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Tablets
The oral route is the most common way of administering drugs and among
these oral dosage forms, tablets of various kinds which are the most common type
of solid dosage form. Tablets may be defined as solid pharmaceutical dosage forms
containing drug substances with or without any diluents.
Advantages
An oral tablet dosage form is usually the most preferred dosage form
because they have the following advantages:
1. Tablets are convenient and easy to use.
2. Unlike liquid dosage forms and powders, tablets provide an accurate dose as
each tablet represent one dose.
3. They are less expensive to manufacture than other oral dosage forms.
4. They are physically and chemically stable.
5. Special release profiles, such as enteric or sustained release, can be
achieved.
6. There is high patient acceptance because of their portability and compact
form.
7. Tablets are the most tamper-proof of all oral dosage forms.
8. They provide economy and convenience of production, storage, and
transportation.
Disadvantages
1. Slow onset of action as compared to capsule & oral liquids.
2. Difficult to swallow by pediatric, geriatric patients, & unconscious patients.
3. Some drugs resist compression into dense compact, owing to amorphous
nature & low density characteristics.
4. Preparing tablets extemporaneously is impractical.
Types of Tablets
Tablets are generally classified according to their method of manufacturing
(moulded versus compressed) and their intended use. Compressed tablets usually
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are prepared by large scale production methods, while moulded tablets generally
involve small-scale operations.
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) Conventional Compressed Tablets
The majority of tablets used today in clinical practice are conventional
compressed tablets. They are manufactured by a single compression cycle using
powders or granules of both active and inactive agents. Disintegration and
dissolution of the tablet after oral administration in the GI tract aid in the
absorption of the drug via the gastric mucosa. Examples: Tylenols tablet,
metformin tablet
2) Moulded Tablets
Moulded tablets are not manufactured by compression. They are prepared by
moulding and are very soft and disintegrate quickly. Moulded tablets are intended
to dissolve rapidly in the mouth. They do not contain disintegrants, lubricants, or
coatings to slow their rate of dissolution. One example of moulded tablets is tablet
triturates. Tablet triturates are administered sublingually, or by placing them on the
tongue followed by swallowing with a small volume of water. Lactose and sucrose
are the common diluents used for tablet triturates. Examples: Nitroglycerin tablet
triturates.
3) Swallowable Tablets
The most common types of tablets are swallowed whole. These tablets
disintegrate and release their contents in the GI tract.
4) Buccal and Sublingual Tablets
Buccal tablets are designed to dissolve slowly in the mouth between the
cheek and the gingiva. These tablets are manufactured so that the release of drug
happens slowly in the mouth without disintegration. The drug is absorbed into the
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blood circulation directly through oral mucosa. Example: Fentanyl buccal tablet.
Sublingual tablets are placed beneath the tongue and dissolve rapidly which may
be critical in cases such as nitroglycerin for chronic heart failure. Other examples
include isoprenaline sulfate (bronchodilator), glyceryl trinitrate (vasodilator), and
testosterone tablets. Buccal and sublingual tablets are usually small and flat, do not
contain a disintegrant, and are intended for dissolution in the local fluids. These
tablets contain large proportions of sweetening agents like mannitol & sucrose to
impart sweetness. Buccal or sublingual routes of drug absorption bypasses hepatic
metabolism, often referred to as the first-pass effect on oral administration, and are
preferred for low dose drugs that have extensive hepatic metabolism. They enable
oral absorption of drugs that are destroyed by the gastric juice and/or are poorly
absorbed from the gastrointestinal tract.
5) Chewable Tablets
Chewable tablets are chewed in the mouth before swallowing. They are not
intended to be swallowed intact. These tablets are intended for children, the
elderly, and patients who have difficulty swallowing. Chewable tablets are used
when a faster rate of dissolution and/or buccal absorption is desired. Chewable
tablets are typically prepared by compression. Chewable tablets consist of the drug
dispersed throughout a saccharide base such as mannitol or sorbitol. that provides
mild sweetness and fillers. However, mannitol is sometimes preferred as a
chewable base diluent, because it has a pleasant cooling effect during dissolution in
the mouth and can mask the taste of some objectionable medicaments. Flavours,
sweeteners, and colours 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. Examples: Pepcids chewable tablet,
chewable aspirin tablet
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6) Effervescent Tablets
Effervescent tablets are produced from compression of effervescence
granules that contain an organic acid; citric and tartaric acid and sodium
bicarbonate. When such tablets are placed in water, the chemical reaction of acid
with the base produces carbon dioxide in the form of gas bubbles. Ingestion of a
dissolved or finely dispersed drug provides 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.
7) Lozenges and Troches Tablets
Lozenges and troches are intended to be sucked and held in the mouth,
where they exert a local effect in the mouth or throat. These dosage forms are most
commonly used in sore throat and cough remedies for common colds. The second
type of lozengeS produce systemic effect, for example, lozenges containing
vitamin supplements (multivitamin tablets). Lozenges are made by fusion,
compression, or a candy-moulding process. Troches are made by a compression
process. These dosage forms do not disintegrate in the mouth but slowly dissolve
or erode with time. Lozenges and troches are palatable and organoleptically
appealing by the addition of flavours, sweeteners, and colours. Examples:
Clotrimazole troches, Chloraseptics lozenges, Nicorettes lozenges.
8) Multiple Compressed Tablets
Multiple compressed tablets are designed to enable the separation of
incompatible ingredients or make sustained release products, or they are merely
designed for appearance. There are two classes of multiple compressed tablets:
layered tablets and compression-coated tablets. Layered tablets are prepared by
initial compaction of a portion of fill material in a die followed by additional fill
material and compression to form two-layered or three layered tablets, depending
on the number of separate fills. Each layer may contain a different medicinal agent.
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Usually, each portion of fill is a different color to produce a distinctive-looking

tablet. In preparation of tablets within tablets, special machines are required to
place the preformed core tablet precisely within the die for application of
surrounding fill material. Examples include Norgesic Tablets, Phenylephedrine
HCL, and Ascorbic acid with Acetaminophen.
9) Coated Tablets
9-1) Sugar-Coated Tablets
Conventional compressed tablets are coated with successive coats of sugar
solution with or without a colour to produce elegant, glossy, and easy-to-swallow
tablets for oral use. The coating is water soluble and quickly dissolves after
swallowing. The sugar coat protects the enclosed drug from the environment and
provides a barrier to objectionable taste or odour. The sugar coat also enhances the
appearance of the compressed tablet and permits imprinting of identifying
manufacturer’s information.
9-2) Enteric-Coated Tablets
Enteric-coated tablets are conventionally compressed tablets coated with a
polymer that does not dissolve in the acidic condition of the stomach but readily
dissolves in the alkaline pH of the small intestine. Enteric-coated tablets are
delayed-release tablets and a coating can protect drugs from the degradative effects
of gastric acidity. They also protect gastric mucosa from irritation from certain
drugs. Polymers that have enteric-coating ability include cellulose acetate phthalate
(CAP), cellulose acetate butyrate (CAB), hydroxypropylmethyl cellulose
succinate, and methacrylic acid co-polymers (Eudragit). Examples: Enteric-coated
aspirin tablet, naproxen enteric-coated tablet.
9-3) Film-Coated Tablets
Film-coated tablets are compressed tablets coated with a coloured polymeric
coating that forms a thin skin-like film around the tablet core. The film coating is
more durable, less bulky, and less time consuming to apply than sugar coating and
can be formed quickly. Polymers used in film coatings include
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hydroxypropylmethyl cellulose, hydroxypropyl cellulose, and Eudragits E100. By

its composition, the coating is designed to rupture and expose the core tablet at the
desired location in the gastrointestinal tract. Example: Glyburide/metformin (5
mg/500 mg) film-coated tablets.
9-4) Gelatin-Coated Tablets
A recent innovation is the gelatin-coated tablet. The innovator product, the
gelcap, is a capsule shaped compressed tablet (Fig. 8.4) that allows the coated
product to be about one-third smaller than a capsule filled with an equivalent
amount of powder. The gelatin coating facilitates swallowing, and gelatin-coated
tablets are more tamper evident than unsealed capsules. Examples include Extra
Strength Tylenol PM Gelcaps (McNeil-CPC).
10) Orally Disintegrating Tablets (ODTs)
Orally disintegrating tablets are a solid dosage form containing medicinal
substances that disintegrate rapidly, usually within a matter of seconds, when
placed on the tongue. They are produced by dry granulation and compression, have
a hardness of 40 N or more, a disintegration time of 30 seconds or shorter, a
friability of 0.1% or less, and an excellent feeling upon ingestion that is capable of
disintegrating with a small amount of water. Example: Zofran ODT (Ondansetron
ODT); Imodium Instant melts (Loperamide HCI ODT).

11) Vaginal Tablets

Vaginal tablets are ovoid- or pear-shaped conventional compressed tablets
that are inserted into the vagina using a plastic inserter. Antibacterial drugs,
antifungal drugs, and steroids are generally administered using this dosage form.
Lactose and sodium bicarbonate are used as diluents for vaginal tablets. These are
often formulated with buffering agent to provide favourable pH to stimulate the
action of given medicament(s). After insertion, the drug is released by slow
dissolution. Disintegration of these tablets must be avoided for proper retention
inside the vagina. Both systemic and local delivery of drugs can be achieved by
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using this dosage form. Examples: Vagifem (estradiol vaginal tablets), nystatin
vaginal tablets, USP
12) Implant Tablets
Implantation or depot tablets are small tablet meant for insertion under the
skin by a small surgery. They are used to prolong drug effect ranging from month
to year. Since they must be sterile & prepared under aseptic conditions & packed in
unit dose sterile container. They can be used as a contraceptive. Generally steroidal
hormone like testosterone, stilbestrol are formulated as implants. These tablets are
more commonly used in veterinary than human medicine.
Release Characteristics of Drug from Tablets
1) Immediate release Tablets (IR)
Most of the conventional tablets fall in this category and most drugs are
formulated as IR tablets. IR tablets are designed to start releasing the drug as soon
as they come in contact with the tablet disintegrating/dissolving fluids. 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). The drug should not show significant instability in the gastric environment.
Tablets are typically designed for manufacturability and rapid drug release on
administration with no special rate-controlling features, such as special coatings
and other techniques. Example is Tylenol tablets.
2) Modified Release Tablets (MR)

In contrast to conventional immediate release (IR) forms, modified-release

products provide either delayed release or extended release of drug. Modified
release drug delivery (MR) refers to the manipulation or modification of drug
release from a dosage form with the specific aim of delivering drugs based on time,
course, and/ or location that are designed to accomplish therapeutic or convenience
objectives not offered by conventional or immediate-release forms.
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2-1) Controlled release (CR)

Controlled release (CR) tablets are designed to release the drug at a

predetermined and controlled rate. Usually used for drugs for chronic ailments that
requires repeated administration. Used for drugs that would benefit the patient
from consistent maintenance of drug’s plasma levels and/or reduced dosing
frequency. The release rate is controlled by the use of slow-release matrix (e.g.,
carnauba wax) or insoluble coating. Insoluble coating-based controlled release
typically provides osmotic or diffusion limited drug release. Insoluble matrix-
based controlled release system typically provides dissolution or diffusion limited
drug release. Example, Oxycodone HCl CR tablet (analgesic).

2-2) Extended release (XR) or sustained release (SR)

Extended release (XR) or sustained release (SR) tablets are designed to

release drug over an extended period of time, but not necessarily at a
predetermined and/or controlled rate. Usually used for drugs for chronic ailments
that requires repeated administration. Used for drugs that would benefit the patient
from consistent maintenance of drug’s plasma levels and/or reduced dosing
frequency. Sustained-release tablets are designed to release an initial
therapeutically effective amount of a drug followed by maintaining this effective
level over an extended period of time. This is achieved by design approaches. The
advantages of sustained-release tablets include maintenance of therapeutic effect
for a longer time, reduced frequency of administration, and enhanced patient
compliance. Examples: Wellbutrin SRs (bupropion hydrochloride) tablet and
Methylin ER (methylphenidate for narcolepsy and attention deficit disorder)
2-3) Delayed release (DR), for example, enteric coated
Delayed release (DR) tablets are designed to delay the release of the drug
from the time it first comes in contact with the tablet disintegrating/ dissolving
fluid. DR is useful for drugs that degrade in the acidic gastric environment (e.g.,
peptides) or are irritating to the gastric mucosa (e.g., aspirin). Enteric coated tablets
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are coated with a coating material that does not dissolve under acidic conditions.
Also, Time-controlled colon release tablets are coated with a coating material that
has a slow rate of dissolution. Drug release is delayed by a physiologically
controlled mechanism such as gastric acidity or a defined period of time.
Commonly used polymers for enteric coating are cellulose acetate phthalate
(CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate
phthalate (PVAP), cellulose acetate trimellitate (CAT), and Eudragits®, which are
copolymers of methacrylic acid and methylmethacrylate. Examples are enteric
coated tablets, time-controlled colon-targeted drug release and Aspirin.
Formulation of Tablets

In addition to the active or therapeutic ingredient, tablets may contain one or

more of functional ingredients such as diluents (also known as fillers), binders,
disintegrants, glidants, lubricants, coating materials, colouring agents, stabilizer(s),
sweeteners, and flavouring agents. These ingredients are called excipients and each
of these excipients serves a unique function and, in some instances, may serve
more than one function. 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.

1) Diluent or Filler

They are inert substances which are added when the quantity of the drug for
an individual dose is very small and cannot be compressed into a tablet. So, it is
added to the drug in order to increase its bulkiness and to produce a tablet of a
reasonable weight, which can be compressed. Tablets normally weigh at least 50
mg and for any drug weight lower than 50 such as potent drugs requires the
incorporation of a diluent. In addition, enabling manufacturability of powder
blends on high speed equipment requires adequate properties such as flow and
compressibility, which are improved by the addition of diluents.
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Diluent properties: The ideal diluent should full a series of requirements, such as:

1. Chemically inert, non-hygroscopic, be biocompatible.

2. Have an acceptable taste, odour and cheap.
3. Possess good solubility and disintegration ability to enhance in vivo
dissolution.
4. Possess good flowing properties, so that it can be uniformly fed into the die
to be compressed.
5. Good binding characteristic to enhance the compressability and the
mechanical strength of the tablet.

Diluents can be categorized into insoluble and soluble. Some commonly

used soluble diluents include lactose, sucrose, dextrose, and mannitol. Calcium
sulfate dihydrate, dibasic and tribasic calcium phosphate, starch, and
microcrystalline cellulose (MCC) are insoluble diluents that are mostly used as
fillers.

Mannitol has a negative heat of solution and, thus, provides a cooling

sensation in the mouth. It is typically used for chewable and orally dissolving
tablets. MCC can absorb water and improves compressibility by undergoing plastic
deformation on compression. Lactose is a fragile excipient that fragments to
undergo brittle fracture during compression. Addition of lactose to powder blends
can improve interparticle bonding during compression.

2) Binders (or an Adhesive)

Binders are adhesive materials used to hold powders together to form

granules and assist in holding the tablet together after compression with adequate
hardness. They impart cohesiveness to the tablet formulation that ensures the tablet
remain intact after compression, as well as improve the free-flowing qualities by
the formulation of granules of desired hardness and size. It is added to a drug- filler
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mixture to ensure that granules and tablets can be formed with the required
mechanical strength. Binders can be added to a powder in different ways:

1. As a dry powder which is mixed with the other ingredients before wet
agglomeration. During the agglomeration procedure, the binder might thus
dissolve partly or completely in the agglomeration liquid.
2. As a solution which is used as agglomeration liquid during wet
agglomeration. The binder is here often referred to as a solution binder.
3. As a dry powder which is mixed with the other ingredients before
compaction (slugging or tableting). The binder is here often referred to as a
dry binder.
Both solution binders and dry binders are included in the formulation at
relatively low concentrations, typically 2–10% by weight. The use of too much
binder or too strong a binder will make a hard tablet that will not disintegrate
easily and will cause excessive wear of punches and dies. On the other hand, small
amount of binders usually result in too soft granules, which tend to crumble on
compression.

Common binders used in wet granulation are cellulose derivatives such as

hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), and starch.

3) Disintegrating Agents

Disintegrants are added to the tablets to facilitate the breakup or

disintegration when tablets come in contact with aqueous fluids in the GI tract or
dissolution medium during in vitro testing. Disintegrants help break a compressed
tablet into constituent granules and primary powder particles. The dispersed
primary drug particles then provide a high surface area for the dissolution of the
drug in the aqueous fluid. Thus, breaking of the tablets by disintegrants increases
the effective surface area and promotes rapid release and dissolution of the drug.
Disintegrants may work by one of the following mechanisms:
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1. Disintegrants can increase the porosity and wettability of compressed

tablets. In doing so, they enhance the penetration and uptake of GI fluids
into the tablet matrix and disintegrate. Starch and microcrystalline cellulose
act by this mechanism.
2. Disintegration can happen due to the effervescence properties of granules,
which can break the tablets very quickly when they come into contact with
water.
3. Swelling of the disintegrant in the presence of water can increase the internal
pressure of the tablet matrix and cause eventual disintegration of the tablet.
Sodium starch glycolate, croscarmellose, and pregelatinized starch work
according to this mechanism.

Disintegrants can be added to formulations before compression by three different

methods:

1. Internal addition: The disintegrant is mixed with other powders before

granulation.
2. External addition: The disintegrant is added to the granules before
compression (mixing prior to compression).
3. Combination method: Both internal and external additions of disintegrants
are used. This is the most efficient way of adding a disintegrant to a tablet
formulation before compression. These agents swell when exposed to gastric
fluids and exert sufficient mechanical pressure from within the tablet to
cause it to break apart into small segments.

4) Glidants

Glidants are added to tablet formulations to improve the flow properties of

the granulations during transfer operations, such as from the hopper to the roller
compactor or tablet press. They improve flow by reducing interparticulate friction.
The commonly used glidants are fumed (colloidal) silica, starch, and talc. These
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glidants are very small size powder particles that occupy surface ridges and
irregularities in coarse powder particles, thus increasing the sphericity and
reducing the tendency to adhere to surfaces.

5) Lubricants

Lubricants help prevent adherence of the tablet material to the stainless steel
processing equipment surfaces under compression forces. Thus, lubricants reduce
or prevent adhesion of powder particles to tablet compression punch faces and dies
or to the rolls of a roller compactor. They promote flow, reduce interparticle
friction, and facilitate the smooth ejection of compressed tablets from the die
cavity. Commonly used lubricants are magnesium stearate, stearic acid, and
sodium stearyl fumarate. These lubricants are small hydrophobic particles that tend
to coat the surface of larger powder particles by spreading out under the mild shear
during mixing. Hydrophobic surface coating reduces noncovalent hydrophilic
interparticle and particleequipment forces that are generally responsible for
adhesion and sticking. Among these, magnesium stearate is the most commonly
used lubricant. The lubricity of magnesium stearate in a formulation can be
increased with either the concentration or the duration of mixing. Most lubricants
are used in concentration ≤ 1% w/w. Over-lubrication, due to the use of high
concentration or excessive mixing can result in reduced compactibility of the blend
and/or rate of drug release from the tablets. Sodium stearyl fumarate is the only
water soluble or hydrophilic lubricant and is used in formulations that are highly
sensitive to hydrophobic lubricants.

6) Flavourants, Colourants, Sweeteners and Stabilizers

Organoleptic ingredients, such as colours, sweeteners, and flavours, are used

for taste masking and improving palatability especially in products such as
chewable and dispersible tablets. Artificial sweeteners, such as acesulfame
potassium and saccharin sodium, are preferred because smaller quantities produce
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similar or higher sweetness than sucrose. Flavouring agents are mostly used in
chewable tablets. Flavours can be available as oils and spray-dried beadlets. Oils
can be sprayed onto dry granules as an alcoholic solution or incorporated in the
lubricant. FD&C colour is normally used to add appropriate colour to a tablet.
Colour can be added to a binding solution or can be sprayed onto the granules. Dye
can also be mixed with the dry powder blend before the wet granulation process.
Chemical stabilizers commonly used in tablet formulations include antioxidants,
such as ascorbic acid and vitamin E, and heavy metal chelators, such as
ethylenediaminetetraacetic acid (EDTA) and ethylene glycol-bis (β-aminoethyl
ether)-N,N,N′,N′-tetraacetic acid (EGTA).

7) Adsorbents

Adsorbents are substances capable of holding fluids in an apparently dry

state. These are the powder particles that can adsorb the liquid while maintaining
the ability to be handled as powders. Oil-soluble drugs or fluid extracts can be
mixed with adsorbents to bring them to a solid form for compression into tablets.
For example, fumed silica, microcrystalline cellulose, magnesium carbonate,
kaolin, and bentonite.

8) Granulating Fluids

Granulating fluids are liquids that are used for wet granulation. Typically,
these are water, ethanol, or isopropanol or the solution of a hydrophilic polymer
(binder) in one of these liquids. Addition of granulating fluid while mixing a
powder blend of the API with excipients promotes surface adhesion of particles.
After granulation, when the granulating fluid is dried off. These particles tend to
have higher sphericity than primary particles and can be milled or sifted to the
desired particle size distribution. Thus, granulation enables flow and
compressibility while modifying the surface properties of primary particles such as
sticking to stainless steel equipment. The granulating fluid is completely removed
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during drying to ensure that the residual fluid does not act as a plasticizer and
contribute to chemical instability in the finished product.

9) Wetting agents

Wetting agents in tablet formulation aid water uptake & thereby enhancing
disintigration & assisting in drug dissolution. Incorporation of anionic surfactant
such as Sodium Lauryl Sulphates (SLS) is known to enhance the dissolution &
bioavailability of poorly soluble drug.

10) Matrix Former

In order to affect or control the release of the drug from the tablet, i.e. to
speed up or to slow down its release rate, the drug may be dispersed or embedded
in a matrix formed by an excipient or combination of excipients. The matrix
former is often a polymer or a lipid and may constitute a significant fraction of the
total tablet weight. When the objective is to increase drug dissolution, the matrix
former can be a water-soluble substance or a lipid and the drug is dissolved or
suspended as fine particles in the matrix. An example of a water-soluble matrix
former is poly ethylene glycol (PEG). When the objective is to prolong the drug
release, the matrix former can be either an insoluble substance (a polymer or a
lipid) or a substance that forms a gel in contact with water. The drug is normally
dispersed in particulate form in the matrix. A common gel-forming substance in
tablets is hydroxy propyl methyl cellulose (HPMC).
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Table 1: Functional excipients used in tablets

Functional
Examples Description and functionality
role
• Microcrystalline cellulose (MCC)
• Add bulk to the dosage form
• Lactose monohydrate or
• May contribute to dissolution
Filler anhydrous
and disintegration
• Mannitol
characteristics
• Sorbitol
• Polyvinylpyrrolidone (PVP)
• Bind the powder ingredients to
Binder • Hydroxypropyl cellulose (HPC)
form granules for processing
• Starch
• Croscarmellose sodium (CCS)
• Disintegration of the tablet to
• Crospovidone (xPVP)
Disintegrant granules and powders on
• Sodium starch glycolate (SSG)
coming in contact with water
• Starch
Glidant • Colloidal silicon dioxide Aid the flow of granules/blend
• Magnesium stearate Aid the flow of granules/blend
Lubricant • Stearic acid and ejection of tablets in the
• Sodium stearyl fumarate tablet press
•Polymers such as hydroxypropyl
methyl cellulose (HPMC), ethyl
cellulose (EC), polyvinyl alcohol
(PVA)
• Provide a physical barrier
Coating • plasticizer (e.g., polyethylene
coating on the surface of the
material glycol)
compressed core tablets
• opacifer (e.g., titanium dioxide)
• glidant (e.g., talc)
• colourant (e.g., iron oxide red
and/or yellow)
Colouring Iron oxide red and/or yellow
• Visual appeal of colour
agent • FD&C Blue #6
• Antioxidants such as ascorbic • Stabilization of the drug in the
Stabilizer
acid, butylated hydroxyanisole dosage form from stresses
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(BHA), butylated hydroxytoluene such as oxidation

(BHT), α-tocopherol
• Sweetening to overcome drug
• Aspartame, saccharin sodium,
Sweetener taste and/or improve palatability
sucralose, acesulfame potassium
for some types of tablets
• Flavouring to overcome drug
Flavouring • Proprietary flavours (orange,
taste and/or improve palatability
agent pineapple, etc.)
for some types of tablets

Methods of Tablets Manufacturing

Tablets manufacturing involves compression of a powder blend and granules

in a die cavity between the upper and the lower punches of a tablet press. The
powder blend and granules used for tablet compression must have good flow
properties, be compressible to form the compact, and have lubricant properties for
ejection of the tablet from the die. Three processes are used for making tablets by
compression:

1. Direct compression.
2. Dry granulation (slugging).
3. Wet granulation.

The purpose of wet and dry granulation processes is to improve the flow and
compressibility of powders that would otherwise be unsuitable for compression.
When the formulation has a satisfactory flow and compressibility, the ingredients
can be mixed and directly compressed. The selection among these processes is
based on the physicomechanical properties of the drug and the raw material blend
(drug with excipients).
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1) Direct compression

Direct compression is the preferred method if powder blend has adequate

flow, compactibility, and cohesion with low segregation potential. Some available
direct compression diluents include lactose, spray-dried lactose microcrystalline
cellulose, calcium sulfate, dibasic calcium phosphate, and starch 1500. This is the
simplest process that involves the least extent of material handling. Steps for direct
compression are milling, mixing of drug and excipients and compression them into
tablets on the press.

Advantages

1. Direct compression is less expensive (labour, time, equipment, space, etc.).

2. This process eliminates heat and moisture.
3. It increases surface area for rapid drug dissolution once the tablet
disintegrates.
4. It creates more stable tablets.

Limitations
1. Differences in particle size and density in direct compression may lead to
segregation in the hopper.
2. Low-dose drugs may not be uniformly blended.
3. High-dose drugs that have poor flow and compressibility characteristics
cannot be used for direct compression.

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.

Dry granulation involves compacting the components of a powder blend by

means of a tablet press. Compaction for the dry granulation process is generally
achieved either by slugging or roller compaction. No water or heat is needed for
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this granulation process. In the slugging process, large tablets are compressed in a
heavy-duty tablet press. These tablets are then broken into granules in a
conventional mill. In the case of a roller compacter, the powders are pressed in a
roller mill, and the thin sheet of compacted materials is further broken into
granules with a conventional mill. These granules are then mixed with
extragranular excipients and compressed on the tablet press.

Advantages

1. Dry granulation eliminates the use of binder solutions and can be used for
moisture-sensitive materials (e.g., aspirin, effervescent tablets).
2. No drying step is involved, so this process can be used for heat-sensitive
materials.
3. This process improves solubility.
4. It improves blending since there is no migration.

Disadvantages

1. Dry granulation requires a heavy-duty press.

2. It does not permit uniform colour distribution.

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. This is the oldest and most conventional method of making
tablets. It is also the method of choice when large-dose drugs are to be compressed.
In this method the powder blend is loaded in a granulator (vessel with a rotating
blade to mix the powder) and granulated with a solution of the binder or water (if a
dry binder is added to the powder mixture). Water is the most widely used blender
vehicle. The formed granules are dried in a tray or fluid bed dryer at moderately
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elevated temperatures. Dried granules are then mixed with extragranular excipients
and compressed on the tablet press.

Advantages

1. Wet granulation modifies the properties of formulation components to

overcome their tableting deficiencies. Granules are relatively more spherical
than the powders and have better flow properties.
2. This process ensures better content uniformity, especially for soluble low
dose drugs.
3. It prevents segregation of components.
4. It may improve the dissolution rate of an insoluble drug by proper choice of
solvent and binder.

Limitations

1. The cost of wet granulation is higher because of the space, time, and
equipment involved.
2. This process is not suitable for moisture- and heat sensitive materials.
3. Migration of soluble materials, including dyes, in the solvent to the surface
of the granules may occur during the drying process.
4. Incompatibilities between formulation components will be aggravated by the
granulating solvent, bringing them into close contact.
5. There is a possibility of material loss during processing due to the transfer of
material from one-unit operation to the other.
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Table 2: Comparison of Various Steps Used in Different Methods of Tablet

Manufacturing Processes.

Wet Granulation Dry Granulation Direct Compression

Milling of all solid Milling of all solid Milling of all solid
ingredients ingredients ingredients
Mixing of powders Mixing of powders Mixing of powders
Preparation of binder Primary compression to
Tablet compression
solution make slugs
Mixing of binder
solution to powder
Screening of slugs
mixture to form wet
mass
Screening of wet mass Mixing with lubricant
through 6- to 12-mesh and
screen to form granules disintegrating agent
Drying of moist
Tablet compression
granules
Screening of dry
granules through 14- to
20-mesh screen
Mixing of screened
granules
with lubricant and
disintegrant
Tablet compression

Tablet Compression

The final step in the manufacture of a conventional tablet is the compression

step. Powders and granules are compressed in a tablet press, and there are two
types of presses each varying in productivity but similar in basic function and
operation. They all compress a tablet formulation within a steel die cavity by the
pressure exerted by the movement of two steel punches, a lower punch and an
upper punch. The formation of tablets compact in these two types of press differs
mainly in the compaction mechanism itself, as well as the mush greater speeds
achieved with rotary press.
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1. Single-punch presses (single-station press): The single-punch basically uses

hammering-type motion (i.e. the upper punch moves down while the lower
remains stationary). Their primary uses as a research & development tool
2. Rotary presses (multi-station press): the rotary presses make use of
accordion-type compression (i.e. both punches moves toward each other).
As they having higher outputs, are used in most production operations.

The basic functional units of these presses are outlined here: (Figure....)

1. Hopper for storing material to be compressed.

2. Feed frame for distributing the materials into dies.
3. Dies for controlling the size and shape of the tablet.
4. Punches for compacting the materials within dies.
5. Cams for guiding the punches for tablet ejection from the dies.

Stages in tablet formation

All commercial types of single statin presses have essentially the same basic
operating cycle, during which filling, compression, & ejection of tablets from the
die are accomplished by punch movement utilizing cam action.

1. Materials are fed to the die from the hopper by feed shoe the position of the
lower punch at this point determines the tablet weight.
2. The feed shoe then moves away & upper punch descends into the die to
compress the tablets.
3. As the upper punch moves upward, the lower punch rises & ejects the tablets
from the die. At this point, the feed shoe moves in & knocks the tablet out of
the machine as the lower punch moves to its bottom position ready for the
next press cycle.
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Manufacturing of Moulded Tablet

Commercial preparation of tablets by moulding has been replaced by tablet
compression. However, moulded tablets, or tablet triturates, may be prepared on a
small laboratory scale. The mould is made of hard rubber, hard plastic, or metal. It
has two parts, the upper part, or die portion, and the lower part, containing squat,
flat punches. The die portion is a flat plate with the thickness of the tablets to be
produced, with 50 to 200 uniformly drilled and evenly spaced circular holes
(Figure). The base for moulded tablets is generally a mixture of finely powdered
lactose with or without a portion of powdered sucrose (5% to 20%). In preparing
the fill, the drug is mixed uniformly with the base by geometric dilution when
potent drugs are used. The powder mixture is wetted with a 50% mixture of water
and alcohol sufficient only to dampen the powder so that it may be compacted. The
upper mould is placed on a clean flat glass surface and the damp mass added by a
rubbing motion. When each opening is filled completely and smoothed, top and
bottom, the mould is fitted on the punch portion of the mould and pressed down,
leaving the tablets raised on the pegs to dry.

Common Processing Problems during Tablet Compression

1) Capping and Lamination

Capping is the partial or complete separation of the top or bottom layer of a

tablet from the main body. Lamination is the separation of a tablet into two or
more layers.

Causes

1- Entrapped air in the granules.

2- Improper setting of the tablet press.

Remedies

1- Change granulation procedures.

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2- Increase binder concentration.

3- Increase or change the lubricant in the formulation.
4- Add dry binder to the formulation.
5- Use tapered dies.

2) Picking and Sticking

Sticking refers to tablet materials adhering to the die wall. Sticking may be
due to slight dampness of the granulation.

Picking is a form of sticking in which a small portion of granulation sticks to

the punch face. Picking may result from compressing granules that are not properly
dried or when scratched punches are used in the compression of tablets.

Remedies

1- Decrease moisture content of the granules.

2- Add an adsorbent (microcrystalline cellulose).
3- Polish the punch face.
4- Clean and coat the punch face with light mineral oil or plate punch faces
with chromium.
5- Reduce the fraction of low-melting tablet components.

3) Mottling

Mottling is defined as an unequal distribution of color on a tablet with light

and dark areas.

Causes

1- Drug colour different from other components.

2- Migration of colors during drying.
3- Uneven distribution of color when using a colored adhesive gel solution
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Remedies

1- Reduce drying temperature.

2- Grind to smaller particle size.
3- Change the binder system.
4- Change the solvent system.

4) Weight Variation

Variations in the ratio of small to large granules and differences in granule

size may lead to filling dies with the same volume but different weight of filling
materials. Segregation due to vibration of a tablet press may lead to weight
variation in tablets.

5) Hardness

The same causes responsible for weight variation may cause hardness
variation. Besides the concentration of binders used and the compression force, the
hardness of a tablet depends on the weight of the material to be compressed and the
space between the upper and lower punches at the time of compression. If the
volume of the material to be compressed and the distance between punches varies,
this will lead to variation in tablet hardness.

Tablet Coating

Coatings may be applied to a wide range of oral solid dosage forms,

including tablets, capsules, multi-particulates and drug crystals. Coating is not used
on buccal, sublingual, chewable, effervescent, or dispersible tablets to avoid any
delay in drug release due to the time required for the rupture or dissolution of the
coating material.

Coating is a process by which an essentially dry, outer layer of coating

material is applied to the surface of a dosage form in order to confer specific
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benefits that broadly range from facilitating product identification to modifying

drug release from the dosage form.

Most tablets are coated for one or more of the following reasons:

1. An enteric coating is used to protect the drug from GI irritation and from
acidic degradation in the stomach.
2. Film and sugar coatings are used to mask unpleasant taste and improve
pharmaceutical elegance of the tablet.
3. A film coating can be used to protect the drug from environmental
degradation (air (oxygen), light, or humidity) and to provide sustained action
dosage forms.
4. Special tablet coatings may help in targeting the drug to a certain area of the
GI tract (e.g., colon delivery).

Five different coatings are commonly used in tablets: 1) sugar coating, 2)

film coating, 3) compaction coating, and 4) air suspension coating.

1) Sugar Coating

Sugar is one of the oldest forms of tablet coatings. In this process, successive
layers of sugar coatings are applied by spraying sugar solution into pans in which
tablets are rotated and tumbled. Coating pans are supplied with air blowers to
admit cold or hot air as needed during the coating operation. Exhaust ducts are
attached to these pans to remove dust and moisture. For this type of coating, a
convex surface tablet is preferred because flat tablets are difficult to coat. The
following steps are commonly used in sugar coating operations:

1. Dusting of tablets to remove excess dust.

2. Applications of a waterproofing seal (shellac, ethyl cellulose, silicones).
3. Sub-coating to fill the edge (heavy sugar solutions containing acacia with
occasional dusting with starch and powder sugar).
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4. Smoothing (addition of heavy syrup followed by drying with warm air).

5. Application of colour coat.
6. Polishing.

2) Film Coating

Sugar coatings are time consuming. To avoid the extra time required for
sugar coatings, formulation scientists introduced film coatings. A polymer solution
is sprayed on the tablet surface with constant rotation and tumbling. Film coatings
avoid the need for the sub-coating and smoothing operations needed for sugar
coating. Similar coating pans that are used for sugar coating are used for film
coating. The polymers used for this coating operation include carboxymethyl
cellulose,
ethyl cellulose, hydroxyl propyl methyl cellulose, cellulose acetate phthalate,
povidone, and acrylate polymers.

3) Compression Coating

Compression coating is also termed dry coating. In this process, very fine
coating materials are compressed over the tablet surface by compression in a die
with the aid of punches. This coating process is beneficial for those drugs that
cannot withstand heat and moisture during the coating operation. Multiple layer
tablets can also be produced by this compression coating to separate two
incompatible drugs. Repeat action and sustained action tablets are produced by this
coating method.

4) Air Suspension Technique

The air suspension technique is a very rapid and efficient method of coating
tablets or granules. The tablets to be coated are suspended in a vertical chamber
with an upward stream of warm air. A coating solution is spread from the bottom
of the fluidized-bed coating chambers. This process is repeated until a uniform
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coating is achieved. In this coating, operation efficiency and quality are controlled
by fluidized air volume, specific humidity of the warm air chamber, solvent
evaporation rate, and the coating spray rate and duration.

5) Enteric Coating

Enteric coating of tablets starts with a waterproof coating with shellac in a

coating pan, followed by several coats with the enteric-coated material. In some
instances, a sugar coat is applied over the enteric coating. Materials that are used in
enteric coating include shellac, cellulose acetate phthalate, cellulose acetate
butyrate, lipids (mixture of myristic acid, hydrogenated castor oil, castor oil,
cholesterol, and sodium taurocholate), hydroxypropylmethyl cellulose succinate,
and methacrylic acid co-polymers (Eudragits). Problems associated with coating of
tablet formulations may include poor adhesion of coating material to the tablet
surface, blistering, colour variation, cracking, abrasion, roughness, and filling of
tablet markings. Quality control of coated tablets must include testing of their
appearance and performance. Checking for colour, size, appearance, and physical
defects in coating that can affect the release or stability of the drug in the dosage
form is essential for quality assurance. The in vitro disintegration and dissolution
methods of the coated tablets in appropriate media need careful evaluation. Other
tests such as evaluation of mechanical strength and resistance to chipping and
cracking during handling need careful evaluation

Quality Control of Tablet Dosage Form

The diameter and shape of tablets depend on the die and the punches
selected for the compression of the tablet. Generally, tablets are discoid in shape,
although they may be oval, oblong, round, cylindrical, or triangular. Their upper
and lower surfaces may be flat, round, concave, or convex to various degrees. The
tablets may be scored in halves or quadrants to facilitate breaking, if a smaller dose
are desired. The top or lower surface may be embossed or engraved with a symbol
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or letters that serve as an additional means of identifying the source of the tablets.
These characteristics, along with the colour of the tablets, tend to make them
distinctive and identifiable with the active ingredient that they contain.

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:

1) Appearance

All tablets should have identical size, shape, thickness, colour, 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.

2) Weight Variation

Tablets generally are manufactured to contain a certain amount of active

ingredients in a certain weight of tablet. A weight variation test is essential to
ensure that this is satisfied. In this test, samples of 10 tablets are removed from a
batch from time to time during compression, and then are weighed to determine
whether they conform to the required weight criteria. There still may be a
difference in the individual weights even when 10 tablets show the expected total
weight.

Weight Variation Test: Twenty tablets are weighed individually. Individual

weights are compared with the average weight. If no more than two tablets are
outside the percentage limit, and if no tablet differs by more than two times the
percentage limit, the tablets pass the weight variation tests (see Table 3).
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Table 3: Weight Variation Specification

Weight variation Weight variation %

specification as per USP specification as per BP Deviation
130 mg or less 80 mg or less 10
More than 130 mg up to More than 80 mg but less
7.5
324 mg than 250 mg
More than 324 mg 250 mg or more 5

3) Content Uniformity Test:

For tablets in which the active ingredients make up about 90% of the tablet
weight, the weight variation test will give a good measure of content uniformity.
The acceptable potency ranges for low dose, highly potent drugs is 90% - 110%.
For large-dose drugs, the range is 95% - 105% of the labelled amount.

Method of Determining Content Uniformity: Select 30 tablets randomly from a

batch. Assay 10 tablets individually. Nine of them must contain not less than 85%
or more than 115% of the labelled drug content. The tenth tablet may not contain
less than 75% or more than 125% of the labelled drug content. If the preceding
conditions are not met, the 30 remaining tablets are assayed individually and none
may fall outside the 85%-115% range. Various factors are responsible for the
variable content uniformity in tablets. This may include non uniform distribution
of the drug in the powder or granules, segregation of the powder mixture or
granulation during manufacturing processes, and tablet weight variation.

4) Thickness

Factors that can affect tablet thickness at a constant compression load

include changes in die fill, particle size distribution, and packing of the particle
mix during compression. Tablet thickness becomes very important in packing
operations. Use of micrometre callipers to measure the thickness of tablets is
common in practice. Variations in tablet thickness should not be more than ±5%.
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5) Hardness

Although hardness is not an official test, diametric crushing is most

frequently used in process control because of its simplicity. 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. Various instruments are used
to measure the breaking strength of tablets, including the Monsanto Tester, Strong-
Cobb Tester, Pfizer Tester, Erweka Tester, and Herberlein Tester. A force of about
4 kg is considered the minimum requirement for a satisfactory tablet.

6) Friability

It is a measure of the tendency of a tablet to powder, chip, and fragment

during handling and is another measure of tablet strength. A Roche friabilator is
used to measure the friability of a tablet. A preweighed tablet sample is placed in
the friabilator and dropped over a distance of 6 inches during each revolution and
operated for 4 minutes (100 revolutions). The tablets are dusted and reweighed.
Accepted tablets are those that do not lose more than 0.5%1.0% of their weight.
The friability of tablets may be influenced by moisture content. Chewable tablets
show a high friability weight loss compared to conventional compressed tablets.

7) Disintegration

The first thing that happens to a compressed oral tablet before absorption is
disintegration, or breaking down of the tablets to granules and powders before
dissolving in the gastric fluid. The time it takes to disintegrate is called
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disintegration time and is measured by a USP disintegration apparatus, as

described in the USP NF. The USP disintegration apparatus uses six tubes (3
inches long) open at both ends with a 10-mesh screen at the bottom of the tube.
Baskets are reciprocated up and down a distance of 56 cm at a frequency of 2832
cycles per minute. The medium can be water or simulated gastric or intestinal
fluid, and the volume of the medium is 1000 mL. The temperature is 37 6 2C.

The tablet must disintegrate and all particles pass through to 10-mesh screen
in the specified time. For ordinary compressed tablets, the disintegration time
should be within 530 minutes. For enteric-coated tablets, no disintegration should
occur within 1 hour in simulated gastric fluid, but the same tablets have to
disintegrate in 2 hours plus the time stated in the USP monograph when they are
placed in simulated intestinal fluid. Many factors can affect the disintegration time
of compressed tablets. Some of the major factors include media and the
temperature of the disintegration test media, the nature of the drug, the diluent used
in the formulation, the type and amount of binder and disintegrant used, and the
compression load.

8) Dissolution

When a tablet is administered, disintegration results in the breaking down of

the tablets into granules and primary particles (see Figure 1). For absorption to take
place, dissolution of the drug in the gastrointestinal fluid has to occur, since only
the drug in solution is absorbed.
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Figure 1: Absorption of a drug from an intact tablet.

Objectives of a Dissolution Study The objectives of a dissolution study are

to ensure that the drug is completely released or close to 100% release from the
tablet, and that the rate of drug release is uniform from batch to batch and is the
same as the release rate from batches proven to be bioavailable and clinically
effective. The rate at which a solid dissolve in a solvent is given by the Noyes and
Whitney (1897) equation:

where dc/dt is the dissolution rate, D is the diffusion coefficient of the solute in
dissolution medium, A is the surface area of the exposed solid, h is the thickness of
the diffusion layer, Cs is the solubility of the solid in the dissolution medium, C is
the concentration of the solute at any time t, and V is the volume of the release
medium.

Factors Affecting Dissolution Rate Various factors can affect the dissolution
of a drug; they are classified under three categories as follows:

1) Physiochemical properties of the drug:

1. Polymorphic form: A metastable form of a solid has higher solubility and

dissolution compared to its stable counterpart.
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2. Particle size: The smaller the particle size of a solid, the larger the particle
surface area and the higher the dissolution.
3. Salt form: A salt form of a drug has a higher aqueous solubility compared to
its conjugate acid or base, as well as higher dissolution.
4. Hydrates versus anhydrates: The anhydrous form shows higher dissolution
than hydrates due to their solubility differences.

2) Factors related to tablet manufacturing

1. The amount and type of binder can affect the hardness, disintegration, and
dissolution of tablets.
2. The method of granulation, granule size, and size distribution can affect
tablet dissolution.
3. The amount and type of disintegrants used, as well as the method of their
addition, can affect disintegration and dissolution.
4. Compression load can influence density, porosity, hardness, disintegration,
and dissolution of tablets.

3) Factors related to method of dissolution study

1. Composition of the dissolution medium, pH, ionic strength, viscosity.

2. Temperature of the medium.
3. Intensity of agitation.
4. Volume of dissolution medium.
5. Sink or non sink conditions (under a sink condition, the concentration of the
drug should not exceed 10%15% of its maximum solubility in the
dissolution medium in use).
6. Type of dissolution equipment.
7. Sensitivity of analytical method used to determine drug concentration in the
release medium.
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Dissolution Testing Method: According to USP 30, there are many dissolution
apparatuses used to determine the dissolution profiles of drugs from different
dosage forms. Some of them are outlined in Table 4. USP dissolution conditions
are maintained as close as possible to the in vivo situation:

Temperature: 37˚ ±0.5˚C

Medium: 0.1 N HCl, pH 7.4 buffer
Simulated gastric fluid
Simulated intestinal fluid, water
Agitation: Mild
Volume of the Medium: Enough to maintain sink
condition (1000 mL)

USP Apparatus #1 (rotating basket) and USP Apparatus #2 (paddle method)

are commonly used to evaluate the dissolution profile of solid dosage forms. The
dissolution testing may be repeated three times for a batch if necessary. First, the
dissolution of six tablets is tested and accepted if all six tablets are not less than the
USP monograph tolerance limit plus 5%. If they fail, another six tablets will be
tested. The tablets will be acceptable if the average of the 12 tablets is greater than
or equal to the USP monograph tolerance limit and no unit is less than this limit
minus 15%. If this fails, an additional 12 tablets will be tested. The tablets will be
acceptable if the average of the 24 tablets is greater than or equal to the USP
monograph tolerance limit and not more than two tablets are less than the USP
monograph limit minus 15%. Dissolution results are plotted as concentration
versus time, and values such as t50% and t90% or the percentage dissolved in 30
minutes are used for comparison purposes. A value of t90% in 30 minutes is
considered satisfactory during a dissolution study.
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Table 4: Comparison of Different USP Dissolution Apparatuses

USP Description of Rotation

Dosage Forms to be Tested
Apparatus the Apparatus Speed
Immediate-release tablets
I Basket 50-120 rpm Delayed-release tablets
Extended-release tablet
Immediate-release tablets
II Paddle 25-50 rpm Delayed-release tablets
Extended-release tablets
6-35 dpm
III Reciprocating
(dips per Immediate-release tablets
cylinder
minute) Extended-release tablets
Flow-through Extended-release tablets
IV N/A
cells Poorly soluble drug
Paddle over
V 25-50 rpm Transdermal
disk
VI Cylinder N/A Transderma
Reciprocating
VII 30 rpm Extended-release tablets
disk

Packaging and Storing Tablets

Following compression and coating, tablets are stored in tight containers and
protected from high temperature and humidity places. Products that are prone to
decomposition by moisture generally are co-packaged with desiccants, such as
silicon dioxide. Drugs that are adversely affected by light are packaged in light-
resistant containers.