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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5577_Библиотеки_им_академика_М_И_Перельмана.pdf
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
systems stems from the fact that the skin is a very eective barrier;
as a result, only medications whose molecules are small enough
to penetrate the skin can be delivered by this method. Although
systemic drug delivery can be achieved using transdermal patches,
the absorption of drug molecules from transdermal patches may be
poor and erratic. The scopolamine transdermal patch is used to prevent nausea and vomiting caused by motion sickness. The nicotine
transdermal patch is another example that is prescribed as an aid
for smoking cessation.
Transdermal patch
14.4.2. Physical Forms
14.4.2.1. Solid Dosage Forms
Solid dosage forms comprise pharmaceutical products with a definite shape and size. They constitute approximately 90% of all pharmaceutical dosage forms used clinically for treating patients due to
a large extent to their portability, convenience and ease of use. This
class broadly encompasses two of the most commonly used dosage
forms, namely tablets and capsules.
Pharmaceutical Dosage Forms
14.4.2.2. Liquid Dosage Forms
Liquid dosage forms include pharmaceutical products that are
administered in the form of solutions, suspensions or emulsions.
Liquid dosage forms can be sterile or non-sterile depending on the
route of administration. Non-sterile liquids include syrups, mixtures
and suspensions for oral consumption while sterile liquids include
injections given via the parenteral route — intravenous, intramuscular, subcutaneous, intraperitoneal or intrathecal injections.
14.4.2.3. Semi-solid Dosage Forms
Semi-solid dosage forms are preparations that are applied on the
skin, or on the mucous membrane to achieve a local or systemic
eect for symptomatic relief or for therapeutic treatment of a variety of medical conditions. Examples of semi-solid dosage forms
include creams, ointments, pastes and gels.
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14.4.2.4. Gaseous or Aerosol Dosage Forms
Gaseous or aerosol dosage forms comprise pharmaceutical products
where the drug substances are packaged under pressure in a holder
coupled with a conveyance valve framework. This gaseous dosage
form contains medicaments that are released upon activation of the
conveyance valve system. Examples of gaseous dosage forms include
the powder inhalers, sprays, nebulizers and the pressurized metered
dose aerosols.
Among the dierent physical forms, the liquids and solids are more
commonly employed. The advantages and disadvantages of liquid
over solid dosage forms are highlighted on the next page.
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Advantages
• Easier to swallow than solids
• Uniform distribution of drug in solutions
• Drug in solution immediately available for absorption
• Reduced irritation of drug to GIT
Disadvantages
• Lower stability than solids
• Greater microbial growth in liquids
• Greater dosage variability
• More pronounced unpleasant taste than solids
• More bulky and inconvenient to transport and to store
Pros and cons of liquid vs solid dosage forms
14.5. Manufacture and Important Characteristics of Common Pharmaceutical Dosage Forms
This section will highlight the important characteristics of the
more common dosage forms and describe briefly how they are
manufactured.
14.5.1. Tablets
Tablets are the pharmaceutical dosage form of choice for the drug
formulation scientist. They are simple and convenient to consume
or administer. They provide a measured dose of the desired drug
substance and are highly portable. Tablets can be formulated to protect the unstable drugs or to mask their bitter or unpalatable taste.
Colored coatings, embossed markings and logos have also been
incorporated onto tablets as part of branding as well as to help in
tablet identification. Various manufacturing processes and technologies may also be adopted by manufacturers to produce tablets with
Pharmaceutical Dosage Forms
special properties, for example, sustained release or rapid-dissolving
formulations. In general, tablets comprise a well-blended mix of the
active drug substances and excipients (collectively known as powder
feed), which are ultimately compressed or compacted into a solid
dosage form using a tablet machine. The tablet machine consists
of a die (that looks like a hollow cylinder) with a lower and upper
punch at opposite ends. Using a hopper, the powder feed is filled into
the die with the lower punch fixed. The upper punch is then lowered into the die and a pressure applied to compact the powder feed
to form a tablet. The lower punch is then raised to eject the tablet
out of the die. The excipients of tablet formulations usually include
diluents, binders, disintegrants, glidants (flow aids) and lubricants.
Sometimes, sweeteners or flavors are added to enhance taste whilst
colored pigments are incorporated to make the tablets visually
attractive or to aid in visual identification of an unknown tablet.
A polymer may be used to coat the tablet to make it smoother and
easier to swallow, control the release rate of the drug, make it more
resistant to the external environment, or simply to enhance its
appearance. Some pure drug substances may be compressed directly
alone without the addition of any excipient. However, tablet formulations usually include several types of excipients. A minimum
mass is needed to process a single unit of tablet. As the dose of drug
in a tablet is generally very low, a diluent is included in a tablet formulation to increase the bulk mass. A binder is added to help hold
the tablet together and to give it strength. Some common examples
of binders include lactose (milk sugar), sucrose (cane sugar), corn
(maize) starch, microcrystalline cellulose, and modified cellulose,
e.g., hydroxypropyl methylcellulose, hydroxyethylcellulose and polyvinylpyrrolidone. A disintegrant is often added to promote tablet break-up and drug release for absorption. Some binders, such as
starch and cellulose, are also excellent disintegrants, hence they can
perform the dual roles of binder as well as disintegrant. In addition
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
to binders and disintegrants, lubricants are added as excipients during the manufacture of tablets to prevent the powder from sticking
to the punches and die wall of the tablet machine. Common lubricants used in tablet production include talcum, silica, magnesium
stearate or stearic acid. The lubricant may also act as a glidant to
improve the flowability of the powder feed into the die to obtain
tablets of uniform weight.
In the manufacture of any tablet, the appropriate amount of drug
substance(s) must be present in each and every tablet. Hence, all the
ingredients, namely the drug and excipients, should be well-mixed.
If a homogeneous mix of the drug and excipients cannot be obtained
with simple blending process, the ingredients must be subject to a
granulation process prior to compression to help assure an even distribution of the drug substance(s) within the final tablet. Two main
techniques are used to granulate powders before compression into
a tablet: wet granulation and dry granulation. Wet granulation is
a process of using a liquid binder to agglomerate the powder mixture. The amount of wetting agent has to be properly controlled
because over-wetting will cause the granules to become too hard,
whilst under-wetting will cause them to be too soft. Aqueous solutions tend to be safer than organic solvent-based systems but may
not be suitable for drug substances which are degraded by hydrolysis. Dry granulation is a process which creates granules by light
compaction of the powder blend under low pressures. No liquid or
wetting agent is used. Dry granulation is often used when the product to be granulated is sensitive to moisture and heat. Overall, dry
granulation is simpler than wet granulation, with reduced production cost. However, dry granulation often produces a higher percentage of fine granules, resulting in lower yields and a compromise in
quality during the manufacture of the tablet. Whether it is wet or
dry granulation, a final lubrication step is carried out to ensure that
Pharmaceutical Dosage Forms
the granules do not stick to the equipment during the tablet compression process.
Tablets of dierent shapes, sizes and colors
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Using punches and dies of dierent configurations, tablets can be
made in many dierent shapes — round or disk-shaped, oval or
oblong-shaped. The latter are known as caplets as they are shaped
like capsules. Most tablets are flat and round in shape. Although
unusual shapes of tablets have been manufactured, patients can find
these unconventionally shaped tablets harder to swallow. Besides,
they are also more vulnerable to chipping or manufacturing problems. Tablets need to be hard enough so that they do not break up
in their containers during transportation and handling before their
consumption. Yet, they should be soft enough to disintegrate in the
GIT. Very hard tablets are known to pass out completely as whole
undisintegrated tablets, from the lower end of the GIT. Standards
for tablet properties, including hardness, are published in various international compendia such as the British Pharmacopoeia,
United States Pharmacopeia, European Pharmacopoeia as well
as the World Health Organization International Pharmacopoeia.
The hardness of tablets is the principal measure of its mechanical
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
strength. The diameter and shape of a tablet are determined by the
machine tools used to produce them, namely, the sets of upper and
lower punches as well as the die. The thickness and hardness of a
tablet is influenced by both the tablet formulation and amount of
powder feed as well as the compaction pressure applied.
Tablet machines can range from small, inexpensive bench-top models that make one tablet at a time (single-station presses), to large
and computerized models (multi-station rotary presses) which can
churn out hundreds of thousands of tablets an hour.
Parts of a tablet machine
Some common problems encountered during tablet manufacturing
operations include:
• Fluctuations in tablet weight due to poor flow properties of
powder feed during tabletting.
• Fluctuations in content of drug substances within tablets caused
by uneven distribution of the drug substances during blending,
prior to granulation.
Pharmaceutical Dosage Forms
Single punch tablet machine
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Multiple punch tablet machine
• Sticking of powder feed to punches and die due to inadequate
lubrication, or due to worn out or dirty punches and die.
• Capping, lamination or chipping caused by air being compressed
together with tablet formulation or high moisture content of
powder feed.
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Many tablets today are coated after being compressed. These
coatings are often polymer- and polysaccharide-based, with plasticizers and pigments included. Tablets are coated for a variety of
reasons such as the masking of unpleasant taste or the provision of
a smoother finish to large tablets to make them easier to swallow.
Tablet coatings are also useful in extending the shelf-life of components that are sensitive to moisture or oxidation. There are also
special coatings with pearlescent eects which can help to enhance
brand recognition. Whatever the purpose of coating a tablet, the
coatings must be stable and strong enough to survive transportation and handling of the tablet. If the active ingredient of a tablet is
sensitive to acid or irritant to the stomach lining, an enteric coating
can be used. Enteric coatings are chosen based on the rate of dissolution of the drug along specific parts of the GIT. If the drug is better
absorbed in the stomach, a coating is selected such that it dissolves
quickly and easily under the acidic conditions of the stomach (with
pH 1 to 2). On the other hand, if the drug is better absorbed in the
Tablet coating machine
Pharmaceutical Dosage Forms
small intestine, the coating selected should be acid-resistant so that
the enteric-coated tablet is able to reach the small intestine (with
pH 6 to 7) before disintegrating.
There are two types of coating machines used in the pharmaceutical industry: coating pans and automatic coaters. Coating pans are
used mostly to sugar coat pellets. Automatic coaters are used for all
kinds of coatings; they can be equipped with a remote-controlled
panel, a dehumidifier, and dust collectors. An explosion-proof design
is required for applying coatings that contain alcohol.
14.5.2 . Capsules
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Many manufacturers have encapsulated drug substances in capsules, promoting them as an easier-to-swallow shape than the usual
disk-shaped tablet. The two main types of capsules are:
• Hard capsules or hard-shelled capsules containing dry powdered
ingredients or pellets. These capsules are made of two halves: a
smaller-diameter “body” that is filled and then sealed using a
larger-diameter “cap”.
• Soft capsules or soft-shelled capsules containing oils or drug substances that are dissolved or suspended in oil.
The process of encapsulation of hard capsules can be done on manual, semi-automatic and automatic capsule filling machines. On
the other hand, soft capsule shells are filled as they are being produced, followed by sealing seamlessly via a fully automatic encapsulation machine. The capsule fill weight is a critical attribute in the
encapsulation process, and various real-time fill weight monitoring