Industrial Pharmacy II

Dr. Myasar Al-kotaji

Ph.D. Pharmaceutics (University of Manchester)

Text books
Industrial Pharmacy, Lechman
Pharmaceutics, Aulton

Myasar.alkotaji@uoninevah.edu.iq

23-9-2023
 The topics
1- Tablets: adv and disadv, classification, excipients used, formulation,
granulation and method of productions, evaluation of tablets.

2- Tablet coating

3- Capsules: hard and soft, materials, processing and control.

4- Modified release dosage form, theory and application

5- Microencapsulation

6- Semisolid dosage form: formulation, types of bases.

7- Suppositories: uses, types of bases , processing and evaluation.
8- Pharmaceutical aerosols.
 Tablets

Tablet is a solid pharmaceutical dosage form prepared by

compressing the medicament or mixture of medicaments,
usually with added substance.
Tablets are the most popular dosage form (70% of all the
pharmaceutical preparations).
Advantages:
1- They are a unit dose form offer the greatest dose precision and
the least content variability.
2- The cost is the lowest of all oral dosage form
3- The lightest and most compact
4- The easiest and cheapest to package and ship.
5- Product identification is the simplest and cheapest.
6- They lend themselves to certain special release profile.
7- Better suited for large scale production.
 Disadvantages

1- Some drug resist compression into dense compact.

2- Drugs with poor wetting, slow dissolution properties,

intermediate to large dosage, optimum absorption high in
the git, or any combination of these features may be difficult
to formulate as tablet with a full bioavailability.

3- Bitter-tasting drugs, drugs with an objectionable odor, or

drugs that are sensitive to oxygen or moisture may require
entrapment or encapsulation prior to compression or the
tablets may require coating. In such cases the best
alternative is capsule dosage form.
4- The manufacture of tablets requires a series of unit
operations and therefore there is an increased level of
product loss at each stage in the manufacturing process.

5- The absorption of therapeutic agents from tablets is

dependent on physiological factors, e.g. gastric emptying
rate, and shows interpatient variation.

6- The administration of tablets to certain groups, e.g.

children and the elderly, may be problematic due to
difficulties in swallowing. These problems may be
overcome by using effervescent tablet dosage forms.
 Properties of tablet dosage form
1- The tablet should include the correct dose of the drug.
2. The appearance of the tablet should be elegant and its weight,
size and appearance should be consistent.

3. The drug should be released from the tablet in a controlled and

reproducible way.

4. The tablet should be biocompatible, i.e. not include excipients,

contaminants and microorganisms that could cause harm to patients.
5. The tablet should be of sufficient mechanical
strength to withstand fracture and erosion during
handling and shipping.

6. The tablet should be chemically, physically and

microbiologically stable during the lifetime of the
product.

7. The tablet should be formulated into a product

acceptable by the patient.

8. The tablet should be packed in a safe manner.

 Types and classes of tablets
Tablets are classified by their route of adminstration or function, by
the type of drug delivery and by their form and method of
manufacture.
I-Tablets ingested orally
1- Compressed tablets or standard compressed tablets.This category
refers to standard uncoated tablets made by compression.
2-Multiple compressed tablets
These are tablets that are composed of at least two layers.
Typically there are two designs of multiple compressed tablets:
(a) multiple-layered; and (b) compression coated. In multiple-layer
tab. the first layer is formed by a relatively light compression of
the drug containing powder mix/granules. The next layer is then
formed by compression of the powder/granule mix (containing
drug) on top of the lightly compressed first layer. Additional layers
are formed in a similar fashion.
In the second approach the initial layer is prepared by light
compression , removed and located in a second tablet press. The
granules/powders of the second coat are fed into the press and
allowed to form a constant mass around the surface (and edges)
of the pressed tablet prior to compression to form the finished
product.
There are several applications of the use of multiple compressed
tablets, including:
■ the separation of incompatible drugs into separate layers.
■ the delivery of therapeutic agents at different rates or to different
sites within the g.i.t from a single tablet. The dissolution /diffusion
of the drug from the layer may be controlled by the inclusion of
polymeric excipients.
■ the production of tablets that are coated. This is important in
cases where the drug has a bitter taste or where the drug is
irritant to the stomach or is chemically unstable under acidic
condition.
3- Enteric-coated tablets
These are tablets that are coated with a polymer that does not
dissolve under acidic conditions (i.e. the stomach) but does
dissolve under the more alkaline conditions of the small intestine.
Enteric polymers are primarily employed as
coatings of conventional tablet dosage forms and, by inhibiting
the dissolution of the therapeutic agent within the stomach, offer
protection against possible drug degradation (e.g. erythromycin)
or irritation of the gastric mucosa (e.g. non-steroidal anti-
inflammatory drugs). Following dissolution of the coating, the
tablet will be disintegrated and the drug will be dissolved in the
gastric fluids (thereby facilitating absorption).
Examples of polymers that are used for this purpose include:
(1) cellulose actetate phthalate/cellulose acetate butyrate;
2) hydroxypropylmethyl cellulose succinate; and
(3) methacrylic acid co-polymers (Eudragit).
4- Sugar-coated tablets
5- Film-coated tablets

6-Chewable tablets
These tablets are chewed within the buccal cavity prior to
swallowing. The main applications for this dosage form
are:
■ for administration to children and adults who have
difficulty in swallowing conventional tablets.
■ antacid formulations in which the size of the tablet is
normally large and the neutralisation efficacy of the
tablet is related to particle size within the stomach.
Conversely, chewable tablets are not useful if the drug has
issues regarding taste acceptability.
 II- Tablets used in the oral cavity
1- Buccal and sublingual tablets
Buccal and sublingual tablets are dosage forms that are held
within the oral cavity and slowly dissolve; the drug is absorbed
across the buccal mucosa to produce a systemic effect. Buccal
tablets are positioned between the cheek and the gingiva,
whereas sublingual tablets are positioned underneath the tongue.
These tablets are employed to achieve either rapid absorption into
the systemic circulation (e.g. glyceryl trinitrate sublingual tablets)
or, alternatively, to enable systemic drug absorption in situations
where oral drug delivery is inappropriate, e.g. nausea. Drug
absorption across the buccal mucosa avoids first-pass
metabolism.
Typically buccal and sublingual tablets should be formulated to
dissolve slowly in vivo (and not disintegrate) and to be retained
at the site of application and should not contain components that
stimulate the production of saliva.
 2-Lozenges
Lozenges are tablets that dissolve slowly in the mouth and so release
the drug dissolved in the saliva. Lozenges are used for local medication
in the mouth or throat, e.g. with local anaesthesia, antiseptic and
antibiotic drugs. They can thus be described as slow release tablets for
local drug treatment.
Disintegrants are not used in the formulation, but otherwise such tablets
are similar in composition to conventional tablets. In addition, lozenges
are often coloured and include a flavour. The choice of filler and binder
is of particular importance in the formulation of lozenges, as these
excipients should contribute to a pleasant taste or feeling during tablet
dissolution. The filler and binder should therefore be water soluble and
have a good taste. Common examples of fillers are glucose, sorbitol and
mannitol. A common binder in lozenges is gelatin.

Lozenges are normally prepared by compaction at high applied

pressures in order to obtain a tablet of high mechanical strength and low
porosity which can dissolve slowly in the mouth.
 III-Tablets used to prepare solution
1-Effervescent tablets
Effervescent tablets are added to aqueous solutions where they
will rapidly disintegrate and produce either a drug suspension
or an aqueous solution. The disintegration of the tablet is due to
a chemical interaction that occurs between two components: (1)
an organic acid (e.g. citric acid); and (2) sodium bicarbonate in
the presence of water. The evolution of carbon dioxide from this
reaction results in tablet disintegration. The patient then
consumes the solution/suspension. The main advantage of the
use of effervescent tablets is to obtain rapid drug action. In
addition it facilitates the intake of the drug.
The main disadvantages of this dosage form are the possible
(un)availability of water and the need to package these tablets
in moisture-impermeable packaging (typically aluminium foil).
2-Dispersible tablets
• Are intended to be added to a given volume of water by
the pharmacist or the consumer, to produce a given drug
concentration. These tablets must comprise totally
soluble ingredients.
IV-Tablets administered by other routes
1-Vaginal tablets
These are ovoid-shaped tablets that are inserted into the
vagina (using a special inserter). Following insertion, retention
and slow dissolution of the tablet occur, releasing the
therapeutic agent to provide the local pharmacological effect
(e.g. for the treatment of bacterial or fungal infection). Vaginal
tablets may also be used to provide systemic absorption of
therapeutic agents. In a similar fashion to buccal/sublingual
tablets, it is important that dissolution, and not disintegration, of
the tablet occurs in vivo, as disintegration will reduce tablet
retention within the vagina.
 2-Implants
Implantation or depot tablets are designed for subcutaneous
implantation in animals or man. Their purpose is to provide
prolonged drug effects, ranging from one month to a year.
These tablets are usually small, compressed or moulded discs of
drug. Such systems include biodegradable polymeric
microspheres (e.g. polylactide co-glycollic acid homo- and
copolymers) containing Hormon.
e.g. ZOLADEX®
(goserelin acetate) Implant 3.6 mg
cylindric and are typically
not more than 8mm in length.
Excipients used in the manufacture of tablets

In addition to the active or therapeutic ingredient, tablets contain a number of

inert materials( excipients). They are classified according to the part they play in
the finished tablet.
1- Those which help to impart satisfactory processing and compression
characteristics to the formulation (diluents, binders, glidants and lubricants).

2- Those which helps to give additional desirable physical characteristics to the

finished tablet (disintegrants, colors, and in the case of chewable tablets,
flavors and sweetening agents, and in the case of controlled- release tablets,
polymers or waxes or other solubility-retarding materials) .
 Diluents
Diluent is an inert substance added to increase the bulk in order
to make the tablet a practical size for compression.
Tablets normally weigh at least 50 mg. Therefore, a low dose of
a potent drug requires the incorporation of a substance into the
formulation to increase the bulk volume of the powder and
hence the size of the tablet. The diluent is not necessary if the
dose of the drug per tablet is high. The ideal filler should full a
series of requirements, such as:
chemically inert, non-hygroscopic, biocompatible, possess
good biopharmaceutical properties (e.g. water soluble or
hydrophilic), possess good technical properties (such as
compactability and dilution capacity), have an acceptable taste
and cheap.

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Examples of diluents for tablets are: anhydrous lactose,
lactose monohydrate, spray-dried lactose, starch, dibasic
calcium phosphate, microcrystalline cellulose (MCC),
and mannitol.

Lactose is the most common tablet filler, it dissolves

rapidly in water, has a pleasant taste, is non-
hygroscopic, it is non-reactive and show good
compactability. Lactose is presented as amorphous and
crystaline form. The spray dried lactose is used in direct
compression operation of tableting.
Certain diluents, such as mannitol, sorbitol and sucrose
can be used as an alternative to lactose in chewable
tablets and lozenges as they impart pleasant taste to
these tablets. Mannitol has a negative heat of solution
and imparts a cooling sensation when sucked or
chewed.
 Celluloses derivatives
Celluloses are biocompatible, chemically inert
and have good tablet-forming and disintegrating
properties. They are therefore also used as dry
binders and disintegrants in tablets. They are
their compatible with many drugs but, owing to
hygroscopicity, may be incompatible with drugs
prone to chemical degradation in the solid state.
The most common type of cellulose powder used
in tablet formulation is microcrystalline cellulose.
Microcrystalline cellulose (MCC)
MCC is a crystalline powder that is prepared by the controlled
acid hydrolysis of cellulose. Several grades of MCC are
commercially available that differ in their physicochemical
properties, e.g. density, flow properties and particle size
distribution. In addition to its use as a diluent, MCC may also be
used as a binder in wet granulation and a disintegrating agent.
Two commonly used grades of MCC are Avicel pH-101 (powder)
and pH-102 (granules).

Dibasic calcium phosphate

Is an inorganic substance, insoluble in water and non-
hygroscopic, but is hydrophilic, i.e. easily wetted by water. The
substance can be obtained in both a fine particulate form, mainly
used in granulation, and an aggregated form. The granulated form
possesses good flowability and is used in tablet production by
direct compaction. Calcium phosphate is slightly alkaline and may
thus be incompatible with drugs sensitive to alkaline conditions.
 Diluents used as excipients for direct compression formulas have
been subjected to prior processing to give them flowability and
compressibility.
Selection of the diluent
Is based partly on the experience of the manufacturer as well as on
diluent cost and compatibility with other tablet ingredients.
However, in the formulation of new therapeutic agents, the compatibility
of the diluents with the drug must be considered, e.g: calcium salts
used as diluents for tetracycline have been shown to interfere with the
drug’s absorption from the gastrointestinal tract.
When drug substances have low water solubility, it is recommended that
water-soluble diluents be used to avoid possible bioavailability
problems.
The combination of amine bases with lactose, or amine salts with
lactose in the presence of an alkaline lubricant, results in tablets which
discolor on aging.
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 Binders
Agents used to impart cohesive qualities to the powdered
material to ensure the tablet remaining intact after compression,
as well as improving the free-flowing qualities by the formulation
of granules of desired hardness and size.
Commonly used binders include: starch, gelatin and sugars
as sucrose, glucose and dextrose. Other types of binders
include: Natural gums (acacia, sodium alginate, carboxy-
methylcellulose,) semisynthetic like ethylcellulose and synthetic
like polyvinyl pyrrolidone .
The quantity of binder used has considerable influence on the
characteristics of the compressed tablets.
The use of too much binder will make a hard tablet which will not
disintegrate easily and which will cause excessive wear of
punches and dies.
Usually materials which have no cohesive qualities of their own
will require a stronger binder than those with these qualities.
• Binders are used both as a solution and in a dry form
depending on other ingredients and method of preparation.

• The same amount of binder in solution will be more effective

than if it were in a dry form and moistened with the solvent.
So it is preferable to incorporate the binding agent in solution.

• If the drug substance is adversely affected by an aqueous

binder , a non aqueous binder can be used or binder can be
added dry.

• The direct-compression method for preparing tablets requires

a material that not only is free-flowing but also sufficiently
cohesive to act as a binder.
 Disintegrants
Is a substance, or a mixture of substances, added to a tablet to facilitate its
breakup or disintegration after administration. Materials serving as
disintegrants have been classified chemically as starches, clays, celluloses,
algins, gums and cross-linked polymers. The oldest and the most popular
disintegrants are corn and potato starch which have been well-dried and
powdered. Starch has a great affinity for water and swells when moistened,
thus facilitating the rupture of the tablet matrix. However, disintegrating
action in tablets might due to capillary action rather than swelling.

• Starch 5%, is suggested, but if more rapid

disintegration is desired, this amount may
be increased to 10 or 15%.
• A group of materials known as super disintegrants have gained
in popularity. As Croscarmelose (a cross-linked sodium
carboxymethylcellulose), crospovidone and sodium starch
glycolate. Sodium starch glycolate swells 7-12 fold in less than
30 seconds while Croscarmelose swells 4-8 fold in less than 10
seconds.
• The disintegrating agent usually is mixed with the active
ingredients and diluents prior to granulation.
• Alternatively, disintegrant may added (prior to compression) i.e.
extragranular addition.
In some cases it may be advantageous to divide starch into two
portions:
One part is added to the powdered formula prior to granulation,
and the remainder is mixed with the lubricant and added prior to
compression.
In such case, the starch serves a double purpose; the portion
added to the lubricant rapidly breaks down the tablet to granules,
• The figure shows the effect of
different disintegrant on the dissolution
time of tablets.

Other factors than the presence of

disintegrants can affect significantly
the disintegration time of compressed
tablets include:
1- The binder
2- Tablet hardness
3- Lubricant.
There are several mechanisms by which disintegrants
elicit their effect:
1- Disintegrants may increase the porosity and wettability of the
compressed tablet matrix. In so doing gastrointestinal fluids
may readily penetrate the tablet matrix and thereby enable
tablet breakdown to occur. Examples of disintegrants that
operate in this fashion include: – starch , MCC, sodium
starch glycolate.
2- may operate by swelling in the presence of aqueous fluids,
thereby speed up tablet disintegration due to the increase in
the internal pressure within the tablet matrix. Disintegrants in
this category are typically hydrophilic polymers.
3- may be mediated by the production of gas whenever the
tablet contacts aqueous fluids. This is the mechanism of
disintegration of effervescent tablets.
 Lubricants
Lubricant functions in tablet manufacture:
Prevent adhesion of the tablet material to the surface of the dies and punches.
Reduce inter particle friction.
Facilitate the ejection of the tablets from the die cavity.
May improve the rate of flow of the tablet granulation.
• Commonly used lubricants include: talc, magnesium stearate, calcium
stearate ,stearic acid, hydrogenated vegetable oils and (PEG).
• Most lubricants, with the exception of talc, are used in concentrations less
than 1%. When used alone, talc may require concentrations as high as
5%.
• Lubricants are in most cases hydrophobic materials. Poor selection or
excessive amounts can result in “waterproofing” the tablets, resulting in
poor tablet disintegration and or delayed dissolution of the drug substance
In addition to concentration, the time of mixing of the lubricant with

the granules/powders and the particle size of the lubricant will affect the
performance of the lubricant. Overmixing (in terms of both shearing stress
and time) may adversely affect tablet disintegration and drug dissolution. In
particular mixing of the disintegrant and the insoluble lubricant together
should be avoided as this leads to the formation of a film of lubricant on the
surface of the disintegrant, which subsequently reduces the wettability of,
and water uptake by, the disintegrant, leading to compromised disintegration.
Furthermore, it has been shown that the efficacy of the lubricant is enhanced
if the surface area is increased (i.e. the particle size of the lubricant is
decreased).
Glidants
Glidants act to enhance the flow properties of the powders
within the hopper and into the tablet die in the tablet press. The
reduced friction between the powders/granules and the
surfaces of the hopper and dies has been suggested to be due
to the ability of the particles of the glidants to locate within the
spaces between the particles/granules. To achieve this effect it
is therefore necessary for the glidant particles to be small and
to be arranged at the surface of the particles/granules.
Traditionally, talc has been used as a glidant in tablet
formulations, in concentrations of about 1–2% by weight.
Today, the most commonly used glidant is probably colloidal
silica, added in very low proportions (about 0.2% by weight).
Because the silica particles are very small they adhere to the
particle surfaces of the other ingredients (i.e. an ordered or
structured mixture is formed;
 Adsorbents
Adsorbents are used whenever it is required to include a
liquid or semisolid component, e.g. a drug or a flavour,
within the tablet formulation. Examples of materials act as
adsorbent are Kaolin and bentonite. These excipients are
employed as adsorbents within the concentration range of
1.0–2.0% w/w.

Antiadherent
The function of an antiadherent is to reduce adhesion
between the powder and the punch faces and thus prevent
particles sticking to the punches. Many powders are prone
to adhere to the punches, a phenomenon (known in the
industry as sticking or picking) which is affected by the
moisture content of the powder. Many lubricants, such as
magnesium stearate, also have antiadherent properties.
 Colors and dyes
Colors and dyes serve to: hide off-color drugs, Provide product
identification and Produce a more elegant product. Food, drug,
and cosmetic (FD and C) dyes are applied as solutions; lakes
(which are calcium or aluminium complex of water soluble dyes)
are usually employed as dry powders.

Flavoring agents
Are usually limited to chewable tablets or tablets intended
to dissolve in the mouth.
• (a) Generally, water-soluble flavors have poor stability; hence,
flavor oils or dry powders usually are used.
• (b) Flavor oils may be added to tablet granulations in solvents,
dispersed on clays and other adsorbents, or emulsified in
aqueous granulating agents. Usually, the maximum amount of
oil that can be added to a granulation without influencing its
tablet characteristics is O.5%—O.75%.
• Artificial sweeteners,

like flavors, are usually used only with chewable tablets or tablets dissolve in

the mouth.

• (a) Some sweetness may come from the diluent (e.g., mannitol, lactose);
• agents, such as saccharin and aspartame, can also be added.
• (b) Saccharin has an unpleasant after taste.
• (c) Aspartame is not stable in the presence of moisture.
• Aspartame is not suitable for some persons. (who?)

• More recent sweetening agents include???

 Aspartame, use it or not
FDA Response to External Safety Reviews
of Aspartame
The FDA is aware of the International Agency
for Research on Cancer (IARC) and Joint
FAO/WHO Expert Committee on Food
Additives (JECFA) conclusions about
aspartame issued July 14, 2023. Aspartame
being labeled by IARC as “possibly
carcinogenic to humans” does not mean that
aspartame is actually linked to cancer.
https://www.fda.gov/food/food-additives-petitions/aspartame-and-other-sweeteners-
food#:~:text=Since%20then%2C%20more%20than%2030,is%20safe%20for%20human%20consumption.