Suspensions

A pharmaceutical suspension may be defined as a coarse dispersion containing finely divided

insoluble material suspended in a liquid medium. Because some products occasionally are
prepared in a dry form to be placed in suspension at the time of dispensing by the addition of an
appropriate liquid vehicle, this definition is extended to include these products.

Suspension dosage forms are given by the oral route, injected intramuscularly or subcutaneously,
instilled intranasally, inhaled into the lungs, applied to the skin as topical preparations, or used
for ophthalmic or otic purposes in the eye or ear, respectively.

They are an important class of dosage form which can offer several advantages.

Suspensions offer an alternative oral dosage form for patients who cannot swallow a tablet or
capsule such as pediatric and geriatric patients. Oral antibiotics, analgesic and antipyretic drugs
are commonly administered as suspensions to these groups of patients.

Suspensions are often used to deliver poorly water-soluble drugs which cannot be formulated as
aqueous solutions. In early drug development studies of potentially new drug candidates,
suspension dosage forms are frequently used to deliver drugs to animals, particularly when the
drug is given orally.

In addition, drugs that have an unpleasant taste may preferably be formulated as a suspension to
reduce interaction of drug with taste receptors in the mouth.

Because suspended drug must undergo dissolution step prior to crossing biological membranes,
suspensions offer a way to provide sustained release of drug by parenteral, topical, and oral
routes of administration.

There are certain criteria that a well-formulated suspension should meet.

The dispersed particles should be of such a size that they do not settle rapidly in the container.
However, in the event that sedimentation does occur, the sediment must not form a hard cake.
Rather, it should be capable of re-dispersion with a minimum of effort on the part of the patient.
Finally, the product should be easy to pour, have a pleasant taste, and be resistant to microbial
attack.

The three major concerns associated with suspensions are:

1. Ensuring adequate dispersion of the particles in the vehicle

2. Minimizing settling of the dispersed particles

3. Preventing caking of these particles when sediment forms.

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Types of suspensions

Suspensions can be classified based on the characteristics of the dispersed phase or the
dispersion medium, and also based on their route of administration.

Based on the particle size (diameter) of the dispersed phase, suspensions can be classified as
(1) coarse suspension (> 1 μm), (2) colloidal dispersion (< 1 μm), or (3) Nano suspension (10–
100 nm).

Based on the concentration of the dispersed phase, highly concentrated suspensions are
termed as slurries (> 50 % w/w), and certain suspensions are considered dilute suspensions
(2%–10% w/w).

Based on the type of the dispersion medium, suspensions can be aqueous or non-aqueous.
Identifying the physical state of the dispersion medium allows the suspensions to be classified as
solid-in-liquid or solid-in-gas (aerosols) suspensions.

Based on the route of administration, suspensions can be classified as oral, topical,

ophthalmic, otic, or nasal suspensions. Each of these present unique challenges and requirements
in terms of desired quality attributes. These are briefly described as follows:

1. Oral suspensions: Suspensions meant for oral route of administration are usually liquid
preparations in which solid particles of the active drug are dispersed in a sweetened, flavored,
sometimes colored, and usually viscous vehicle. For example, amoxicillin oral suspension
contains 125–500 mg dispersed active pharmaceutical ingredient (API) per 5 mL of suspension.

2. Topical suspensions: Lotions are externally applied suspensions. These are designed for
dermatologic, cosmetic, and protective purposes. Topical suspension formulations need to pay
particular attention to the lack of grittiness and smooth feel on the skin. These suspensions are
typically colored and may have some perfume, but do not need sweeteners and flavors typically
used for oral administration.

3. Injectable suspensions: Parenteral suspensions may contain from 0.5% to 30% w/w of solid
particles. Viscosity and particle size are significant factors because they affect the ease of
injection and the availability of the drug in depot therapy. Most parenteral suspensions are
designed for intramuscular or subcutaneous administration. For example, procaine penicillin G
suspension is intended for intra-muscular administration. Sterility is an important consideration
for parenteral suspensions. Being a suspension dosage form, they cannot be sterilized by terminal
filtration. Thus, the use of sterile API and aseptic processing is required for their manufacturing.
In addition, antimicrobial preservatives are not recommended for intravenous (IV) suspensions.

4. Otic suspensions: These are intended for administration into the ear. Most otic suspensions
are antibiotics, corticosteroids, or analgesics for the treatment of ear infection, inflammation, and

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pain. Otic suspensions are generally formulated as sterile suspensions since they come in contact
with the mucosal surface.

5. Aerosols: Aerosols are suspensions of drug particles or drug solution in the air and are used
for inhalation of drug delivery to the lung. Volatile propellants are frequently used as vehicles for
pharmaceutical aerosols.

6. Liposomes and micro-/nanoparticles: Suspensions of liposomes, microspheres,

microcapsules, nanospheres, or nanocapsules are used for targeted and controlled delivery of
drugs. These are usually intended for parenteral administration.

7. Vaccines: Vaccines are used for the induction of immunity and are often formulated as
suspensions. For example, cholera vaccine and tetanus vaccine are suspensions.

Powder for suspension

The inherent physical instability of suspensions and the desirability of a relatively long shelf life
have led to the popularity of powder for suspension (PFS) dosage forms. These dosage forms are
developed as powder mixtures of typical ingredients required for an aqueous suspension and are
marketed in unit dose sachet or multi-dose bottles. The pharmacist reconstitutes these dosage
forms with water before dispensing to the patient. The reconstituted suspension has a limited
shelf life under designated storage conditions, such as 14 days under refrigeration.

1. Unit dose powder for suspension: A unit dose sachet of powder could be administered to a
patient by suspending in a suitable vehicle, such as water, immediately before administration.
This mode of administration is preferred for pediatric and geriatric populations, who may have
swallowing difficulty, and for high dose compounds.

2. Multi-dose powder for suspension: The multi-dose PFS are dispensed as powders in a
suitable-sized bottle for reconstitution with water by the pharmacist immediately before
dispensing. This allows the advantage of custom flavoring by the pharmacist to increase patient
compliance and the reduced requirement for the duration of physical and chemical stability of the
formulation. Superior stability of the powder dosage form allows long shelf life of the
commercial product at room temperature of a drug that is very unstable in the presence of water.
The pharmacist reconstitutes this PFS immediately before dispensing. The reconstituted
suspension is required to be stored by the patient under refrigerated conditions and consumed
within 14 days.

Formulation considerations

Suspensions are formulated to meet key quality requirements. Additional formulation

considerations for suspensions include managing the bitterness and grittiness of the API, and
dose volume. For example, a highly bitter API is likely to impart an unpleasant taste to the
suspension due to its solubility in the suspension vehicle, even though this solubility may be

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extremely low. A gritty particle shape of an API, such as needle-shaped crystals, is likely to have
poor mouth feel unless the particle size of the suspension is reduced significantly. In addition,
reasonable dose volume for a patient is one teaspoon (5 mL) or one tablespoon (15 mL).
Typically, the following ingredients are used in suspensions.

1. Drug

A water-insoluble drug is usually the dispersed phase in an aqueous suspension. Drugs should be
of a narrow particle size distribution within the range of 1–50 μm.

2. Wetting agents

The surface of dispersed drug particles can be either hydrophilic or hydrophobic. Drugs with
hydrophobic surfaces are usually difficult to disperse in an aqueous medium. Wetting agents are
surfactants that reduce the surface tension of an aqueous medium and facilitate the wetting of
hydrophobic particles. Wetting agents adsorb onto the hydrophobic particle surface to either coat
the surface or form a complete monolayer. Examples of typical wetting agents are sodium lauryl
sulfate and polysorbate 80.

3. Suspending agents

Suspending agents are hydrophilic colloids, such as acacia and xanthan gum that are added to a
suspension to increase viscosity inhibit agglomeration, and decrease sedimentation. Typical
suspending agents are listed in Table 1. Although increasing the viscosity of a suspension
improves its physical stability, on oral administration highly viscous suspensions may prolong
gastric emptying time, slow drug dissolution, and decrease the absorption rate. Thus, the dose
volume of a suspension and fluid viscosity on dilution of the suspension in the gastric fluid must
be considered to understand potential impact on oral drug absorption.

Table 1. Commonly used suspending agents

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 4. Flocculating agents

Zeta potential (ζ) is a measurable indication of the potential existing at the surface of a particle.
When ζ is relatively high (25mV or more), the repulsive forces between two particles exceed the
attractive London forces. Accordingly, the particles are dispersed and are said to be
deflocculated. Even when brought close together by random motion or agitation, deflocculated
particles resist collision due to their high surface potential.

The addition of a preferentially adsorbed ion whose charge is opposite to that on the particle
leads to a progressive lowering of ζ. At some concentration of the added ion, the electrical forces
of repulsion are lowered sufficiently and the forces of attraction predominate. Under these
conditions the particles may approach each other more closely and form loose aggregates, termed
flocs. Such a system is said to be flocculated.

The continued addition of the flocculating agent can reverse the above process, if the zeta
potential increases sufficiently in the opposite direction. Thus, the adsorption of anions onto
positively charged, deflocculated particles in suspension will lead to flocculation.

The addition of more anions eventually can generate a net negative charge on the particles. When
this has achieved the required magnitude, deflocculation may occur again. The only difference
from the starting system is that the net charge on the particles in their deflocculated state is
negative rather than positive. In short, flocculation is the formation of loose, light, and fluffy
flocs (associations of particles) held together by weak van der Waals forces. In contrast, particles
in deflocculated suspensions tend to exhibit strong inter-particle attraction forces, leading to
aggregation. Properties of flocculated and deflocculated suspensions are shown in Table 2.

Table 2. Properties of flocculated and deflocculated suspensions

5. Preservatives

Preservatives are often added in aqueous suspensions because suspending agents and sweeteners
are good media for microbial growth. Some preservatives are ionic, such as sodium benzoate,

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and may interact or form complexes with other suspending ingredients thus reducing their
preservative efficacy. Some antimicrobial preservatives are shown in Table 3.

Table 3. Commonly used antimicrobial preservatives

Thus, effective aqueous concentration of the preservative must be monitored and controlled.
Solvents, such as alcohols, glycerin, and propylene glycol, may also have some preservative
effect depending on their concentration. Typical microbial preservatives are listed in Table 3.

6. Sweeteners, flavors, and colorants

Sweeteners are often added to suspensions to reduce any unpleasant taste of the partially
dissolved drug and to improve palatability in general. Examples include sorbitol, corn syrup,
sucrose, saccharin, and aspartame. Flavors are added to enhance patient’s acceptance of the
product. Colorants are added to provide a more esthetic appearance to the final product. Choice
of colorant is usually tied to the choice of flavor, and their choices are also linked to the patient
population, such as age group and geographic region, and the therapeutic need. For example, red
colorant is usually used with strawberry flavor for pediatric formulations.

Table 4 shows two examples of suspension formulations. One is benzoyl peroxide topical
suspension, which is used for treating mild to moderate acne. The other is triamcinolone
diacetate parenteral suspension, which is used for treating allergic disorders.

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Table 4. Examples of suspension formulations

Methods of Preparation of suspension

Direct Incorporation/ Dispersion Method

This method involves

1. Dissolution of the soluble components in the appropriate volume of diluent (vehicle).

2. Dispersion of the solid therapeutic agent into the vehicle with the aid of mixing, prior to
correction for volume.

When the dispersion method is used for suspension preparation, the vehicle must be formulated
so that the solid phase is easily wetted and dispersed. Wetting agents and suspending agents may
be used to achieve that.

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The mixing rate employed during the dispersion of the solid therapeutic agent is an important
determinant in the manufacture of the formulation. If the suspension is flocculated, high-speed
mixing may be employed. However, if the formulation has been poorly designed and has poor
flocculation properties, high-speed mixing will result in an increase in the viscosity of the
product (termed dilatant flow).

Precipitation method

The preparation of suspensions by precipitation method is as follows:

1. The drug is dissolved in the vehicle (or a portion of the available volume), prior to
precipitation following the addition of a counterion; the salt formed is insoluble.

2. The excipients are then dissolved in the vehicle, or dissolved in a portion of the vehicle, which
is then added to the suspension of drug.

3. At this stage, the formulation may be exposed to high shearing rates to ensure homogeneity.

4. The volume of the formulation is then corrected by adding the required mass of diluent.

One potential problem with this method of suspension formulation is the production of ionic
byproducts from the precipitation interaction. If the concentration of these is too high, then there
is need to wash the precipitated therapeutic agent with an aqueous solvent.

Controlled flocculation

Flocculation imparts structure to suspensions with virtually no increase in viscosity. The

preparation of suspensions by controlled flocculation is as follows:

1. The wetting agent is dissolved in approximately half the final volume of the aqueous vehicle.

2. The drug is micronized and is uniformly spread over the surface of the vehicle at the desired
concentration.

3. The drug is allowed to be wetted undisturbed and the wet slurry thus formed is passed through
a fine wire sieve or a colloid mill to remove poorly wetted powder.

4. The slurry concentrate of the drug is agitated and the flocculating agent is added till
flocculation endpoint is reached. To determine the endpoint, small samples are transferred to a
graduated cylinder, an equal amount of vehicle is added and the cylinder is gently shaken and
allowed to stand undisturbed. The sample with the highest ratio of sediment to total suspension
volume, exhibiting a clear supernate and good drainage characteristic, is considered to be at the
appropriate endpoint.

5. The remaining formulation adjuvants (preservatives, colorant, flavor, buffer etc.) are added
and the slurry is brought to final volume with liquid vehicle.

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