Chapter - 5, Pharmaceutics
Chapter - 5, Pharmaceutics
Introduction
The development of a new chemical entity (NCE) requires the testing of its biological activity at various
stages of development. For systemically acting drugs, animal studies are carried out at early stages of
development using parenteral administration of a solubilized form of the drug. As drug development
proceeds to later stages, human clinical studies are preferred with an orally administered dosage form that
is both simple to formulate and provides adequate bioavailability. Preferred drug product
(DP) dosage form choices are determined based on the drug substance’s (DS’s) physico-chemical
properties, patient and disease state constraints and preferences, dose, manufacturability, and
commercial factors such as other therapeutic options available to the patient.
An oral tablet dosage form is usually the most preferred dosage form because of patient convenience and
acceptance. Most drugs are formulated in tablet dosage forms. Tablets are available in a wide variety of
shapes, sizes, colors, and surface markings. This chapter would describe the types of tablets and discuss
its formulation components, manufacturing pro-cesses, quality attributes, and some key considerations in
the design and development of an oral tablet dosage form.
Types of tablets
Depending on the physicochemical properties of the drug, site and extent of drug absorption in the
gastrointestinal (GI) tract, stability to heat, light, or moisture, biocompatibility with other ingredients,
solubility, and dose, the following types of tablets are commonly formulated.
1. Swallowable tablets
The most common types of tablets are swallowed whole. These tablets dis-integrate and release their
contents in the GI tract.
2. Effervescent tablets
These tablets are formulated to allow dissolution or dispersion in water prior to administration and should
not be swallowed whole. In addition to the DS, these tablets contain sodium carbonate or bicarbonate and
an organic acid such as tartaric acid. In the presence of water, these additives react, liberat-
ing carbon dioxide, which acts as a disintegrator and produces effervescence. The drug is released into
the aqueous medium as a solution, if it is highly soluble, or suspension. Ingestion of a dissolved or finely
dispersed drug pro-vides a rapid rate of drug absorption. Therefore, effervescent tablets can be suitable for
acute conditions that require immediate relief, such as pain and gastric acidity. For example, cephalon’s
fentanyl effervescent tablet can be used to reduce the intensity of breakthrough pain in cancer patients.
3. Chewable tablets
Chewable tablets are used when a faster rate of dissolution and/or buc-cal absorption is desired. Chewable
tablets consist of the drug dispersed throughout a saccharide base that provides mild sweetness. Flavors,
sweet-eners, and colors are also added to chewable tablets to improve palatability and organoleptic appeal.
The drug is released from the dosage form by physical disruption associated with chewing and dissolution
in the fluids of the oral cavity, and the presence of a effervescent material. For example,
some antacid tablets can be chewed to obtain quick indigestion relief. Chewable tablets are typically
prepared by compression and usually contain mannitol or sorbitol as saccharide, mildly sweet, fillers.
Mannitol is some-times preferred as a chewable base diluent, because it has a pleasant cooling sensation in
the mouth due to negative heat of dissolution and can mask the taste of some objectionable medicaments.
Buccal and sublingual tablets dissolve in the cheek pouch (buccal) or under the tongue (sublingual). Buccal
or sublingual route of drug absorption bypasses hepatic metabolism, often referred to as the first-pass
effect on oral administra-tion, and is preferred for low dose drugs that have extensive hepatic metabo-lism.
Sublingual administration also allows rapid drug absorption, which may be critical in cases such as
nitroglycerin for chronic heart failure. Other exam-ples include isoprenaline sulfate (bronchodilator),
glyceryl trinitrate (vasodila-tor), and testosterone tablets. These tablets are usually small and flat, do not
contain a disintegrant, and are intended for dissolution in the local fluids.
5. Lozenges
Lozenges are slow dissolving compressed tablets that do not contain a disin-tegrant. Some lozenges
contain antiseptics (e.g., benzalkonium) or antibiotics for local effects in the mouth. Lozenges are also
used for systemic effect, such as those containing vitamin supplements. Lozenges are palatable and
organo-leptically appealing by the addition of flavors, sweeteners, and colors.
6. Coated tablets
Most tablets are coated for one or more of the following reasons:
Coating is not used on buccal, sublingual, chewable, effervescent, or dis-persible tablets to avoid any delay
in drug release due to the time required for the rupture or dissolution of the coating material
7. Enteric-coated tablets
GI fluid pH increases progressively from acidic to basic from the stomach through the intestines to the
colon. The changes in GI pH can be utilized to release a drug at a particular physiological location in the
GI tract. In particular, oral solid dosage forms can be coated with a polymer that is insoluble at the acidic
stomach pH and soluble at basic intestinal pH. Such polymers are known as enteric polymers and such
coatings are termed enteric coatings. Enteric-coated tablets are the tablets coated with enteric polymers.
Complete coating of the tablet with these polymers allows the polymer to form a barrier between the core
of the tablet and the surround-ing aqueous medium. Thus, the enteric-coated tablet remains insoluble in
the low pH environment of the stomach, but dissolves readily on passage into the small intestine with its
elevated pH.8. Immediate release tablets
Most tablets (discussed earlier) are immediate release (IR) tablets, that is, they make all the drugs available
to the dissolution medium immediately on coming in contact with the aqueous medium. The drug
dissolves at a rate determined by the composition of the dissolution medium (such as pH) and
physicochemical properties of the drug (such as solubility and particle size).
In contrast to the IR tablets, certain dosage forms, such as controlled-release (CR) or extended-release
(XR) tablets, are designed to control or extend, respectively, the rate at which drug dissolves in the
aqueous medium. Thus, CR tablets reduce the rate of drug release to a slow, controlled rate, which is
typically zero order. XR tablets, on the other hand, extend the duration of drug release by slowing down
the rate of drug release but may not have control on the rate (i.e., may not provide zero-order kinetics of
drug release). CR or XR tablets are sometimes also called SR tablets.
Tablet formulation
In addition to the active drug, called DS or active pharmaceutical ingredi-ent (API), tablets may contain
one or more of functional ingredients such as diluents (also known as fillers), binders, disintegrants,
glidants, lubri-cants, coating materials, coloring agents, stabilizer(s), sweeteners, and fla-voring agents.
These ingredients are called excipients. Excipients are added to improve one or more of the three key
functional properties of a dosage form: (1) bioavailability, (2) manufacturability, and (3) stability.
Excipients facilitate optimum bioavailability, that is, rate and extent of drug absorption from the
dosage form, by providing reproducible and optimum rate, extent, and the 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 stability of the API for the duration of time a product may be stored between the
manufacture and the consump-tion (called shelf life).
Sodium starch
Disintegrant
Glycolate,crospovidone
sweetner Saccrinr sodium Sucralose Sweetening to over come the drug taste
Processing of Tablet-
Types of manufacturing processes
Based on the characteristics of the starting materials that influence the properties of the powder blend,
three general processes are used for prepar-ing granulation blends for compression:
Direct compression
Dry granulation or roller compaction
Wet granulation
1. Direct compression: Direct compression is the preferred method if powder blend has adequate flow,
compactibility, and cohesion with low segregation potential. This is the simplest process that involves the
least extent of material handling. Direct compression involves simply mixing the required ingredients and
compressing them into tablets on the press.
2. Dry granulation: Dry granulation is preferred in circumstances where powder flow, cohesion, and/or
segregation potential need to be improved, but compactibility is adequate. This process involves com-
pacting a powder blend. It can be carried out by either of two processes: (a) slugging, which involves
compression using large punches and dies in a tablet press; or (b) roller compaction, which involves
forcing the powder blend between two counterrotating rolls that are pressed together under hydraulic
pressure. This squeezes the powder blend into a solid cake between rollers.
3. Wet granulation: Wet granulation is preferred when compactibility of the powder is not very high and
there is a need to improve the flow, cohesion, and/or segregation potential of the powder blend. The
powder blend is loaded in a granulator (vessel with a rotating blade to mix the powder and granulated with
a solu-tion of the binder or water (if a dry binder is added to the powder mixture). Water is the most
widely used blender vehicle. The use of nonaqueous granulation liquids, such as ethanol, is no longer pre-
ferred for safety and environmental reasons. The formed granules are dried in a tray or fluid bed dryer at
moderately elevated tempera-tures. Dried granules are then mixed with extragranular excipients and
compressed on the tablet press.
Evaluation of tablets
The compendia, such as the United States Pharmacopeia (USP), and the regulatory bodies, such as the
United States Food and Drug Administration (FDA), in addition to historic product-development
experience, inform the desired quality attributes of the tablets. Tablets are usually tested for the following
characteristics:
Appearance
All tablets should have identical size, shape, thickness, color, and surface markings. The general
appearance of the tablet allows monitoring a lot-to-lot and tablet-to-tablet uniformity. Tight control
of tablet thickness is required to ensure automated machine operations during its packaging and
handling. Tablet-to-tablet thickness within a batch and average thickness of tablets across all batches are
defined and controlled.
Uniformity of content
All tablets must be demonstrated to contain the labeled active ingredient and there should be tablet-to-
tablet uniformity in drug content. This is usually tested by an analytical method for drug potency (such as
high-performance liquid chromatography) in a several individual tablets.
Hardness
Tablet hardness refers to the amount of force required to diametrically crush a tablet. It is representative
of the tensile strength of a tablet and is determined by the cohesion characteristics of the powder
blend. Tablet hardness impacts tablet disintegration, dissolution, and friability. If tablets are too hard, they
may not disintegrate within a reasonable period of time. This can lead to reduced bioavailability and
failure to meet the dissolution specification. If they are too soft, then they may not withstand the handling
and shipping operations, leading to tablet breakage or chipping (breaking away from edges) and failure
during friability testing. Friability is the ten-dency of the tablets to chip or break by tumbling motion.
Friability
Tablet friability represents the tendency of a tablet to shed powder or break into smaller pieces under
mechanical stress, such as falling from a fixed dis-tance. It is a function of the fragility of the compressed
powder blend, tab-let shape, cohesion, and hardness. Low tablet friability is desired to ensure its physical
integrity during packaging, shipment, and handling.
Weight uniformity
Tablets are compressed at a predefined weight. Under the assumption of normality of statistical
distribution of tablet weight, all tablets are required to be within a certain range of the
predefined tablet weight. Several tablets are weighed individually, and both the average weight and
variation of indi-vidual tablet weight from the average are calculated and controlled during the
manufacturing to ensure that the tablets contain the desired amounts of drug substances, with no more
than acceptable variation among tablets within a batch.
Disintegration
Disintegration of tablets is evaluated to ensure that the tablet dissolves or breaks apart into smaller
particles or granules on contact with water under agitation. This allows the DS to dissolve from its
primary particles, being fully available for dissolution and absorption from the GI tract. Tablet dis-
integration is evaluated in a standardized apparatus that subjects six tablets to a defined mechanical stress
in individual reciprocating cylinders in a suitable aqueous medium at 37°C, to reflect the conditions on
oral inges-tion. The time it takes for the last of six tablets to disintegrate into smaller particles and
disappear from the reciprocating cylinders is called disinte-gration time. The disintegration media required
varies depending on the type of tablets to be tested. The disintegration time is generally not more than 15
min for IR tablets.
The disintegration test is used as a control for tablets intended to be admin-istered by mouth, but not for
the tablets intended to be chewable and SR.
Dissolution
As drug absorption and physiological availability depend on having the DS in the dissolved state at the site
of absorption, dissolution, also termed drug release, is an important property of tablets. The rate and
extent of dissolution of a drug are tested in vitro by a suitable dissolution test. Dissolution is used as both
a quality control tool to ensure batch-to-batch and tablet-to-tablet uniformity in drug-release
characteristics of the tab-lets and sometimes also as a tool for in vitro–in vivo correlation (IVIVC) of drug
release (in vitro) and drug absorption (in vivo). Dissolution test provides a means of control in ensuring
that a given tablet formulation is similar with respect to the rate and extent of drug release as the batch
of tablets were shown initially to be clinically effective.
Capsules
Introduction
Capsules are the dosage forms in which the drug formulation in a powder, semisolid, or liquid form
is enclosed in a shell. This shell is generally made from gelatin, but can be made from other polymers such
as hydroxypro-pyl methylcellulose (HPMC), polyvinyl alcohol (PVA), seaweed, or starch. Depending on
the composition of the gelatin shell, the capsules can be hard or soft gelatin capsules.
Soft gelatin capsules (also known as softgels) are made from a relatively more flexible,
plasticized gelatin film than hard gela-tin capsules. Hard capsules, such as hard gelatin or HPMC capsules,
are typically used for powder or solid fills, whereas soft gelatin capsules are used for semisolid or liquid
fills. Lately, hard capsules have also been used for liquid or semisolid fills.
Shapes of capsule-
Gelatin is a colorless, almost tasteless, translucent proteinaceous substance that is brittle when dry and
elastic when mixed with controlled amount of moisture. It is produced by irreversible, partial hydrolysis of
collagen, which is obtained from animal skin and bones. It forms a semisolid col-loid gel in the presence of
water, which displays a temperature-dependent gel–sol transformation and viscoelastic flow. It has
crystallites (microscopic crystals formed during the cooling phase of manufacture of capsule shells) that
stabilize the three-dimensional gel network structure and are respon-sible for streaming birefringence in
gelatin solutions.
A hard gelatin capsule shell consists of two pieces: a cap and a body. The body has slightly lower diameter
than the cap and fits inside the cap. They are produced empty and are then filled in a separate operation.
During the capsule filling unit operation, the body is filled with the medicament, fol-lowed by the insertion
of the cap over the body.
The shapes and interlocking arrangement of the body and the cap have evolved to meet the manufacturing
and use requirements of hard gelatin capsules as shown in Figure
Formulation components
The powder formulations for encapsulation into hard gelatin capsules require a careful consideration of
the filling process requirements, such as lubricity, compactibility, and flow. Additives present in capsule
formula-tions, 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): Active ingredient is mixed with a sufficient vol-ume of a diluent, usually
microcrystalline cellulose, lactose, man-nitol, starch, or dicalcium phosphate, to increase the bulk of the
formulation.
2. Glidants: Glidants are finely divided dry powders added to the formu-lation 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, and magnesium stearate,
improve flow by
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 just as the tablet formulations 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 fric-tion between the sliding surfaces in
contact with the powder. The most 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 cap-sule formulations of poorly water-
soluble drugs to reduce the contact angle, increase the wettability of drug particles, and enhance drug
dissolution. The most commonly used surfactants in capsule formula-tions are sodium lauryl sulfate and
sodium docusate (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. Powder wettability and dissolution rate of several drugs, such as
hexo-barbital and phenytoin, were enhanced with the inclusion of methyl-cellulose or
hydroxyethylcellulose in their capsule formulations.
5. Disintegrants: A disintegrant is frequently included to aid rapid disin-tegration and dissolution of the
contents. Common disintegrants used in hard gelatin capsule formulations include croscarmellose sodium,
crospovidone, and sodium starch glycolate.
Controlled-release beads and minitablets are often filled into gelatin capsules for convenient
administration of an oral controlled-release (CR) dosage form. For example, SR antihistamines,
antitussives, and analgesics are first manufactured into extended-release (XR) micro-capsules or
microspheres, and then placed inside a gelatin capsule. Another example is enteric-coated lipase
minitablets that are placed in a gelatin capsule for more effective protection of these enzymes from the
acidic environment.
Manufacturing process
Very small-scale and experimental filling of the hard gelatin capsules can simply be carried out manually,
that is, by removing the cap from the body of an empty capsule shell, filling the body with a preweighed
amount of API or formulation, and attaching the cap. This can be carried out in early clinical studies by
the sponsor or by the pharmacist. Compounding by
1. the pharmacist is preferred when the stability of the drug in the capsule is unknown and is called on-
site compounding.
2. Small-scale manufacture (several hundred capsules) can be done by using a manual capsule-filling
machine., the manual-filling operation involves the following steps:
3. Placing empty gelatin capsules on the removable plate with bodies facing downward. This removable
plate is then placed on the base plate and the bodies of the capsules are locked in position with the
base plate using a lever.
4. The removable plate is removed with the caps on it. The body is filled with the formulation manually
using a plastic spetula, and the excess powder is removed.
5. he removable plate is placed back on the base plate and pressing the flat plate seals the capsule caps.
The sealed capsules are removed from the base plate by opening the lock on the body using the lever
and inverting the base plate.
6. Large-scale filling of hard gelatin capsules follows the same principles using a high-speed capsule-
filling machine, with two significant improvements:
7. Capsule alignment and separation are driven by vacuum, instead of mechanical interlocking.
8. Powder filling may require a soft compact (plug) formation depend-ing on the formulation weight
and capsule fill volume. This compact is usually much softer than a typical tablet. The compaction
force used for plug formation is typically 20–30 N, compared to 10–30 kN typically used for
tableting.
9. The high-speed powder filling is accomplished by either of the two dosing devices: (a) dosator device
or (b) dosing disk/tamping device.
1. The dosator device uses an empty tube that dips into powder bed, which is maintained at a height
approximately two-fold greater than the desired length of the plug. The dosator piston’s forward
movement helps form the plug, which is then transferred to the body of the capsule, and released.
2. The tamping device operates by filling the cavities bored into the dosing disk, similar to the die-filling
operation during tableting. A tamping punch slightly compresses the filled powder by repeated action,
which is followed by the ejection of the plug into the capsule body.
Soft gelatin capsules consist of a hermetically sealed outer shell of gelatin that encloses a liquid or
semisolid medicament in the unit dosage. Soft gelatin capsules are a completely sealed dosage form and
cannot be opened without destroying the capsules. Drugs that are commercially prepared in
soft capsules include cyclosporine, declomycin, chlorotrianisene, digoxin, vitamin A, vitamin E, and
chloral hydrate.
Manufacturing process
Soft gelatin capsules are filled with solutions or suspensions of drugs in liquids, and sealed in a single
operation. They are prepared from a more flexible plasticized gelatin by a rotary-die process. As shown
in Figure 21.4, this process involves the following sequential operations:
1.Two heated sheets of gelatin of similar thickness are produced by the controlled flow of the fluid gelatin
from its heated storage container (gelatin tank) by using a controlled pore opening and fill in
a spreader box.
2 The gelatin film flows through a series of oil rolls that stretch the sheets and direct them appropriately
toward die rollers.
3. The two sheets of gelatin merge on the metallic rollers that contain dies of appropriate shape and size
and move in the opposite direc-tion toward each other. The application of vacuum inside the rollers
combined with pressurized filling of the components enables the for-mation of a cavity. The application of
heat and mechanical pressure enables sealing of the shells as they pass through the rollers.
4. As the gelatin sheets are being annealed, a calibrated amount of the drug formulation is pumped into
each cavity by the product pump through an injection wedge.
5. The concurrent process of drug product injection into the die cavity and sealing of the cavity is either
accompanied by the cutting and release of individual soft gelatin capsules (if the rollers are suitably
designed) or, the capsules may be cut from the sheets in a separate, subsequent operation.
6.The filled capsules are dried at ambient conditions to remove moisture from the outer surface and may
be tray dried for an extended period of time (e.g., up to 48 hours).
7. Finished capsules are passed on a conveyor belt for the next unit operations of packaging and labeling.
Evaluation of capsule drug products
1. In-process testing, during the manufacture of the drug product. These batteries of tests are carried out
at predefined intervals during the product manufacturing, by the manufacturing personnel, and their
results recorded on the batch record. Adverse findings in these tests can be used as a guide to alter the
manufacturing-process parameters.
2. Finished product testing, after the whole batch has been manufac-tured. These tests help identify
whether the batch is acceptable for marketing or its intended usage.
3. Shelf-life testing, after the whole batch has been packaged. These tests are frequently carried out after
defined periods of storage at prede-termined conditions. They help to assign and verify the shelf life and
usability of the drug product.
In-process tests
Visual inspection of soft gelatin capsules is done to ensure absence of clearly malformed, damaged, or
improperly filled capsules. During the encapsula-tion of soft gelatin capsules, the following parameters are
usually closely monitored and controlled:
Visual inspection, fill weight, and fill-weight uniformity are the key in-process tests used for hard
gelatin capsules.
Permeability and sealing-Soft gelatin capsules are tested for physical integrity (absence of leakage) by
visual inspection. Similarly, hard gelatin capsules are tested for any breach of physical integrity (breakage
or opened cap and body).
Potency and impurity content-All capsules are tested for drug content (potency, as a percent of label claim).
In addition, most drug products are tested for the related substances or impuri-ties. These must meet
predefined specifications for a batch to be acceptable.
Ten hard gelatin capsules are usually weighed individually and the con-tents are removed. The emptied
shells are individually weighed and the net weight of the contents is calculated by subtraction. The content
of active ingredient in each capsule may be determined by calculation based on the percent drug content in
the formulation for high drug load formulations.
For soft gelatin capsules, the gross weight of 10 gelatin capsules is deter-mined individually. Then
each capsule is cut open, and the contents are removed by washing with a suitable solvent (that dissolves
the fill but not the shell). The solvent is allowed to evaporate at room temperature, fol-lowed by weighing
of the individual washed shells. The net contents are calculated by subtraction and the content
of active ingredient in each of the capsules can be determined by calculation based on the percent drug
content in the formulation.
Fill-weight variation of capsules is often a function of equipment setup and filling operation. An
automated capsule sizing machine and/or weight checker is frequently used to discard over- or
underfilled capsules.
Uniformity of content
Uniformity of content of the active ingredient can be determined by weight variation of the fill of hard or
soft gelatin capsules for high drug load (API ≥25% w/w of the total fill weight), high fill-weight (250
mg/capsule) formu-lations. For low drug load and low fill-weight formulations, each capsule must be
analyzed individually by the potency method for the content of the active ingredient. The uniformity of
content is assured if predetermined criteria for the range and variation in the content of
the active ingredient are met.
Disintegration
Disintegration of hard and soft gelatin capsules is evaluated to ensure that the drug substance is fully
available for dissolution and absorption from the GI tract. The disintegration media varies depending on
the type of capsules to be tested.
Dissolution
Drug absorption and physiological availability depend on the drug sub-stance being in the dissolved state
at the site of drug absorption, viz. the GI fluids. The rate and extent of dissolution of the drug from
the capsule dosage form is tested by a dissolution test. Dissolution test provides means of quality control
in ensuring that (a) different batches of the drug prod-uct have similar drug release characteristics and (b)
that a given batch has similar dissolution as the batch of capsules that was shown initially to be clinically
effective.
Moisture content
Water content of the entire capsule or the capsule contents are determined by Karl Fisher titrimetry to
enable the correlation of water content with the degradation profile or drug-release characteristics
of capsules.
Microbial content
The capsules are tested to ensure lack of growth of bacteria and mold by microbiological tests. These tests
are usually carried out by incubation of the capsule contents in a growth medium and counting
the colonies formed after a predefined period of time. Selection of the growth medium and duration of the
test, as well as maintenance of aseptic conditions during the testing, are critical to successful assessment
of microbial contamination by this method.
Shelf-life tests
For example, for a product intended for sale in the United States with recommended storage at room
temperature and ambient humidity, real-time stability is carried out at 25°C and 60%
relative humidity (RH) with periodic testing up to the recommended shelf life, for example, 2
years. Accelerated stability testing on such a product is usually carried out at 40°C and 75% RH for a
limited duration of time, for example, 3 months. The exact conditions for real-time and accelerated storage
testing depend on the geographic and climatic region where the drug product is intended to be
manufactured and marketed.
Sterile formulations –
Introduction
Parenteral drug products are the dosage forms intended for administration by a route that does not
involve the gastrointestinal (GI) tract (thus, parenteral). Most of the parenteral drug products are
injectable dosage forms that are intended for administration by injection using a syringe and a needle.
Parenteral dosage forms are preferred for one or more of the following reasons:
· Instability of the drug in the GI tract. For example, most protein drugs are highly unstable.
· Ability to immediately stop drug administration is important. For example, most emergency room
medications and anesthetics.
· High degree of flexibility in dosage adjustment with or without real-time patient physiological
response is needed. For example, emer-gency medications such as analgesics, anticancer drugs, and fertility
medications.
The IV administration provides immediate access of the drug to the sys-temic circulation, resulting in the
rapid onset of drug action. Depending on the rate of drug administration, IV injections could be a bolus
or an infusion. A bolus means the drug is injected into the vein over a short period of time. A bolus is
used to administer a relatively small volume and is often written as IV push (IVP). An infusion refers to
the introduc-tion of larger volumes (100–1000 mL) of the drug over a longer period of time. A continuous
infusion is used to administer a large volume of drug at a constant rate. Intermittent infusions are used to
administer a relatively small volume of drug over a specified amount of time at speci-fied intervals.
IV infusion can be administered through peripheral veins, typically in the forearm or the peripherally
inserted central catheter. The commonly administered IV infusion products include Lactated Ringers
Injection USP; Sodium Chloride Injection USP (0.9%), which replenish fluids and electro-lytes; and
Dextrose Injection USP (5%), which provides fluid plus nutrition; and various combinations of dextrose
and saline. Other solutions of essen-tial amino acids or lipid emulsions are also used as infusions.
Intramuscular route
IM injections of drugs into the striated muscle fibers that lie beneath the SC layer provide effects that are
less rapid but generally longer lasting than those obtained from IV administration. Aqueous or oleaginous
solutions or suspensions of drugs may be administered intramuscularly. Drugs in aque-ous solution
are absorbed more rapidly than those in oleaginous prepara-tions or in suspensions. An IM medication is
injected deep into a large muscle mass, such as the upper arm, thigh, or buttocks. Up to 2 mL of the drug
may be injected into the upper arm and 5 mL in the gluteal medial muscle of each buttock.
Numerous dosage forms are administered through this route of adminis-tration, including solutions
(aqueous- or oil-based), emulsions (o/w or w/o), suspensions (aqueous- or oil-based), colloidal
suspensions, and reconsti-tutable powders. Slow drug absorption leading to a sustained-release (SR) effect
can be achieved with highly insoluble drugs or formulations that are oleaginous or particulate. IM
injections are often painful and nonre-versible, that is, the administered drug cannot be withdrawn if
needed. Antibiotics are often administered by this route.
Subcutaneous route
The SC route is used for small volume injections, typically 1 mL or less. SC injections
are administered beneath the surface of the skin, between the dermis and muscle.
Medications administered by this route are slowly absorbed and consequently have a slower onset of
action than medications given by IV or IM routes. Drugs often given by this route include epineph-rine,
insulin, heparin, scopolamine, and vaccines. Small injection volume often puts limitations on the drugs
that can be administered by this route. For example, high dose drugs that tend to become highly viscous at
high concentrations, such as most globular proteins, are usually difficult to for-mulate as subcutaneous
injectable dosage forms.
Other routes
Certain types of injections are intended for specific purposes. For example,
· Intradermal administration involves injection just beneath the epider-mis, within the dermal or skin
layers. The usual site for intradermal injection is the anterior forearm. The volume of solution that can
be administered intradermally is limited to 0.1 mL. The onset of action and the rate of absorption of
medication from this route are slow. This route is used for diagnostic agents, desensitization, testing for
potential allergies, or immunization.
· Intrathecal route involves drug administration into the cerebrospinal fluid (CSF). This route is
needed if CSF is the desired site of drug action because most drugs do not reach the CSF from the
systemic circulation. Drugs administered intrathecally include antineoplastics, antibiotics, anti-
inflammatory, and diagnostic agents.
· An intraarticular injection is made into the synovial cavity of a joint, usually to obtain a local
therapeutic effect. For example, an intraar-ticular injection of a corticosteroid provides an anti-
inflammatory action in an arthritic joint.
· An intraarterial injection is made directly into an artery that has been surgically isolated if it is
necessary to deliver a high concentration of drug to a diseased organ, such as kidney, with minimal
distribution to other systemic locations.
· An intraocular injection is made directly into the eye. For example, an injection into the vitreous
humor provides access of drug to the rear regions of the eye, such as the retina, which does not receive
high drug concentration on topical administration.
Rate and extent of absorption
The route of administration has a significant impact on the rate and extent of systemic absorption of a
drug. Drugs injected intravenously are imme-diately available in the systemic circulation. Systemic
availability of the drug from other sites of injection, such as SC, IM, and intraperitoneal (IP), requires
drug absorption. The rate of drug absorption from the site of administration to the systemic circulation
depends on the blood flow to the site and drug diffusivity in the tissue. Thus, increase in local blood
flow increases the rate of drug absorption. Increasing tissue diffusivity in the extracellular matrix (ECM)
of the injection site also increases the rate of drug absorption. Thus, hyaluronidase, which breaks down
the ECM, increases drug diffusion and absorption. The extent of drug absorption from a
parenteral route could be lower if the drug is metabolized in the tissues.
Selection of a parenteral route of administration for a new therapeutic moi-ety depends on several
considerations, such as
· Desired rate of onset of action: IV route provides the most rapid onset of action, whereas the SC,
IM, and IP routes have slower rate of drug absorption into the systemic circulation. SC route is often
preferred for SR dosage forms when slow drug absorption over a prolonged period is desired.
· Location of drug action: Intraarterial injections are preferred for localized drug action in an organ,
whereas IP route is preferred if drug action is desired in the lymphatic system.
· Tissue irritability: Injection of an irritant drug is likely to be more painful by the IM than the
SC route due to higher blood flow and sensory innervations in the muscles.
· Injection volume: The volume of drug injected is lower for SC than for IM or IV routes. In certain
cases, formulation of low volume injec-tions is not feasible, especially for protein drugs with high doses.
Injectable parenteral drug products are available as single or multiuse containers in different container–
closure systems and volumes. Small-volume parenterals (SVPs) are available in volumes of less than 1 ml,
and up to 50 ml. Large-volume parenterals (LVPs) are usually packaged in volumes up to 1000 mL.
Types of formulations
1. Solutions
2. Suspensions
3. Emulsions
LIQUID ORAL PREPARATIONS
Oral liquids are homogeneous liquid preparations, usually consisting of a solution, an emulsion, or a
suspension, of one or more active ingredients in a suitable liquid base. They are prepared for oral
administration either as such or after dilution. They may contain other substances such as suitable
dispersing, solubilizing, wetting, emulsifying, stabilizing, suspending, and thickening agents and
antimicrobial substances for preservation. They may also contain suitable sweetening agents,
flavoring agents, and permitted coloring agents. Classes of oral liquid dosage forms include:
Syrup
Syrup: a viscous oral liquid that contains one or more active ingredients in solution. The base
generally contains large amounts of sucrose, other sugars, or sweetening agents. Syrups may
contain ethanol (95%) as a preservative or as a solvent for flavors. Antimicrobial agents may also
be added to syrups to maintain the microbial quality of preparation.which having the 66.7% W/v
Sugar concentration according to IP.
Method of Preparation
–This method is used for the preparation of syrup containing volatile substances.
–In this process active substance is added in solution and agitated in a glass stoppered bottle.
–Closing of bottle is necessary to protect the syrup from contamination and loss of solution during
the process.
–Cough syrups are commonly prepared by this process. E.g. Codeine syrup, Ephedrine sulphate
syrup.
–This process is generally prepared as it is simple, less time consuming method, particularly if the
constituents are not affected by heat and non-volatile in nature.
–Sugar is generally added to the purified water and heat is applied until solution is formed.
–This method to put to use in those cases in which tinctures, fluid extracts or other medicated
substances in liquid forms are added to syrup to medicated.
–In this process some time precipitation takes place due to presence of resinous and oily substances.
4. Percolation
–In this method, either sucrose may be percolated to prepare the syrup, or the sucrose of the
medicinal components may be percolated to form an extractive to which sucrose or syrup may be
added.
Vehicle
Preservatives
Flavouring and Colouring agents
Stabilizers
Aromatic waters
Buffers
Viscosity Enhancers
Antioxidants
Advantages of Syrups
Any water soluble drug which is stable in aqueous solution may be added to flavored syrup.
Disadvantages of Syrups
They are not suitable for patients who are on a restricted intake or those who are diabetic.
Pleasant taste may attract the children to consume extra doses than actually prescribed.
If sucrose concentration is not proper i.e. 66.7% w/w, it is prone to microbial growth, which requires
addition of preservatives.
Elixir:
Elixir: a clear, flavored oral liquid containing one or more active ingredients dissolved in a suitable
base that contains a high proportion of sucrose and may also contain ethanol (95%) or a diluted
ethanol.
Method of Preparation
Simple dissolutions or mixtures of two or more liquids can be used to prepare elixirs after the
ingredients have been dissolved in their respective solvents.
Those that are alcohol-soluble will dissolve in alcohol, and those that are water-soluble will dissolve in
water
Aqueous solutions are added to alcoholic solutions to maintain the strength of the alcohol.
In this stage, some of the flavoring agents can separate from the product due to the reduction in
alcohol strength.
Once the elixir is allowed to stand for a while, oil globules begin to precipitate
The filtrate is then added. The excess oils are absorbed by talc The resulting product is clear after
filtration.
Advantages of Elixirs
Hydroalcoholic preparation maintains both water soluble and alcohol soluble drugs in solutions.
Hence they are the stable dosage forms compared to syrups.
Elixirs containing more than 10% alcohol usually acts as self-preservative and does not require
additional preservatives.
Elixirs are less viscous than syrups and thus do not create difficulty in filtration.
Disadvantages of Elixirs
Elixirs having high percentage of alcohol require sweetening agent other than sucrose since sucrose
is slightly soluble.
– Nanocrystal
– Nanomorph
– Sonocrystallization
Oral Suspension: an oral liquid that contains one or more active ingredients suspended in a suitable
base.
A Pharmaceutical suspension is a biphasic liquid dosage form in which the therapeutic agent is
dispersed or suspended in the external phase.
The particle size of the dispersed solid is usually greater than 0.5 pm. E.g. Magnesium hydroxide
mixture, calamine lotion, etc.
Type of Suspension
Classification of Suspensions
Oral
Parenteral
Topical
Flocculated
Deflocculated
Preparation of Suspensions
Those in which the insoluble substances are added to the vehicle or the vehicle is added to the
insoluble substances.
Those in which the insoluble material is formed in the liquid due to the interaction of two or more
ingredients.
Diffusible solids are those substances which do not dissolve in water, but on shaking they can be
mixed with it and remain evenly distributed throughout the liquid for sufficiently long time allowing
uniform distribution of the drug in each dose.
Indiffusible solids are those substances which do not dissolve in water and do not remain evenly
distributed in the vehicle for sufficiently long time to ensure uniformity of the measured dose.
The highly diluted solutions of the reacting substances are mixed together so as to form very finely
divided precipitates that can be easily distributed throughout the liquid by shaking.
Precipitate-forming liquids are not only insoluble in water but they form indiffusible precipitates
particularly when salts are present. They contain resinous matter and when mixed with water lead to
precipitation of the resin and may stick to the sides of the bottle which will be difficult to re-disperse
by shaking.
Suspending agents
Flocculating agents
Thickeners/Protective Colloids
Wetting agents
Preservatives
Antioxidants
Chelating agents
Buffering agents
Sweetners
Flavors
The sediment formed should be easily re-suspended by the use of moderate shaking.
It should be easy to pour.
It should have pleasant odor, color and palatability.
It should have good syringeability.
It should be physically, chemically microbiologically stable.
Parenteral ophthalmic suspension should be sterile.
Advantages of Suspensions
Certain drugs which are unstable in solution form are stable when suspended and dispensed as
suspensions.
The disagreeable taste of certain drugs in solution form is negligible when they are given in their
suspension form.
Mostly oral suspensions have aqueous vehicles which might be flavored or sweetened to impart
patient compliance.
Disadvantages of Suspensions
These are fundamentally unstable and therefore require formulation skill to ensure that the physical
stability of the formulation is retained over the period of the shelf-life.
Suspension being the liquid dosage form is susceptible for physical, chemical and microbial
contamination.
Rheological properties of suspension are often difficult to maintain in suspension with high
concentration of in-diffusible solids.
Evaluation of Suspensions
Emulsions
Emulsion is a biphasic liquid preparation containing two immiscible liquids one of which is dispersed
as globules (dispersed phase or internal Phase) in the other liquid (continuous phase or external
phase) by using a suitable emulsifying agent.
Advantages of Emulsion
Emulsions may commonly use to administer oils that may have a therapeutic effect.
Medicines having an unpleasant taste and odor can be made more palatable for oral administration in
the form of an emulsion.
Emulsion provides protection against drugs which are prone to oxidation or hydrolysis.
Emulsions are thermodynamically unstable and therefore must be formulated to stabilize from
separation of the two phases.
The formulation should be easily spread over the affected area in case of topical or external
application.
If the emulsion is designed for oral route, the flavor must be acceptable.
Types of Emulsions
Emulsions can be classified on the basis of the properties of the dispersed phase and dispersion
medium.
Classification of Emulsions
Emulsions are classified on the basis of emulsifying agents used and mode of administration.
Emulsions for oral administration: They are usually o/w type of emulsions used for
administering oils having medicinal values. E.g. castor oil, cod-liver oil, almond oil.
Emulsions for external use: They can be o/w or w/o type of emulsions. E.g. Creams, lotions.
Emulsions for parenteral use: They can be o/w or w/o type of emulsions. o/w type of emulsions are
administered through intramuscular route, whereas w/o type through subcutaneous route. E.g. fat
soluble vitamins, oil soluble sex hormones.
Emulsions for rectal use: They are used in the form of enemas for the evacuation of bowels. E.g.
enema.
Emulsifying Agents
An emulsifying agent must be employed in the preparation of stable emulsion. Its purpose is to
prevent coalescence of droplets and maintain the stability of individual droplets of the continuous
phase.
Griffin devised a method for calculating balanced mixtures of emulsifying agents to provide a
particular type of emulsion.
It is called Hydrophilic Lipophilic Balance (HLB). Every emulsifying agent is given a number on HLB
scale, which is divided into 18 units.
Dilution Test
An assembly is used, in which a pair of electrodes connected to an electric bulb is dipped into an
emulsion.
An o/w emulsion will conduct electricity as water conducts electricity, but a w/o will not conduct
electricity.
Dye Solubility Test
In this test an emulsion is mixed with a water soluble dye (amaranth) and observed under the
microscope.
If the continuous phase appears colored (red), it means that the emulsion is o/w type as water is in
the external phase and the dye will dissolve in it to give color.
If the scattered globules appear red and continuous phase colorless, then it is w/o type.
Similarly if an oil soluble dye (Scarlet red C or Sudan III) is added to an emulsion and the continuous
phase appears red, then it is w/o emulsion.
Fluorescence Test
Creaming
Separation of dispersed phase into two regions, one containing more of the dispersed phase.
Cracking
The globules of the dispersed phase coalesce and there is separation of dispersed phase into a
separate layer.
Phase Inversion
Change of one type of emulsion into other type i.e. O/W into W/O and vice-versa.
Flocculation
Coalescence, where the dispersed phase droplets merge to form large droplets, takes place in two
distinct stages. Drainage of liquid films of continuous phase between the oil droplets. As they
approach to one another, they end with the rupture of the film when a critical thickness is reached.
Oxidation
Many of the oils and fats used in emulsion formulation are of animal or vegetable origin and can be
Susceptible to oxidation by atmospheric oxygen or by the action of microorganisms.
Evaluation of Emulsions
Introduction
Parenteral drug products are the dosage forms intended for administration by a route that does not
involve the gastrointestinal (GI) tract (thus, parenteral). Most of the parenteral drug products are
injectable dosage forms that are intended for administration by injection using a syringe and a needle.
Parenteral dosage forms are preferred for one or more of the following reasons:
Low oral bioavailability and/or high variability in oral drug absorption.
Instability of the drug in the GI tract. For example, most protein drugs are highly unstable.
Rapid onset of drug action is desired.
Ability to immediately stop drug administration is important. For example, most emergency room
medications and anesthetics.
High degree of flexibility in dosage adjustment with or without real-time patient physiological
response is needed. For example, emer-gency medications such as analgesics, anticancer drugs, and
fertility medications.
Intravenous route
The IV administration provides immediate access of the drug to the sys-temic circulation, resulting in the
rapid onset of drug action. Depending on the rate of drug administration, IV injections could be a bolus
or an infusion. A bolus means the drug is injected into the vein over a short period of time. A bolus is
used to administer a relatively small volume and is often written as IV push (IVP). An infusion refers to
the introduc-tion of larger volumes (100–1000 mL) of the drug over a longer period of time. A continuous
infusion is used to administer a large volume of drug at a constant rate. Intermittent infusions are used to
administer a relatively small volume of drug over a specified amount of time at speci-fied intervals.
IV infusion can be administered through peripheral veins, typically in the forearm or the peripherally
inserted central catheter. The commonly administered IV infusion products include Lactated Ringers
Injection USP; Sodium Chloride Injection USP (0.9%), which replenish fluids and electro-lytes; and
Dextrose Injection USP (5%), which provides fluid plus nutrition; and various combinations of dextrose
and saline. Other solutions of essen-tial amino acids or lipid emulsions are also used as infusions.
Intramuscular route
IM injections of drugs into the striated muscle fibers that lie beneath the SC layer provide effects that are
less rapid but generally longer lasting than those obtained from IV administration. Aqueous or oleaginous
solutions or suspensions of drugs may be administered intramuscularly. Drugs in aque-ous solution
are absorbed more rapidly than those in oleaginous prepara-tions or in suspensions. An IM medication is
injected deep into a large muscle mass, such as the upper arm, thigh, or buttocks. Up to 2 mL of the drug
may be injected into the upper arm and 5 mL in the gluteal medial muscle of each buttock.
Numerous dosage forms are administered through this route of adminis-tration, including solutions
(aqueous- or oil-based), emulsions (o/w or w/o), suspensions (aqueous- or oil-based), colloidal
suspensions, and reconsti-tutable powders. Slow drug absorption leading to a sustained-release (SR) effect
can be achieved with highly insoluble drugs or formulations that are oleaginous or particulate. IM
injections are often painful and nonre-versible, that is, the administered drug cannot be withdrawn if
needed. Antibiotics are often administered by this route.
Subcutaneous route
The SC route is used for small volume injections, typically 1 mL or less. SC injections
are administered beneath the surface of the skin, between the dermis and muscle.
Medications administered by this route are slowly absorbed and consequently have a slower onset of
action than medications given by IV or IM routes. Drugs often given by this route include epineph-rine,
insulin, heparin, scopolamine, and vaccines. Small injection volume often puts limitations on the drugs
that can be administered by this route. For example, high dose drugs that tend to become highly viscous at
high concentrations, such as most globular proteins, are usually difficult to for-mulate as subcutaneous
injectable dosage forms.
Other routes
Certain types of injections are intended for specific purposes. For example,
Intradermal administration involves injection just beneath the epider-mis, within the dermal or skin
layers. The usual site for intradermal injection is the anterior forearm. The volume of solution that
can be administered intradermally is limited to 0.1 mL. The onset of action and the rate of
absorption of medication from this route are slow. This route is used for diagnostic agents,
desensitization, testing for potential allergies, or immunization.
Intrathecal route involves drug administration into the cerebrospinal fluid (CSF). This route is needed
if CSF is the desired site of drug action because most drugs do not reach the CSF from the systemic
circulation. Drugs administered intrathecally include antineoplastics, antibiotics, anti-inflammatory,
and diagnostic agents.
An intraarticular injection is made into the synovial cavity of a joint, usually to obtain a local
therapeutic effect. For example, an intraar-ticular injection of a corticosteroid provides an anti-
inflammatory action in an arthritic joint.
An intraarterial injection is made directly into an artery that has been surgically isolated if it is
necessary to deliver a high concentration of drug to a diseased organ, such as kidney, with minimal
distribution to other systemic locations.
An intraocular injection is made directly into the eye. For example, an injection into the vitreous
humor provides access of drug to the rear regions of the eye, such as the retina, which does not
receive high drug concentration on topical administration.
According to volume-
Opthalmic solution
Dialysis Solution
Implants
Solution Of Irrigation
Diagnostic Agent
Sterile solution
Sterile suspension
Sterile Emulsion
Sterile solid
Direct inoculation: The drug product is added to the nutrient media and
Membrane filtration: Whenever the nature of the drug product is likely to hinder
growth.
a) Rabbit test
b) LAL. Test
3)Clearity Test
4)Leakege test
Formulation components-
Injectable products contain active drugs and inactive ingredients, also called
excipients or adjuvants. Adjuvants are excipients that are added to vaccines to help
boost body’s immune response. The excipients could be vehicles, cosolvents,
buffers, preservatives, antioxidants, inert gases, sur-factants, complexing agents,
and chelating agents.
Vehicle is the larger continuous phase or the medium in which the formulation
is prepared. Water is the most common vehicle, although oil-based injections are
formulated in a vegetable oil, such as corn oil, sesame oil, and cottonseed oil or
peanut oil.
Sesame oil is the preferred oil for most of the official injections in oil. Sesame oil
has also been used to obtain slow release of fluphenazine esters given
osmosis, and stored in a manner to ensure that it is pure and free from pyrogens.
Sodium chloride injection USP is a sterile solution of 0.9% w/v sodium chloride in
and suspensions.
used to increase drug solubility in the medium. When cosolvents are used as
vehicles, the preparations should not be diluted with water or precipitation may
occur.
and stability.
Preservative is used in drug products packaged in multiple-dose vials to prevent
pierced for dosing. When preserva-tives are used, their compatibility with drugs
Salts of sulfur dioxide, including bisulfite, metasulfite, and sulfite, are the most
Chelating agents are added to inactivate metals, such as copper, iron, and zinc
corresponds to 0.9% w/v sodium chloride or 5% w/v dextrose. An isotonic solution has
an osmotic pressure close to that of the body fluids. This minimizes patient
than the red blood cells, which cause the red blood cells to shrink. In contrast,
the red blood cells, causing the red blood cells to swell and possibly burst.