JOURNAL OF AEROSOL MEDICINE

Volume 7, Supplement 1, 1994

Mary Ann Liebert, Inc., Publishers

Pharmaceutical Formulations—
Suspensions and Solutions
PETER EDMAN

Astra Draco AB
Pharmaceutical Department
P.O. Box 34
S-221 00 Lund, Sweden

ABSTRACT

Solutions and suspensions of drugs are used widely in the pharmaceutical industry for production
of dosage forms for different routes of administration; for example, oral, parenteral and inhalation.
Pharmaceutical solutions and suspensions might appear to be simple formulations but they can present
many technical problems both for the manufacturing industry and for the individual pharmacist.
Substances can be chemically unstable, insoluble in water, distasteful etc. Suspensions are often used
as a dosage form when the drug is insoluble in water and when use of solubilizing agents is not

possible. Based on method of preparation, suspensions can be divided into two categories, flocculated
and deflocculated systems.

SOLUTIONS

What is a pharmaceutical solution? A true molecular solution is defined as a mixture of two or more
components which form a homogeneous molecular dispersion in a one-phase system. They can be
divided into aqueous solutions and non-aqueous solutions. Obviously non-aqueous solutions are
inappropriate nebulizing therapy; nevertheless a few words about their nature would not be out of
for
place.

Non-aqueous Solutions
The vehicles for non-aqueous solutions are often oils, alcohols, or esters of alcohols and fatty
acids. Usually the main constituent is an oil of vegetable origin such as olive oil, maize oil, cottonseed
oil or sesame oil, all of which have parenteral applications. Alcohols may be used in non-aqueous
solutions, ethanol being the most common and often employed for external or topical use. Isopropyl
alcohol may also be used in these preparations as may glycols such as polyethylene glycol.

KEYWORDS: Solutions, suspensions, co-solvent, pH, solubilization, surfactant, additives, particle size,
solids, flocculation, nebulizing therapy.

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Aqueous Solutions
Aqueous solutions are the most used vehicle for pharmaceutical purposes. The quality of the water
is important aspect of the formulating of solutions and is well regulated and defined in different
an
pharmacopoeias; for example, water for injection or purified water. If the substance is poorly soluble in
water, a co-solvent might be used; this is a water miscible agent in which the substance is freely
soluble: by adding a co-solvent to the water the solubility of the compound is increased. We use blends
of water and ethanol and sometimes glycerols and glycols such as polyethylene glycol. The dielectric
constant of a co-solvent is an important consideration and as a rule we use one with a constant of
between 25 and 80, approximately the same as water.
The control of pH is another critical issue when dealing with aqueous solutions. By choosing the
correct pH, the solubility of weak acids and bases can be increased. pH is also involved in the chemical
stability of a compound. If the pKa and water solubility of a compound are known, its solubility at a
given pH may be calculated by use of the Henderson-Hasselbalch equation. This is an issue that must
be addressed when formulating solutions.
Solubilization is another important aspect of pharmaceutics. Surfactants such as Tween are often
added to a poorly soluble compound to increase solubility. As a rule, a surfactant should have a
hydrophile-lipophile balance (HLB) of 15 or more, and be miscible with water.
Finally, a number of additives are available for a variety of purposes. For example, buffers must be
added to increase buffer capacity; those most commonly used in pharmaceuticals are citrates, acetates,
phosphates and certain carbonates. Isotonicity modifiers can be introduced although they are not so
applicable in nebulizing formulations as they are in parenteral solutions. Preservatives are required in
any multi-dose preparation, and if a compound is sensitive to oxidation, anti-oxidants can be added.

SUSPENSIONS

A suspension is a dispersed system in which insoluble solid particles are dispersed in a liquid
medium. This medium is often water. Suspensions can be divided into colloidal suspensions, in which
the solid particles are <lum in diameter, and coarse suspensions in which they are >lum in diameter.
Clearly, particle size is a critical issue, and to achieve an optimum particle size the compound often
has to be either dry milled or wet milled. Milling in a jet mill is usually required if the particle size is to
be reduced to the sub-micrometer or micrometer range.
Optimal particle size may also be achieved by controlled crystallization that is crystallizing the
compound from the solution either by chilling or by adding another solvent in which the compound is
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less soluble.
I have recently performed scanning electronmicroscopy of two commercially available products.
The particles in Pulmicort have a mean diameter of about 2.4|j.m (SD,1.0um) and are solid with a
roughish surface. The particles in Becotide have a mean diameter of about 3.7um (SD,1.0p:m) and are
rod shaped.

Internal Phase Characteristics

Solids may be divided according to whether they are hydrophilic or hydrophobic. Hydrophilic
solids or particles have a very low interfacial tension and are easily wetted by water. Hydrophobic
solids are not so readily wetted.
Since the wetting step is critical in the formulation of suspensions, wetting agents may be required.
The most used are surfactants, or surface-acting agents, usually in low concentration in the order of
0.05-0.5%. Their mode of action is to reduce the contact angle between the solid particles and the
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liquids. Wetting can also be induced by the use of hydrophilic colloids such as cellulose derivatives or
alginates. These are uncommonly used in nebulizing solutions and suspensions but are commonly

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employed in other suspensions. Hydrophilic colloids act by coating the solid particles, thereby
changing the character of the surface from hydrophobic to hydrophilic. A third technique, which is not
much used, for inducing wetting involves the addition of solvents such as ethanol, glycol or glycerol.
These interact with the surface of the solids to render it more hydrophilic.

Flocculation and Deflocculation

Suspensions may also be divided into flocculated and deflocculated suspensions. Usually we try to
formulate flocculated rather than deflocculated suspensions. In a deflocculated suspension the particles
are dispersed as concrete units and sediment down slowly; as a result they form a distinct cake in the
bottom of the vessel, a phenomenon known as caking or claying. This cake is difficult to redisperse and
should it form, the suspension is unlikely to be of use. We therefore use flocculated systems in which
the particles form larger aggregates, or flocks; these sediment down more rapidly, do not form a clear
cake in the bottom of the vessel and are easy to redisperse so that the suspension may be used again.
The production of a flocculated suspension requires the addition of electrolytes, normally potassium
chloride or sodium chloride, to reduce or to neutralize the zeta potential around the compound. This
means that repelling forces between the particles are neutralized and the particles can then interact with
each other to form large aggregates which rapidly sediment and are easily redispersed. Usually
monovalent ions are used, but sometimes divalent or trivalent ions such as citrates or phosphates might
be employed.

BIBLIOGRAPHY

AULTON, M.E., ed. (1988). Pharmaceutics: The Science of Dosage Form Design. Churchill
Livingstone, New York.
LACHMAN, L„ LIEBERMAN, H.A., and KANIG, J.L., eds. (1986). The Theory and Practice
of Industrial Pharmacy. 3rd ed, Lea and Febiger, Philadelphia.
LIEBERMAN, H.A., RIEGER, M.M., and BANKER, G.S., eds. (1988, 1989). Pharmaceutical
Dosage Forms: Disperse Systems, vols 1 and 2. Marcel Dekker, Inc., New York.

QUESTIONS
SMALDONE: Suspensions are unusual because of their physical characteristics. What aspects of
their formulation are important for a nebulizing suspension?
EDMAN: Particle size is very important. If we are creating droplets, we must be sure that the
particle size is adapted to the droplet size, otherwise it is almost impossible to achieve good nebulization
therapy.
SMALDONE: Does flocculation affect the final particle distribution in terms of what is nebulized, or
does size simply depend on the milling?
EDMAN: The basic characteristics depend on the milling process.
QUESTION: Do you have any data about crystal growth?
EDMAN: No, but I would agree that this could be a critical issue. It is well known that the use of
surfactants or other kinds of stabilizing agents in suspensions can retard crystal growth and/or increase
it. It is a critical issue but I have no data.
JOHN PRITCHARD (Ware, UK): Preservatives have recently been reported to cause irritation to
the airways. What is your view on the inclusion of preservatives in formulations?
EDMAN: With single dose units it is possible to reduce the use of preservatives.
QUESTION: If a deflocculated system is used in a nebulizer, will nebulizing both deflocculate and
decrease the viscosity of the formulation?

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 EDMAN: Stressing the formulation, for example by increasing the rate of shear, will deflocculate or
reduce viscosity. This has an impact on the distribution of the particles and also on the ease of using the
formulation in a nebulizer.

Address reprint requests to:

Peter Edman, Ph.D.
Astra Draco AB
Pharmaceutical Department
P.O. Box 34
S-22J 00 Lund
Sweden

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