INTRODUCTION

1. INTRODUCTION

1. DRUG DELIVERY SYSTEM

Dosage forms are also referred to as Drug Delivery Systems or Finished Drug
Products. A drug delivery system (DDS) is defined as a formulation or a device that enables the
introduction of a therapeutic substance into the body and improves its efficacy and safety by
controlling the rate, time, and site of release of drugs in the body. The goal of any drug delivery
system is to provide a therapeutic amount of drug in the proper site in the body to achieve
promptly and then to maintain the desired drug concentration. That is, the drug delivery system
should deliver drug at a rate dedicated by the needs of the body over a specified period of
treatment. Oral route of drug administration is most appealing route for delivery of drugs for
various dosage forms. The tablet is one of the most preferred dosage forms, because of its ease of
administration, accurate dosing and stability as compared to oral liquid dosage forms.

Tablets may be defined as solid unit pharmaceutical dosage forms containing drug
substance with or without suitable excipients and prepared by either compression or molding
methods (Aulton M.et al., 2002).

The first step in the development of dosage form is preformulation, which can be defined
as investigation of physiochemical properties of drug substances alone and when combined with
excipients. The main objective of preformulation studies, is to develop stable and bioavailable
dosage form and study of factors affecting such as stability, bioavailability and to optimize so as
to formulate the best dosage form. Here, optimization of formulation means finding the best
possible composition (Ansel H.et al., 2004). Compressed tablets are formed by applying
pressure, for which compression machines (tablet presses) are used and they are made from
powdered crystalline or granular material, alone or in combination with binder, disintegrants,
release polymers, lubricants and diluents and in some cases with colorant.

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1.1 Tablets
Tablets may be defined as the solid pharmaceutical dosage forms containing drug
substances with or without suitable diluents and prepared either by compression or moulding
methods. They have been in wide spread use since the latter part of the 19 th century and their
popularity continues. The term compressed tablet is believed to have been first used by JOHN
WYETH. Tablets remain popular as a dosage form because of the advantages afforded both to
the manufacturer and the patient (Banker GS.et al., 2002).

1.1.1 Properties of tablets

The attributes of an acceptable tablet are as follows:
The tablet must be sufficiently strong and resistant to shock, abrasion, should withstand
handling during manufacturing, packing, shipping, and use. Hardness and friability tests
measure this property.
Tablet must be uniform in weight and in drug content of the individual tablet. This is
measured by the weight variation and content uniformity tests.
The drug content of the tablet must be bioavailable. This property is measured by the
dissolution test. Accurate bioavailability can be obtained from the drug levels in the
blood after its administration.
Tablets must be elegant in appearance, characteristic shape, color and other markings
necessary to identify the product.
Tablets must retain all these functional attributes which include drug stability and
efficacy (Herbert A.et al., 2003).

1.1.2 Advantages of Tablets

They are unit dosage forms, so they offer greater capabilities of all oral dosage forms
for the greatest dose precision and the least content variability.
They are easy to administer.
Large scale manufacturing is feasible in comparison to other dosage forms. Therefore
economy can be achieved.
Accuracy of dose is maintained since tablet is a solid unit dosage form.
Longer expiry period and minimum microbial spillage owing to lower moisture
content.

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As tablet is not a sterile dosage form, stringent environmental conditions are not
required in the manufacturing department.
Ease of packaging (Blister or Strip) and ease of handling over liquid dosage forms.
In comparison to capsules, tablets are more tamper proof.
1.1.3 Disadvantages of tablets:
Some drugs resist compression into dense compacts, owing to their amorphous nature
or flocculent, low density character.
Drugs with poor wetting, slow dissolution properties, intermediate to large dosages,
and optimum absorption in the gastrointestinal tract or any combination of these
features may be difficult or impossible to formulate and manufacture as a tablet that
will still provide adequate of full bioavailability.
Bitter tasting drugs, drugs with objectionable odour or drugs that are sensitive to
oxygen or atmospheric moisture may require encapsulation or a special type of
coating which may increase the cost of finished product.
Some drugs may be unsuitable for administration by oral route.
Difficult to swallow for kids, terminally ill and geriatric patients.

1.2 Types of tablets

Tablets are classified as follows:
1.2.1 According to the drug release rate from the tablet.
1.2.2 According to the method of manufacturing.
1.2.3 According to the route of administration or function.

1.2.1.2 According to the drug release rate from the tablet (USP classification)
(a) Immediate release or conventional tablets: The tablet is intended to be released
rapidly after administration or the tablet is dissolved and administered as a solution. It is
the most common type and it includes.
Disintegrating tablet
Chewable tablet
Sublingual tablet
Buccal tablet
Effervescent tablet

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(b) Modified release tablets: They have release features based on time, course or location.
They must be swallowed intact.
Delayed release tablets Drug release is delayed due to physiological conditions.
Extended release tablet Allows the reduction in dosing frequency.

1.2.1.3 According to the method of manufacturing :

(a) Compressed tablet: It is obtained by compressing uniform volume of particles using
Tablet compression machine. It is used for large scale production. E.g. paracetamol
tablet.
(b) Moulded tablet: Moulding means shaping, hardening of semisolid mixture of drug and
excipients. It is obtained by tablet mould. It is restricted to small dose tablet and small
scale production. E.g. Nitro-glycerine Tablet (Herbert A.et al., 2003).
1.2.1.4 According to the route of administration:

i) Tablets ingested orally: These tablets are to be swallowed intact with sufficient
quantity of water. Exception is chewable tablet. Over the 99% of the tablets manufactured
today are to be ingested orally. This shows that this class of formulation is most popular
worldwide.
a) Compressed tablets
b) Multi compressed tablets
c) Multi layered tablets
d) Sustained action tablets
e) Enteric coated tablets
f) Sugar coated tablets
g) Film coated tablets
h) Chewable tablets
i) Targeted tablets
ii) Tablets used in oral cavity: The tablets under this group are aimed to release API in
oral cavity or to provide local action in this region. The tablets under this category avoids
first-pass metabolism, decomposition in gastric environment, nauseatic sensations and
gives rapid onset of action. The tablets formulated for this region are designed to fit in
proper region of oral cavity.
a) Buccal tablets
b) Sublingual tablets
c) Lozenge tablets and trouches
d) Dental cones

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iii) Tablets administered by other routes: These tablets are administered by other route
other than oral cavity and so the drugs are avoided from passing through the gastro
intestinal tract. These tablets may be inserted into other body cavities or directly placed
below the skin to be absorbed into systemic circulation from the site of application.
a) Implantation tablets
b) Vaginal tablets
iv) Tablets used to prepare solutions: The tablets under this category are required to be
dissolved first in water or other solvents before administration or application This
solution may be for oral ingestion or parenterals application or for topical use depending
on the type of medicament used.
Eg: Effervescent granules

v) Molded tablets or tablet triturates:

a) Dispersing tablets
b) Hypodermic tablet

1.3 Immediate release drug delivery system

Immediate release drug delivery system is also conventional type of drug delivery system
as it is defined as Immediate release tablets are designed to disintegrate and release their
medicaments with no special rate controlling features such as special coatings and other
techniques (Syed azeem.et al., 2011).

1.3.1 Advantages of immediate release drug delivery systems:

Release the drug immediately.
More flexibility for adjusting the dose.
It can be prepared with minimum dose of drug.
There is no dose dumping problem.
Immediate release drug delivery systems used in both initial stage and final stage of
disease.
At the particular site of action the drug is released from the system.

1.3.2 Tablet Excipients

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An excipient is generally a pharmacologically inactive substance used as a carrier for

the active ingredients of a medication. In many cases, an "active" substance (such
as acetylsalicylic acid) may not be easily administered and absorbed by the human body; in such
cases the substance in question may be dissolved into or mixed with an excipient.

1.3.2.1 Properties of Excipients

1 They must be physiological inert.
2 They must be acceptable to regulatory agencies
3 They must be physiologically and chemically stable.
4 They must be free of any bacteria considered to be pathogenic or otherwise objectionable.
5 They must not interfere with the bioavailability of the drug.
6 They must be commercially available in the form and purity commensurate to
pharmaceutical standards.
7 Cost must be relatively inexpensive.
8 They must conform to all current regulatory requirements (Leon Lachman.et al., 2003).

1.3.2.2 Types of Excipients

Diluents
Binders
Antiadherents
Disintegrants
Fillers and diluents
Flavours
Colours
Lubricants
Glidants
Preservatives
Sorbents
Sweeteners

Diluents:
When the dosage of active pharmaceutical agent is inadequate to produce the bulk some inert
substances are added to make the bulk. Examples are lactose, direct compressible starches,
microcrystalline cellulose, sucrose, Mannitol, sorbitol, calcium carbonate.

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Antiadherents

Antiadherents are used to reduce the adhesion between the powder (granules) and the
punch faces and thus prevent sticking to tablet punches. They are also used to help protect tablets
from sticking. Most commonly used is magnesium stearate.

Binders

Binders hold the ingredients in a tablet together. Binders ensure that tablets and granules
can be formed with required mechanical strength, and give volume to low active dose tablets.
Example: starch, cellulose, micro crystalline cellulose, gelatin, tragacanth, etc.

Coatings

Tablet coatings protect tablet ingredients from deterioration by moisture in the air and
make large or unpleasant-tasting tablets easier to swallow.

Examples: Hydroxypropyl methylcellulose, shellac, zein, etc.

Disintegrants

Disintegrants expand and dissolve when wet causing the tablet to break apart in
the digestive tract, releasing the active ingredients for absorption.

Examples: carboxymethyl cellulose (croscarmellose sodium), polyvinyl pyrrolidone etc.

Method of addition of disintegrants

Disintegrating agent can be added either prior to granulation (intragranular) or prior to

compression (after granulation i.e. extragranular) or at both processing steps.

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Extragranular fraction of disintegrant (usually, 50% of total disintegrant requires)

facilitates breakup of tablets to granules and the intragranular addition of disintegrants produces
further erosion of the granules to fine particles.

Flavours

Flavours can be used to mask unpleasant tasting active ingredients and improve the
likelihood that the patient will complete a course of medication.

Examples: mint, cherry, anise, vanilla, raspberry, peach, apricot, liquorice etc.

Colours

Colours are added to improve the appearance of a formulation. Colour consistency is

important as it allows easy identification of a medication.

Lubricants

Lubricants prevent ingredients from clumping together and from sticking to the tablet
punches or capsule filling machine. Lubricants also ensure that tablet formation and ejection can
occur with low friction between the solid and die wall.

Examples: talc, silica, magnesium stearate, stearic acid etc.

Glidants

Glidants are used to promote powder flow by reducing inter particle friction and
cohesion. These are used in combination with lubricants as they have no ability to reduce die
wall friction. Examples include fumed silica, talc, and magnesium carbonate.

Preservatives
Some typical preservatives used in pharmaceutical formulations are:
Antioxidants like vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium
The amino acids cysteine and methionine.
Citric acid and sodium citrate.

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Synthetic preservatives like the parabens: methyl paraben and propyl paraben.

Sorbents

Sorbents are used for tablet/capsule moisture-proofing by limited fluid sorbing (taking up
of a liquid or a gas either by adsorption or by absorption) in a dry state.

Sweeteners

Sweeteners are added to make the ingredients more palatable, especially in

chewable tablets such as antacid or liquids like cough syrup. Therefore, tooth
decay is sometimes associated with cough syrup abuse. Sugar can be used
to disguise unpleasant tastes or smells.

1.4 Tablet-manufacturing methods

A). Direct compression
B). Granulation
A) Direct compression
The term direct compression is defined as the process by which tablets are compressed
directly from powder mixture of API and suitable excipients. No pretreatment of the
powder blend by wet or dry granulation procedure is required. (G.S.Banker.et al., 2002).
Manufacturing steps for direct compression
Direct compression involves comparatively few steps:
Milling of drug and excipients
Mixing of drug and excipients
Tablet compression
B) Granulation
Granulation may be defined as a size enlargement process which converts small particles
into physically stronger and larger agglomerates.
Granulation Techniques
(1) Dry Granulation
(2) Wet Granulation
1.4.1 Dry granulation:

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When tablet ingredients are sensitive to moisture or are unable to withstand elevated temperature
during drying and when the tablet ingredients have sufficient inherent binding or cohesive
properties, slugging may be used to form granules. This method is referred to as dry granulation,
pre compression or double compression. When slugging is used, large tablets are made as slugs
because fine powders flow better into large cavities. These compressed slugs are comminuted
through the desirable mesh screen either by hand or for large quantities through the Fitzpatrick or
similar comminuting mills after this the granulation is blended gently with lubricants and then
compressed to form tablets. The other method is to pre compress the powder with pressure rolls
using a machine such as Chilsonator (Lieberman H.et al., 1986).
Steps in Dry Granulation:
Milling of drugs and excipients.
Mixing of milled powders.
Compression into large, hard tablets to make slugs.
Screening of slugs.
Mixing with lubricant and disintegrating agent.
Tablet compression.
Two main Dry Granulation processes:

a) Slugging process: Granulation by slugging is the process of compressing dry powder of

tablet formulation with tablet press having die cavity large enough in diameter to fill quickly. The
accuracy or condition of slug is not too important. Only sufficient pressure to compact the
powder into uniform slugs should be used. Once slugs are produced they are reduced to
appropriate granule size for final compression by screening and milling.

b) Roller compaction: The compaction of powder by means of pressure roll can also be
accomplished by a machine called Chilsonator. Unlike tablet machine, the chilsonator turns out a
compacted mass in a steady continuous flow. The powder is fed down between the rollers from
the hopper which contains a spiral auger to feed the powder into the compaction zone. Like
slugs, the aggregates are screened or milled for production into granules. (Remington J. et al.,
2005).

1.4.2 Wet granulation:

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The most widely used process of agglomeration in pharmaceutical industry is wet granulation.
Wet granulation process simply involves wet massing of the powder blend with a granulating
liquid, wet sizing and drying the unique portions of wet granulation process involve the wet
massing of powders, wet sizing or milling and drying.
Important steps involved in the Wet Granulation:
Mixing of the drug(s) and excipients.
Preparation of binder solution.
Mixing of binder solution with powder mixture to form wet mass.
Coarse screening of wet mass using a suitable sieve.
Drying of moist granules.
Screening of dry granules through a suitable sieve.
Mixing of screened granules with disintegrant, glidant, and lubricant (Ansel H.et al.,
2004).
1.5 Tablet compression

After the preparation of granules (in case of wet granulation) or sized slugs (in case of
dry granulation) or mixing of ingredients (in case of direct compression), they are compressed to
get final product. The compression is done either by single punch machine (stamping press) or
by multi station machine (rotary press).

The tablet press is a high-speed mechanical device. It 'squeezes' the ingredients into the
required tablet shape with extreme precision. It can make the tablet in many shapes, although
they are usually round or oval. Also, it can press the name of the manufacturer or the product on
the top of the tablet. Each tablet is made by pressing the granules inside a die, made up of
hardened steel. The die is a disc shape with a hole cut through its centre. The powder is
compressed in the centre of the die by two hardened steel punches that fit into the top and bottom
of the die.

The punches and dies are fixed to a turret that spins round. As it spins, the punches are
driven together by two fixed cams - an upper cam and lower cam. The top of the upper punch
(the punch head) sits on the upper cam edge .The bottom of the lower punch sits on the lower
cam edge. The shapes of the two cams determine the sequence of movements of the two

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punches. This sequence is repeated over and over because the turret is spinning round. The force
exerted on the ingredients in the dies is very carefully controlled. This ensures that each tablet is
perfectly formed. Because of the high speeds, they need very sophisticated lubrication systems.
The lubricating oil is recycled and filtered to ensure a continuous supply (Ansel H.et al., 2004).

Fig: 1 Rotary Punching Machine

1.6 PROCESS VALIDATION FOR SOLID DOSAGE FORMS

Each Production has its own idiosyncrasies requiring special product tests that would be
required for validation of solid dosage form The testing can be conducted on samples during
Manufacturing (In- Process), Finished product tests.

In-Process Tests:

1. Moisture content of the dried granules

2. Granule particle size distribution
3. Blend uniformity
4. Tablet weight
5. Thickness
6. Disintegration time
Finished Product Tests:
1. Appearance
2. Assay
3. Content uniformity
4. Hardness

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5. Friability
6. Dissolution

1.6.1. GUIDELINES FOR PROCESS VALIDATION OF SOLID DOSAGE FORMS

Numerous Factors should be considered when developing and validating solid dosage forms.

Process Evaluation and Selection: The following Unit operations determinations are useful for
the manufacturing of tablets.

A. Mixing and Blending

Unit operation may occur at once or several times during the tablet manufacturing.
E.g. Direct compression formulation may include one blending step in drug and excipients are
blended together prior to the compression. A Wet Granulation formulation required blending
prior to granulation and after milling of dried granules.
i. Bulk Density and particle size distribution, Surface areas are some of the physical factors
should be considered to obtain uniform mix or blend.
ii. Type of the technique used for mixing and blending, equipment speed, mixing time, drug
uniformity and excipients uniformity are the following tests to be carried out before
compression of the tablets (Ansel H.et al., 2004).
B. Wet Granulation
Wet granulation parameters that should be considered in the development and validation
of listed below:
i. Binder concentration: The optimum binding concentration will be determined for the
formulation.
ii. Amount of the Binder solution or granulating solution: It is required for the
granulation technique will be determined.
iii. Binder addition and mixing time: Time required to get uniform mixing of the
granulating solvent with ingredients will be determined.
iv. Wet milling: Equipment Size and Capacity, Screen Size, Mill Speed, Feed Rate is the
factors determined.
v. Drying: The type of drying technique required for the formulation needs to be
determined because change in the technique may affect such tablet properties as hardness,
disintegration, dissolution and stability.
Optimum Moisture content needed to be determined because moisture content results in
Picking and sticking to the tablet punch and poor chemical stability as a result water. Moisture

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content analysis could be performed using the conversational loss on drying technique. Inlet or
outlet temperature, moisture content is the following parameters to be considered during drying.
C. Milling: Operation will reduce the particle size of the dried granules. The resultant particle
size distribution may affect such material properties as flow, disintegration, dissolution, mill
type, speed rate, screen size, mill speed are the factors considered in the selection of the mill.
D. Tablet compression: It is the critical step in the production of the tablet dosage form. The
materials being compressed will need to have adequate flow and compression properties. The
material should readily flow from the hopper on to the feed frame and to the dies. Inadequate
flow can result in RAT HOLING in hopper and segmentation of blend in hopper or feed frame.
This can cause tablet weight and content uniformity problems. Tooling, Compression speed,
Compression or Ejection forces are the factors considered during compression (Herbert A.et al.,
2003).

2.1 SUBLIMATION

Sublimation is the process of transformation directly from the solid phase to the gaseous phase
without passing through an intermediate liquid phase. Sublimation is an endothermic phase
transition that occurs at temperatures and pressures below a substance's triple point in its phase
diagram.

At normal pressures, most chemical compounds and elements possess three different states at
different temperatures. In these cases, the transition from the solid to the gaseous state requires
an intermediate liquid state. Note, however, that the pressure referred to here is the partial
pressure of the substance, not the total (e.g., atmospheric) pressure of the entire system. So, all
solids that possess an appreciable vapor pressure at a certain temperature usually can sublime in
air (e.g., water ice just below 0C). For some substances, such as carbon and arsenical,
sublimation is much easier than evaporation from the melt, because the pressure of their triple
point is very high, and it is difficult to obtain them as liquids.

Sublimation requires additional energy and is an endothermic change. The enthalpy of

sublimation (also called heat of sublimation) can be calculated as the enthalpy of fusion plus
the enthalpy of vaporization. The reverse process of sublimation is deposition. The formation
of frostis an example of meteorological deposition.

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The key to rapid disintegration for mouth dissolving tablets is the presence of a porous structure
in the tablet matrix. Conventional compressed tablets that contain highly water-soluble
ingredients often fall to dissolve rapidly because of low porosity of the matrix. Hence to generate
porous matrix, volatile ingredients are used that are later subjected to a process of sublimation. In
studies conducted by Heinemann and Rothe, Knitsch et al., and Roser and Blair, inert solid
ingredients that displayed high volatility (e.g., ammonium bicarbonate, ammonium carbonate,
benzoic acid, camphor, hexamethonium tetramine, naphthalene, phthalic anhydride, urea, and
urethane were compressed along with other excipients into a tablet. The volatile material was
then removed by sublimation, leaving behind a porous matrix. Solvents such as cyclohexane and
benzene were also suggested for the generation of porosity in the matrix.

Figure:2 Process of sublimation of volatilizing agent from Compressed Tablet

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