible propellant, an
aqueous product concentrate or drug in suspension/emulsion and a vapor phase. Aerosol
containers are made from glass (coated and uncoated), tin, aluminum, and stainless steel
containers. There are various forms of spray valves and metered valves (for more accurate dosing
of potent drug). Oral aerosols are mostly used via the buccal route, e.g., Nitrolingualw spray that
emits nitroglycerin at a dose of 0.4 mg per metered dose. The respiratory tract offers several
advantages for administration of drugs. Inhalation systems should be capable of producing fine
particles, usually ,10 mm for effective drug delivery. Inhalation drug delivery has been
traditionally used to treat respiratory disease, but in recent times the lung has been used as a
portal for administering drugs to the systemic circulation. With their large effective surface area,
the lungs offer an attractive route for systemic drugs. Three main dosage forms, viz. metered dose
inhalers (MDIs), dry powder inhalers (DPIs), and nebulizers have gained prominence (4).
Metered dose inhalers are pressurized systems consisting of drug suspension in a propellant and
may contain other additives such as surfactants, antioxidants, and solvents, although some
solution systems are available. Traditionally MDIs have been formulated using
chloroflurocarbons (CFCs). These propellants are now being phased out under the terms of the
“Montreal Protocol” due to their ozone depleting potential (5). This has resulted in an increasing
urgency to reformulate existing MDI formulations with alternative hydroflurocarbon (HFC)
propellants such as HFC-143a and HFC-227. Formulations using the new propellants have
recently won FDA approval (Airomirw, 3M Pharamceuticals). To offer better coordination
between actuation and patient inhalation of the emitted dose, several spacer devices are available
(Nebuhalerw, AeroChamberw, and Breathancerw) with marketed MDI formulation. Recent
trends in devices include the breath actuated MDI (Autohalerw, 3M Pharmaceuticals), where the
patient inhalation triggers the dose. Due to the phase out of FCs and extensive difficulties in
reformulating using HFCs, dry powder inhalers, and nebulizers are becoming popular. Dry
powder inhalers consist of mixtures of micronized drug and a large particle size carrier (usually
lactose). These drugcarrier ordered mixtures are packaged in unit doses (capsules or blisters), as
in Spinhalerw (Fisons Pharmaceuticals) and Rotahalerw (GlaxoWellcome Pharmaceuticals) or as
pure drug bulk powder, which can be metered into single doses (Turbohalerw, AstraZeneca
Pharmaceuticals). In many instances the patients inhalation maneuver causes the active particles
to separate from the carrier in the air stream. More recently, to overcome intra-patient variability
in dosing, active DPIs have been designed (Dryhalerw, Dura Pharmaceuticals). In these devices,
the patient’s breath triggers a deaggregation mechanism, which separates the drug particles from
the carrier, which are then inhaled. Newer fine particle generation technologies, such as spray
drying and supercritical fluid extraction, are being used to produce fine particles of drug
including proteins and peptides for delivery to the deep lung. This can facilitate the use of
inhalation delivery systems for systemic drug delivery. Nebulizers generate fine mists from
aqueous and nonaqueous drug solutions, using either compressed air or ultra-sonication. Their
main disadvantage is that they are bulky and are not portable. Recent developments in this field
have focused on the development of battery operated portable devices, which can nebulize
aqueous solution containing minimal, or no preservatives.
SEMISOLID DOSAGE FORMS
Ointments, creams, and pastes are semisolid dosage forms intended for topical application. They
may be applied to the skin, used nasally, rectally, and vaginally. Most of them contain some form
of medicament. Medicated ointments are semi-solid preparations intended for application to skin
or mucous membranes. Nonmedicated ointments are used as protectants, lubricants, and
emollients. Ointment bases used for ointment preparation are of four types, hydrocarbon bases,
absorption bases, water-removable bases, and water-soluble bases. Hydrocarbon bases have
emollient properties and are effective as occlusive dressings (e.g., Petrolatum, USP). Absorption
bases permit the incorporation of aqueous solutions to form w/o emulsions (e.g., hydrophilic
petrolatum and lanolin). Water-removable bases are also o/w emulsions and are water washable
(e.g., hydrophilic ointment). Watersoluble bases have no oleaginous component and are referred
to as greaseless water-washable bases (e.g., polyethylene glycol ointment). The potential for
absorption depends on the choice of the bases, and intended use of the medicament. Appropriate
selection of ointment bases is important for dermal therapy. Ointments for rectal preparation
(e.g., Tronolanew ointment for hemorrhoidal analgesia) and vaginal preparations (e.g., Mycelex-
7w ointment as antifungal) are available in the market. Creams are semisolid emulsions with one
or more medicinal agents intended for external use. The so called vanishing creams are o/w
emulsions with stearic acid and cold creams are w/o emulsions with an oily base. Creams spread
more easily than ointments and are preferred by some patients. Gels are semisolid systems with
dispersions of small or large molecules in an aqueous vehicle with a gelling agent e.g., high
molecular weight Carbopolsw that are cross-linked polyacrylic acid. Some gels like milk of
magnesia or magma has two phases. These behave as thixotropic systems with the viscosity
changing due to a gel–sol transition on shaking. Pastes are ointments with large amount of
powder levigated into the base and are intended for application to the skin. Pastes are more
hygroscopic than ointments and are used to absorb serous secretions. (e.g., zinc oxide paste).
Plasters are solid or semisolid masses spread on backing paper, plastic, or fabric. Nonmedicated
forms are termed as adhesive plasters while medicated plasters provide a therapeutic effect at the
site of application. Some medicated plasters are termed as cataplasm, e.g., ibuprofen (3) and
salicylic acid plasters. Transdermal drug delivery systems (TDDS) are used for delivery of
actives through the skin into the systemic circulation. Several methods have been used to
facilitate the transport of active through the barriers of the skin. Certain absorption enhancers are
used to temporarily increase permeability of the skin for increased delivery. More recently,
iontophoretic techniques have allowed the delivery of charged chemicals across the skin using an
applied electric field (e.g., amino acids and proteins). Sonophoresis or high-frequency ultrasound
is also being studied as a means of effectively enhancing transdermal delivery of drugs.
Transdermal delivery systems are of two main types the monolithic matrix system that contains
the excess drug dispersed in the polymeric matrix and cast into a matrix with a backing layer and
frontal membrane, e.g., Estradermw (Novartis). Membranecontrolled transdermal patches contain
drug reservoir in the form of a gel or saturated solution of drug with a backing adhesive and a rate
controlling membrane e.g., Transderm-Scopw (Novartis). Currently, the market is flooded with a
variety of transdermal systems for smoke cessation and hormonal delivery patches. More recently
efforts are on to develop transmucosal delivery patches.