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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
Hard shell capsules
Soft shell capsules
techniques such as near-infrared spectroscopy and vibrational spectroscopy are used to ensure product quality. The shells of both
hard and soft capsules are made from aqueous solutions of gelling
agents, such as animal protein (e.g., gelatin) or plant polysaccharides
and their derivatives (e.g., tapioca starch and hypromellose). Other
ingredients that may be added to the gelling agent solution include
coloring agents, opacifiers (e.g., titanium dioxide) to make the shells
opaque, and plasticizers (e.g., glycerin and sorbitol) to decrease the
Pharmaceutical Dosage Forms
hardness of the capsule. The animal protein commonly used to produce capsule shells is gelatin, which is obtained from the collagen of
animal skin or bone.
14.5.3. Solutions
A pharmaceutical solution is a homogeneous one-phase liquid system consisting of a solute and a solvent. The solute is the substance
that is dissolved as small molecules or ions in the solvent. Solutions
may be aqueous or non-aqueous. Depending on their composition
or route of administration, they are given dierent names such
as syrup, elixir, linctus, mouth wash, enema, eye lotion, eye drop,
injection or infusion (see examples shown below).
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Pharmaceutical solutions
Water is the solvent for aqueous solutions. The quality of water
required depends on the type of solutions which are to be made. For
oral solutions which are not intended to be sterile, potable water or
pharmacopeial-grade purified water (e.g., Purified Water BP) may
be used. In contrast, water which is sterile, free from particulate
matter and toxins (e.g., Water for Injection BP) must be used for
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
solutions which are intended for injection into the human body.
It may not be possible to ensure complete dissolution of all ingredients into water at ambient temperature. Various methods may
be employed to increase the apparent solubility of drug substances
in an aqueous medium. A common method is the addition of
another solvent. A vehicle or a second solvent used in combination
to increase the solubility of a drug is called a co-solvent. Co-solvents
that are commonly employed in the manufacture of solutions
include ethanol, glycerin (or glycerol), polypropylene and polyethylene glycol. Appended below are some examples of pharmaceutical
solutions containing co-solvents:
• Co-trimoxazole + Propylene glycol + Water
• Paracetamol + Alcohol + Propylene glycol + Syrup
• Betamethasone valerate + Isopropanol + Water
Co-solvents, such as glycerin and propylene glycol, have been found
to be adulterated with toxic industrial-grade diethylene glycol by
unscrupulous suppliers and manufacturers. From time to time,
such as in 1986 (India), 1990 (Nigeria), 1995 (Haiti), 2006 (Panama)
and 2022 (Gambia), the use of these diethylene glycol-adulterated
solvents caused internal body injuries and deaths to patients, young
and old (see 2022 press report on next page).
For non-aqueous solutions, the common solvents used are mineral
oils or fixed oils of vegetable origin. These oils are employed to prepare solutions of drugs which are unstable in water, or to prepare
intramuscular injections of drugs for depot therapy, where drug
release is prolonged to give a sustained drug action. Fixed oils of vegetable origin include almond oil, arachis oil, olive oil, corn oil, soya
oil, castor oil, cottonseed oil, sesame oil and coconut oil. These oils
Pharmaceutical Dosage Forms
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Source: The Hindu, 17 October 2022
have been used in the formulation of injections, eye drops, liniments
and oral preparations, as shown below:
• Oily Phenol Injection BP (almond oil)
• Dimercaprol Injection BP (arachis oil)
• Methyl Salicylate Liniment BP (arachis oil)
• Physostigmine Oily Eye drops BP (castor oil)
Additives are commonly incorporated into pharmaceutical solutions for a variety of reasons. They include the following examples:
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
• Colors — to improve attractiveness and to enable easy identification of products.
• Sweeteners — to enhance the taste of the solution.
• Flavors — to make the product more palatable; they include
fruit juice, aromatic oils, herbs and spices.
• Antimicrobial preservatives — to prevent microbial contamination of product.
• Antioxidants — to prevent degradation of compounds by
oxidation.
• Density modifiers — to adjust density of the product, especially
intrathecal injections.
• Isotonicity modifiers — to adjust tonicity of the product, especially infusions.
A key step in the manufacture of a non-sterile pharmaceutical solution is the mixing of the various components, e.g., drug substance
and additives in a suitable solvent. Liquid mixing is relatively simple
and the mixing operation has two requirements, namely localized
mixing which applies shear to the liquid, and general movement
(flow) which takes all parts of the material through the shearing
zone to produce a uniform liquid product. The solution is filtered
to remove any insoluble particles, stored and transferred by means
of pumps to a filling machine for packing into bottles, labelled and
then subject to final quality control before they are released for distribution to the market.
The quality control assessment of pharmaceutical solutions includes
tests for drug content, density, tonicity, viscosity, color, clarity and
presence of particulate matter, where applicable.
Pharmaceutical Dosage Forms
Manufacture of pharmaceutical solutions (syrups)
Some pharmaceutical solutions are employed as injections which
are administered to patients via the intravenous or other parenteral
routes. These pharmaceutical solutions have to be free from microorganisms (sterile), free from particulate matters (clear) and free
from endotoxins (non-pyrogenic). They are injected into the body
of the patient using sterile syringe and needle or by way of an infusion set. Endotoxins which originate from Gram-negative bacteria
can cause fever and death in patients.
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Injection administered via syringe
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Injections administered via infusion set
As for non-sterile pharmaceutical solutions, the key step in the
manufacture of an injection involves liquid mixing. However, for
sterile pharmaceutical solutions such as injections, the liquid mixing has to be carried out in cleanrooms, the entry to which should
be through separate airlocks for production personnel and starting materials used for making the injection. Cleanrooms must be
Diagram of a cleanroom
Pharmaceutical Dosage Forms
maintained to an appropriate standard of cleanliness and supplied
with air that has passed through High Eciency Particulate Air
filters to remove microorganisms and particulate matter from the
air, thus preventing these contaminants from getting into the injection product. The design, construction, maintenance and servicing
of Cleanrooms and the overall manufacture of injections have to
meet international Good Manufacturing Practice (GMP) standards
such as the PIC/S Guide to GMP for Medicinal Products including
its Annex 1 for the Manufacture of Sterile Products.
14.5.4. Suspensions
A suspension is a liquid dosage form in which there is a dispersion
of finely divided solid particles in a liquid medium. Suspension may
be aqueous or non-aqueous, and may be categorized as coarse or colloidal suspensions depending on the particle size of the suspended
particles. A coarse suspension contains particles whose sizes are >1
micron, while a colloidal suspension contains particles whose sizes
are <1 micron. The applications of suspensions are manifold. Suspensions may be formulated and manufactured for oral use as a
means of:
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• administering insoluble drugs in liquid form, e.g., Amoxycillin
Oral (Antibiotic) Suspension and Cephalexin Oral (Antibiotic)
Suspension.
• supplying distasteful drugs in a more palatable form, e.g.,
Panadol Suspension and Ibuprofen Oral Suspension.
• administering insoluble compounds for their absorptive or
antacid properties in the treatment of gastric disorders, e.g.,
Mylanta (Antacid) Oral Suspension.
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Suspensions have also been manufactured for injection to provide a means of sustaining drug release as in depot therapy, e.g.,
Depo-Medrol (Hormone) Injection, and eye drop as in Pred-Forte
(Steroid) Ophthalmic Suspension. In addition, suspensions have also
been formulated for external use to provide a means of applying
insoluble drugs to the skin, e.g., Calamine Topical Suspension.
Examples and uses of suspensions
The desirable properties of a pharmaceutical suspension include:
• Chemical stability of the product.
• Low rate of sedimentation of the particles.
• Particles should be readily re-dispersed upon gentle shaking of
container.
• Size of particles remaining fairly constant throughout storage.
• Ease of pouring liquid from container.
• Ease of flowing readily through a syringe needle in the case of a
suspension for injection.
Pharmaceutical Dosage Forms
• Ease of spreading over the skin and yet not so mobile that they
run o the skin surface when applied, in the case of suspension
for topical (external) use.
So, the next time you consume a suspension, you may wish to assess
if the suspension product meets these desirable qualities or not.
In addition to a suspending agent, suspensions often have a thickening agent added to its formulation whose function is to increase
the viscosity of the liquid medium and prolong the suspension of
the solid particles. Common examples of thickening agents added
to suspensions include gums, gelatin, bentonite, carboxymethyl
cellulose and polyvinylpyrrolidone. Depending on the concentration used, these agents may exert other eects (flocculation/
deflocculation) that may aect the properties of the suspension.
As with other pharmaceutical solutions, excipients such as buers,
antimicrobial preservatives, coloring agents, flavors and fragrances
may be added to a suspension to provide optimal stability, control
microbial contamination, and enhance taste, smell and appearance. In the manufacture of pharmaceutical suspensions, the solid
components are initially mixed with the suspending agent to form
a paste before it is topped up with the liquid medium to form the
suspension using a mixer.
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14.5.5. Emulsions
A pharmaceutical emulsion is a liquid dosage form consisting of
two immiscible liquid phases, namely oil and water, one of which
is dispersed as fine droplets throughout the other. The droplets are
in micron size and cannot be seen using the naked eye. This system
is stabilized by the addition of an emulsifying agent or emulgent.