Section 9

Suspensions
by Drs. Clyde M. Ofner and Roger l. Schnaare

Table of Contents
Suspensions ..................................................................................................................................1
Table of Contents ....................................................................................................................1
Introduction and Background ........................................................................................................3
Definitions ................................................................................................................................3
Uses of Suspensions................................................................................................................3
Formulations ..................................................................................................................................4
Typical Ingredients....................................................................................................................4
Drug ....................................................................................................................................4
Wetting Agent ....................................................................................................................4
Suspending Agent ..............................................................................................................4
Protective Colloid ..............................................................................................................5
Flocculating Agent ..............................................................................................................5
Sweetener ..........................................................................................................................5
Preservative ........................................................................................................................6
Buffer ..................................................................................................................................6
Flavor ..................................................................................................................................6
Color ..................................................................................................................................6
Sequestering Agent ............................................................................................................6
Typical Formulations ................................................................................................................7
Antacid/Antiflatulent Formula (cellulose gums and Avicel suspending agents) ..............7
Sulfamethazine Suspension (synthetic polymer suspending agent)..................................7
Sulfamethazine Suspension (clay and cellulose gum suspending agents)........................8
Benzoyl Peroxide Suspension (cellulose and natural gums suspending agents)..............8
Sterile Triamcinolone Diacetate Aqueous Suspension (synthetic polymer) ......................9
Prednisolone Acetate Ophthalmic Suspension (cellulose gum suspending agent) ..........9
Steps in Suspension Preparation ................................................................................................10
Wetting of Drug ......................................................................................................................10
Surfactants ......................................................................................................................10
Solvents Polar and Nonpolar ........................................................................................10
Levigation ........................................................................................................................10
Dispersing Suspending Agent................................................................................................10
High Shear ........................................................................................................................10
Heat ..................................................................................................................................10
Non-polar Liquids ............................................................................................................10
Water Soluble Ingredients ................................................................................................10
Combined Drug and Suspending Agent ................................................................................11
Other Ingredients....................................................................................................................11
1

Final Processing ....................................................................................................................11

Published Processing Guidelines ..........................................................................................11
FMC Problem Solver, 1984 (excerpted) ..........................................................................11
Nash (paraphrased) ..........................................................................................................11
How Suspensions Behave ..........................................................................................................12
Sedimentation ........................................................................................................................12
Factors Stokes Law ......................................................................................................12
Particle Size............................................................................................................................12
Density Difference ..................................................................................................................12
The Gravitational Constant, g ................................................................................................12
Viscosity ................................................................................................................................12
Dynamic Suspension Interactions..........................................................................................13
Flocculation ............................................................................................................................13
Charge Repulsion zeta potential ..................................................................................13
Polymer Adsorption ..........................................................................................................14
Caking ..............................................................................................................................14
Crystal Growth........................................................................................................................15
Retardation ......................................................................................................................15
Polymorphic Changes ......................................................................................................15
Controlling the Properties of a Suspension ................................................................................16
Sedimentation ........................................................................................................................16
Suspending Agents and Type of Flow..............................................................................16
Pseudoplastic vs. Thixotropic ..........................................................................................16
Yield Value ........................................................................................................................16
Electrostatic Flocculation ......................................................................................................17
Deflocculated vs. Flocculated Formulations: A Structured Vehicle Approach ......................18
A Universal Approach ..................................................................................................................19
Experimental Suspension Parameters ........................................................................................20
Zeta Potential ........................................................................................................................20
Density....................................................................................................................................20
Viscosity ................................................................................................................................20
Sedimentation ........................................................................................................................20
Redispersibility ......................................................................................................................20
Particle Size............................................................................................................................20
Reconstitutable Suspensions ......................................................................................................21
Introduction ............................................................................................................................21
Formulations ..........................................................................................................................21
Typical Formulations ..............................................................................................................21
Preparation ............................................................................................................................21
Powder Blends ................................................................................................................21
Granulated Products ........................................................................................................21
Combination Products......................................................................................................21
References ..................................................................................................................................22
Selected Readings ......................................................................................................................22

Introduction and Background

Definitions

Today all of these preparations are referred to

as suspensions.

Suspensions are pharmaceutically stable

dispersions of a finely divided solid in a liquid
vehicle, usually an aqueous solution. The
USP1 defines suspensions as finely divided,
undissolved drugs dispersed in liquid
vehicles and can be ready-to-use, e.g.,
Trisulfapyrimidines Oral Suspension or
for reconstitution, e.g., Tetracycline Oral
Suspension. In the latter case, the drug is
mixed with other ingredients in the dry state
and reconstituted with water at the time of
dispensing to the patient.

One other aspect needs to be clarified at this

point and that is the difference between a
suspension and a colloid. Both can be
dispersions of a solid in a liquid, however,
the particle size of a suspension is such that
sedimentation occurs due to the force of
gravity, while the particle size of a colloid is
small enough so that thermal energy or
Brownian motion is sufficient to keep the
particles uniformly dispersed and prevent
sedimentation.

Uses of Suspensions

The USP also defines several dosage forms that

are essentially suspensions but historically are
referred to by other names. For example;

Suspensions are basically used to prepare

liquid preparations of drugs that cannot be
prepared as solutions; either the drug is not
soluble or cannot be solubilized by cosolvents,
surfactants, etc. They find use in a range of
routes of administration including topical, oral,
parenteral, ophthalmic, otic, and nasal. As a
dosage form, they offer several advantages:

Gels are by definition, semi-solid systems

consisting of either suspensions made up
of small inorganic particles or large organic
molecules interpenetrated by a liquid. These
can be suspensions if composed of a twophase network of small discrete particles,
e.g.,aluminum hydroxide gel or a magma if
composed of relatively large particles, e.g.,
bentonite magma.

The term gel also refers to a single-phase

dispersion of organic macromolecules
uniformly distributed throughout a liquid in such
a manner that no apparent boundaries exist
between the dispersed macromolecules and the
liquid, e.g., gelatin gel. These gels are clearly
not suspensions in that the dispersed material
is soluble.

Lotions are fluid emulsions or suspensions

intended for external application.

Milks are suspensions with a larger particle

size than gels, e.g., Milk of Magnesia. The
distinction between two-phase gels, magmas
and milks is largely historical.

Preferred for patients, geriatric and

pediatric, who have difficulty in swallowing
solid oral dosage forms such as tablets and
capsules.
Disagreeable tastes can be often overcome
by purposefully limiting the amount of drug
in solution and by flavoring the liquid
vehicle.
Prolonged action can be achieved, for
example, in intramuscular injections as
well as in oral suspensions.
Bioavailability is high and generally viewed in
the following order for various oral dosage
forms: solutions > suspensions > capsules >
tablets.
Improved chemical stability compared to
solutions.

Formulations
Table 1. Typical Wetting Agents

Typical Ingredients

Wetting Agent

Drug

Sodium Lauryl Sulfate

Docisate Sodium
Polysorbate 80

Typically, the particle size distribution is between

1 and 50 m. Ideally, one would prefer a uniform
size; however, in practice, there is always a size
distribution. With high-speed attrition impact
mills the distribution is usually between 10 to 50
m, while fluid-energy mills, can reduce particle
size below 5 m.

Ionic Charge
Anionic
Anionic
Nonionic

Suspending Agent
Suspending agents are materials added to a
suspension to increase viscosity and retard
sedimentation. There are many materials that
fall into this classification and include cellulose
derivatives, clays, natural gums, synthetic
polymers and a few miscellaneous materials.
Most suspending agents are either neutral or
negatively charged and generally effective in
a concentration range of 1 to 5%.

The drug surface can be either hydrophilic or

hydrophobic. Ionic surfaces such as aluminum
hydroxide, are readily wetted and dispersed
easily in aqueous vehicles. Most organic drugs
form particles with a hydrophobic surface and
are difficult to disperse in an aqueous medium.
Wetting Agent

Being polymeric in nature, most suspending

agents have hydrophilic and hydrophobic
regions in their molecular structure and, as
such, can interact with a suspension particle
surface. Some adsorption of the suspending
agent to the particle surface almost always
occurs giving the particle surface the solubility
characteristics of the suspending agent. As
with adsorption of wetting agents, the particle
surface, after adsorption of a suspending
agent, will be hydrophilic and either neutral
or negatively charged.

Wetting agents are surfactants that reduce the

surface tension of an aqueous medium, coat
the surface of suspension particles, and thereby
facilitate the wetting of each particle. The goal
is to displace air from the particle surface and
to separate each particle from adjacent particles
using the minimum concentration necessary.
Since wetting agents are surfactants, they
adsorb onto the particle surface and, depending
on the concentration, can partially coat the
surface or form a complete monolayer. If the
surfactant is charged, the particle surface will,
therefore, carry the same charge, whereas if
the surfactant is nonionic, the particle surface
will be hydrophilic but not charged.

Table 2. Typical Suspending Agents

Suspending Agent

Rheologic
Behavior

Ionic
Charge

Concentration
Range (%)

Pseudoplastic/plastic
Pseudoplastic
Pseudoplastic
Plastic/thixotropic

Neutral
Neutral
Anionic
Anionic

1-5
0.3-2
1-2
0.5-2

Plastic/thixotropic
Plastic/thixotropic

Anionic
Anionic

1-6
0.5-5

Carbomer
Povidone

Plastic
Newtonian/Pseudoplastic

Anionic
Neutral

0.1-0.4
5-10

Gums
Xanthan gum
Carrageenan

Plastic/thixotropic
Newtonian/Pseudoplastic

Anionic
Anionic

0.3-3
1-2

Cellulose Derivatives
Methylcellulose
Hydroxypropyl Methylcellulose
Sodium Carboxymethylcellulose
Microcrystalline Cellulose with
Sodium Carboxymethylcellulose
Clays
Bentonite
Magnesium Aluminum Silicate
Polymers

A protective colloid is a polymeric suspending

agent absorbed on the surface of a hydrophobic
suspension particle giving the particle a
hydrophilic surface.

relatively high concentrations and also

contribute to the viscosity of the suspension.
Other sweetening agents such as saccharin,
sodium and aspartame, used in relatively low
concentrations, do not affect the overall
viscosity.

Flocculating Agent

Table 3. Typical Sweetening Agents

Protective Colloid

Sweetener

Flocculating agents enable suspension particles

to link together in loose aggregates or flocs.
These flocs settle rapidly but form a large fluffy
sediment which is easily redispersed.

Comments

Saccharides
Sucrose

Up to 80%

Polyols
Materials that function as flocculating agents
include electrolytes, surfactants, and polymers;
the same materials that serve as wetting and
suspending agents. The mechanism by which
they function is involved and will be discussed in
more detail later.

Mannitol
Cooling effect, considered noncaloric,
fairly expensive, can cause diarrhea.
Sorbitol
Half as sweet as sucrose, considered
noncaloric, can cause diarrhea.
Synthetic

Sweetener

Sodium Saccharin
500 times as sweet as sucrose,
inexpensive.
Aspartame
Good acid stability

Sweeteners are added to suspensions to

produce a more palatable preparation, to
cover the taste of the drug and other ingredients.
Sorbitol, corn syrup and sucrose are used at
5

Preservative

Buffer

Preservatives are required in most suspensions

because suspending agents and sweeteners
are good growth media for microorganisms.
Many preservatives are ionic, such as sodium
benzoate, and may interact and bind or
complex with other suspension ingredients.
Bound preservatives are not generally active.
Even the activity of neutral preservatives, i.e.,
the parabens, may be compromised by
adsorbing onto the suspension particle
surface.Solvents such as alcohol, glycerin
and propylene glycol are often used as preservatives at concentrations approaching 10%.

Many chemical buffer systems have been used

in suspensions to control pH. The optimal pH is
chosen to minimize solubility of the drug, control
stability of the drug, and to ensure compatibility
and stability of other ingredients.

Table 4. Typical Preservatives

Colorants are intended to provide a more

aesthetic appearance to the final product.
As relatively large cations or anions, these
agents may be chemically incompatible with
other ingredients. They also need approval
by the FDA.

Preservative

Flavor
Flavoring agents enhance patient acceptance
of the product, which is particularly important
in pediatric patients.

Color

Concentration Range (%)

Alcohols
Ethanol
Propylene Glycol
Benzyl Alcohol
Quaternary Amines
Benzalkonium Chloride

>20
15-30
0.5-3

Sequestering Agent
0.004-0.02

Sequestering agents may be necessary to bind

metal ions to control oxidative degradation of
either the drug or other ingredients.

Acids
Sorbic Acid
Benzoic Acid

0.05-0.2
0.1-0.5

Parabens
Methylparaben
Propylparaben

0.2
0.05

Typical Formulations

Sulfamethazine Suspension
(synthetic polymer suspending agent)

Antacid/Antiflatulent Formula (cellulose gums

and Avicel suspending agents)
Ingredient
Aluminum hydroxide gel (8.9%)
Magnesium hydroxide paste (29.5%)
Simethicone
Hydroxypropyl cellulose
Methylcellulose
Avicel RC-591
Sorbitol
Citric acid, anhydrous
Methylparaben
Propylparaben
Saccharin sodium
Flavors
Purified water qs

% by Weight

Use

21.00
12.90
0.37
0.33
0.03
0.11
6.00
0.06
0.16
0.03
0.02
0.12
100.00

Drug
Drug
Antiflatulant
Suspending agent
Suspending agent
Suspending agent
Sweetener
Buffer
Preservative
Preservative
Sweetener
Flavor
Solvent

Ingredients
Sulfamethazine
Carbomer 934
Sodium lauryl sulfate
Sucrose
Saccharin sodium
Methylparaben
Propylparaben
Flavor mixture
Citric acid
0.1 N NaOH
Purified water qs

% by Weight
10.1
0.5
0.02
40.0
0.08
0.2
0.02
1.0
0.2
~10 mL
100 mL

Use
Drug
Suspending agent
Wetting agent
Sweetener
Sweetener
Preservative
Preservative
Flavor
Buffer
Adjust pH
Solvent

Preparation
1. Hydrate the carbomer for 24 hours in a
solution of the sodium lauryl sulfate in 30 mL
of water

Preparation

2. Suspend the sulfamethazine in the above

vehicle with the aid of a mixer.

1. Charge the mixing tank with purified water

at about 40% of the total water required.

3. Dissolve the preservatives and sucrose in

40 mL of water by heating.

2. Separately disperse the methylcellulose in

1.5% of the above purified water, add the
simethicone and add to the mixing tank.

4. Cool the solution and add the saccharin

sodium and citric acid.

1. Mix the methyl and propyl parabens

into a slurry with about 2% of the
purified water and add to the mixing
tank.

5. Add the solution to the suspension in step 2.

6. Add the flavor, adjust the pH to 5.5 and mix
in a homogenizer.

2. Add to the mixing tank in the following

order; magnesium hydroxide paste,
aluminum hydroxide gel, citric acid,
saccharin sodium, sorbitol, and
flavorings.
3. Add to the mixing tank.
4. Mix Avicel and hydroxypropyl cellulose with
about 13% of the purified water and add to
the mixing tank.
5. Add the remainder of the purified water to
the desired volume and mix until uniform.

Sulfamethazine Suspension
(clay and cellulose gum suspending agents)

Benzoyl Peroxide Suspension

(cellulose and natural gum suspending agents)

Ingredient

% by Weight

Ingredient

Sulfamethazine
Magnesium aluminum-silicate
Sodiumcarboxymethylcellulose
Sodium lauryl sulfate
Saccharin sodium
Sucrose
Methylparaben
Propylparaben
Flavor
Purified water qs

10.0
0.6
1.3
0.02
0.08
40.0
0.2
0.02
1.0
100

Use
Drug
Suspending agent
Suspending agent
Wetting agent
Sweetener
Sweetener
Preservative
Preservative
Flavor
Solvent

% by Weight

Use

Benzoyl peroxide

5.0

Drug

Hydroxypropyl methylcellulose

1.5

Suspending agent

Xanthan gum

1.5

Suspending agent

Polysorbate 20

5.0

Wetting agent

Isopropyl alcohol
Phosphoric acid
Purified water qs

10
0.03
100

Solvent
pH adjustment
Solvent

Preparation
1. Add the hydroxypropyl methylcellulose
and xanthan gum to water heated to
approximately 70C with stirring.

Preparation
1. Hydrate the magnesium aluminum silicate
and sodium carboxymethylcellulose for 24
hours in a solution of the sodium lauryl
sulfate in 30 mL of water.

2. Cool to 50C and add the polysorbate 20.

3. Cool to 35C and successively add the
isopropyl alcohol, phosphoric acid, and
benzoyl peroxide (as a 70% aqueous slurry).

2. Suspend the sulfamethazine in the above

vehicle with the aid of a mixer.

4. Mill to obtain a smooth suspension.

3. Dissolve the preservatives and sucrose in

40 mL of water by heating.
4. Cool the solution and add the sodium
saccharin.
5. Add the solution to the suspension in step 2.
6. Add the flavor and mix in a homogenizer.

Sterile Triamcinolone Diacetate Aqueous

Suspension (synthetic polymer)

Prednisolone Acetate Ophthalmic

(cellulose gum suspending agent)

Ingredient

% by Weight

Ingredient

Triamcinolone diacetate
Polyethylene glycol 3350
Polysorbate 80
Sodium chloride
Benzyl alcohol
Water for injection qs

4.0
3.0
0.2
0.85
0.9
100

Use
Drug
Suspending agent
Wetting agent
Toxicity agent
Preservative
Solvent

Prednisolone acetate
Hydroxypropyl methylcellulose
Polysorbate 80
Sodium chloride
Edetate disodium
Benzalkonium chloride
Phosphate buffer
NaOH or HCl
Purified water qs

Preparation
(Not considering sterility or presence of pyrogens)

% by Weight

Use

1.0
qs
qs
qs
qs
0.01
qs
qs
100

Drug
Suspending agent
Wetting agent
Tonicity agent
Chelating agent
Preservative
Buffer
pH adjustment
Solvent

Preparation

1. Dissolve the polysorbate 80 in a portion of

the water for injection.

(sterilization not considered)

2. Disperse the triamcinolone diacetate in the

polysorbate 80 solution.

1. Dissolve the phosphate buffer, edetate

disodium, sodium chloride, and
benzalkonium chloride in a portion
of the water.

3. Dissolve the polyethylene glycol 3350 in a

portion of the water for injection.

2. Disperse the hydroxypropyl methylcellulose

in another portion of water.

4. Add the triamcinolone diacetate dispersion

to the polyethylene glycol 3350 solution.

3. Disperse the prednisolone acetate in a

solution of the polysorbate 80 in water
using a high-shear mixer.

5. Successively add the sodium chloride and

the benzyl alcohol.

4. Add the prednisolone acetate dispersion to

the aqueous solution containing the buffer.

6. Adjust to volume with water for injection.

5. Add the hydroxypropyl methylcellulose

solution to the combined suspension of
the drug and buffer solution.
6. Adjust pH.
7. Adjust to final volume with purified water.

Steps in Suspension Preparation

Wetting of Drug

Dispersing Suspending Agent

Surfactants
Solvents - polar and nonpolar
Levigation

Some solid drugs have a polar, hydrophilic

surface, i.e., aluminum hydroxide and bentonite,
and can be wetted by simply sprinkling the solid
on the surface of water and letting the mixture
stand overnight. Simple mixing of the hydrated
material will disperse the solid uniformly.

High shear
Heat
Non-polar liquids
Water soluble ingredients

Suspending agents also need to be uniformly

dispersed to be fully functional. Since they are
all hydrophilic, i.e., clays, simple hydration may
be sufficient for complete dispersion.
Those which are water soluble, i.e., cellulose
derivatives, present particular problems. As
the water soluble suspending agents are added
to water, the outer layer of particles or clumps
of particles start to dissolve producing a thick
rubbery gel with the powdered, unhydrated
polymer inside. If this layer is not dispersed
quickly, the entire mass of particles will tend
to stay as a mass and complete dispersion
will be very slow or nearly impossible. This
is evident by the appearance of opaque or
transparent fish eye-like clumps.

Most drugs of organic origin, however, have a

hydrophobic surface and require some degree
of assistance to be thoroughly wetted. The
wetting agent can be dissolved in approximately
half the final volume of aqueous vehicle and the
drug sprinkled on the surface of the surfactant
solution and allowed to wet for a period of time
followed by a mixing step to uniformly disperse
the solid.
Alternately, the drug can be added to the
surfactant solution in small portions with
agitation or mixing. Using excessive or high
shear has the disadvantage of producing foam
which may be difficult to dissipate but may be
necessary to wet the solid thoroughly. Mixing
the drug with a solid, water soluble component
of the suspension, i.e., sucrose, can often aid
in preventing clumping of the drug when added
to an aqueous vehicle.

To avoid this problem, the suspending agent

must be dispersed in the aqueous vehicle
before the rubbery gel can form. This can be
done by adding the suspending agent to the
aqueous vehicle in small portions with high
shear, then letting the dispersion stand to
dissipate the foam or air bubbles.
Alternately, the suspending agent can be
dispersed in an organic liquid, such as glycerin
or propylene glycol, using the levigation process
described above. The suspending agent will
eventually solvate in the organic liquid, but this
process is much slower than hydration in water.
Thus, the slurry must be added to the aqueous
vehicle with mixing before the solvation process
occurs in the organic liquid.

Drugs may also be wetted by using a watermiscible liquid, such as glycerin or propylene
glycol, to produce a thick, smooth paste or
slurry with the drug by levigation. The uniform
slurry is then added to the part of the aqueous
vehicle or surfactant solution. The wetting agent
may be dissolved in solution prior to adding the
slurry or may be mixed with the drug at the
beginning of the levigation process.

The suspending agent can also be mixed

with a solid, water soluble component of the
suspension, i.e., sucrose, before being added
to the aqueous vehicle with mixing.

10

7. Most suspension vehicles can tolerate the

addition of flavors in the form of oils as long as
the final batch is processed through a colloid mill.

Combined Drug and Suspending Agent

Since the drug and suspending agent must be
uniformly dispersed during suspension preparation, they can be combined in the dry state and
dispersed in the aqueous vehicle using an
appropriate method described above.

8. Process the batch through a colloid mill to

completely disperse the drug. The mill will
efficiently disperse large, soft agglomerates.
9. Process the batch through deaerating equipment.

Other Ingredients

10. Avoid excessive water losses, especially if

prolonged heating is required.

Other water soluble ingredients can be added

to the dispersion of drug and suspending agent
during the stage of adding solvent to final
volume.

11. Avoid excessive shearing and high temperatures

which can depolymerize colloids.

Nash2 (paraphrased)

Final Processing

1. Dry-grind insoluble particles to the smallest and

most uniform size practical and maintain control
of the crystallographic form of the drug during
bulk chemical manufacture.

The final product is usually passed through a

homogenizer or colloid mill to ensure an even
distribution of all ingredients and the break-up
of clumps. Proper wetting of both drug and
suspending agents cannot depend on this final
step. In addition, the suspending agent clumps
and the fish eyes cannot be removed at this
stage.

2. Where practical, allow suspension particles to

wet completely, without agitation, in a small
portion of the aqueous component of the
suspending vehicle containing the wetting agent
in order to release entrapped air and reduce the
number of non-wetted agglomerates.

Published Processing Guidelines

3. Dissolve or disperse the suspending agent in the

main portion of the liquid vehicle.
4. Slowly add the slurry of wetted suspension
particles to the main portion of the suspending
agent(s) with the aid of low shear agitation.

FMC Problem Solver, 1984 (excerpted)

1. Disperse the drug by slow addition to a water,
water-glycol or glycol system containing the
wetting agent.

5. Carefully control the addition of electrolytes,

acids, bases, buffers, and/or tonicity agents to
prevent variations in particle charge.

2. Add all other excipients which require solution

in as dilute a system as possible.
3. Make sure that the solvent system exceeds
solubility limits of dissolved ingredients.

6. Colloid mills, homogenizers, ultrasonic devices, or

pumps should be used only after all additions and
adjustments have been completed as a finishing
procedure.

4. Allow sufficient water for easy dispersion and

hydration of suspending agents(s) and protective
hydrocolloids.

7. All finished aqueous suspensions must be

carefully preserved against microbial growth.

5. If more than one drug compound is to be

incorporated in the formula, ascertain their
compatibility.
6. Use sufficient drug overages to compensate for
losses during manufacture and to maintain label
claim for the shelf life of the product.

11

How Suspensions Behave

Sedimentation

Density Difference
If the difference in density between the
suspended particle and suspension medium
can be matched, the sedimentation rate could
be reduced to zero. Densities approaching 1.3
can be obtained with high concentrations of
sucrose, which is comparable to the crystal
density of 1.25 for many organic drugs. The
disadvantage of this approach is that it is
difficult to maintain a constant density of a
solution which has large changes in density
with concomitant changes in temperature.

Factors - Stokes Law

Sedimentation will potentially always occur in
a pharmaceutical suspension since the particle
size is generally greater than that of a colloidal
dispersion. The rate is described by Stoke's Law
for a single particle settling in an infinite container
under the force of gravity as follows:

d
d2 ( 2 - 1 ) g
=
dt
18

The Gravitational Constant, g

where:
d
/dt = the sedimentation rate in distance/time
d = particle diameter
2 = particle density
1 = suspension medium density
g = acceleration due to gravity
= viscosity of the suspension medium

This parameter is not of much interest since

it cannot be controlled or changed unless in
space flight.

Viscosity
Viscosity turns out to be the most readily
controllable parameter in affecting sedimentation
rate. While the viscosity in Stoke's Law refers
to the viscosity of the fluid through which a
particle falls, in reality the viscosity that controls
sedimentation is the viscosity of the entire
suspension. Thus, doubling the viscosity of
a suspension will decrease the sedimentation
rate by a factor of 2.

While Stoke's Law does not quantitatively

describe sedimentation in a suspension, it does
provide a clear collection of factors and their
qualitative influence on sedimentation.

Particle size
Reducing particle size can have a significant
effect on sedimentation rate. Since the diameter
is squared in Stoke's Law, a reduction in size
2
by will reduce the sedimentation rate by ()
or a factor of 4.

12

Electrolytes that affect the adsorption of

surfactants and polymers can themselves be
adsorbed onto the suspension particle surface
directly affecting the surface charge of the
particle.

Dynamic Suspension Interactions

Since a suspension is composed of many
ingredients, it must be kept in mind that all these
ingredients interact with each other. Figure 1 is
a simple representation of some of the possible
interactions that affect suspension behavior.

Flocculation

Although the drug in a suspension is described

as being insoluble, there is always a finite solubility of a drug in water, i.e., the aqueous vehicle
surrounding the suspension particle will be a
saturated solution of the drug. This equilibrium
changes with changes in temperature and has
an influence on crystal growth, polymorphic
changes and chemical degradation.

Charge Repulsion - zeta potential

Suspensions can exist in essentially two states,
deflocculated or flocculated, depending on how
suspension particles interact. The deflocculated
state is defined as the condition where each
suspension particle exists independently and
behaves as a single particle. Flocculation is the
state where suspension particles attract each
other and form loosely bound aggregates or
flocs. These flocs behave as a unit but are easily
broken up with shear.

Figure 1: Dynamic Model of Suspension

Interactions
+
+
++

_- (electrolyte)
D (saturated solution)

_-

Deflocculation occurs when the particles either

repel each other or have no reason to aggregate.
Figure 2 depicts an electrostatic model of
flocculation. In Figure 2A., each particle carries
a positive charge of such magnitude that the
particles repel, hence, this condition would be
deflocculation. Adding negative ions, from a
soluble electrolyte, causes the positive charge
of the original suspension particles to be neutralized or shielded so that the particles no
longer repel each other but rather aggregate
producing a flocculated state (Figure 2B). Further
addition of negative ions can reverse the original
particle charge and produce negatively particles
and if this negative charge is large enough, the
particles will again repel each other and become
deflocculated (Figure 2C).

Drug
Suspension
Particle

(surfactant monomers)

(surfactant micelles)

(polymer)

Surfactants used to wet the suspension

particle will exist in an equilibrium between
surfactant adsorbed on the particle surface,
monomers in solution, and surfactant in micelles.
Changes that promote micelle formation, i.e.,
surfactant concentration, electrolytes, and
solvent polarity, will also promote adsorption
of the surfactant onto the particle surface.
Likewise, polymers added as protective colloids
and suspending agents will be in equilibrium
between molecules adsorbed on the suspension
particle surface and molecules in solution in
the aqueous vehicle. Changes that decrease
polymer solubility, i.e., electrolytes and solvent
polarity, will also promote deposition of the
polymer on the particle surface.

13

Figure 2: Electrostatic Model of

Flocculation
+
+

_
+

ions

+
+
+

+
+

_
+

_+

_+
+

+
+

__
+

__

__

__ +

_+

__

_
_

__

__

ions

_
+

__
__+

Figure 3: Polymer Model of Flocculation

__+
+

Poor Solvent/
Electrolyte
Flocculated

Good Solvent
Deflocculated

__
__
+

__

__
+

__

Caking

__+

Positive Charge

Neutral Charge

Negative Charge

Deflocculated

Flocculated

Deflocculated

Caked Sediment

Fluffy Sediment

Caked Sediment

The state of flocculation will have a profound

effect on the physical properties of the suspension as summarized in the following table and
figure. Agglomerations of flocculated particles
(flocs) act as large particles but are fluffy and
easily broken up and redispersed. A deflocculated suspension, while settling more slowly than
a flocculated suspension, will eventually settle
in a dense, hard cake which may be difficult
or impossible to redisperse.

Polymer Absorption
A suspension can also be deflocculated and
flocculated by polymers adsorbed on the
particle surface as depicted in Figure 3.
Polymers will almost always be adsorbed
on the particle surface and, if the suspension
vehicle provides a good solvent for the polymer,
the coated suspension particles will behave as
hydrophilic particles. Thus the particles have no
reason to aggregate and will be in a deflocculated
state. The colloid literature calls this condition
stabilized, and the polymer functions as a
protective coating.

Figure 4: Sediment Volume of a

Deflocculated (caked) and a Flocculated
Suspension (not caked)

If the suspension vehicle is changed such that

it becomes a poor solvent for the polymer, i.e.,
by the addition of electrolyte or a less polar
solvent, then the polymer will become less
soluble, polymer molecules will start to interact
and, if the changes are severe enough, the
polymer will precipitate. The polymer molecules
on the particle surface will also start to interact
causing an attraction between particles. This
interaction will produce a flocculated state.

100

100

50

50

Deflocculated

14

Flocculated

A comparison of properties of flocculated and defloccuated suspension particles follows:

Deflocculated
1.
2.
3.
4.
5.

Particles exist as separate entities.

Sedimentation is slow - particles settle separately.
Sediment is formed slowly from bottom of container.
Sediment eventually becomes caked due to weight of succeeding layers of sediment.
Pleasing appearance - suspended material remains suspended for a relatively long time.
Supernatant remains cloudy.

Flocculated
1.
2.
3.
4.
5.

Particles are loose aggregates.

Sedimentation is rapid - particles settle as large flocs.
Sediment is formed rapidly from top of container.
Sediment is loosely packed and easy to redisperse.
Somewhat unsightly - obvious, clear supernatant.

Crystal Growth

Retardation
Polymorphic changes

The equilibrium solubility behavior of the drug

in a suspension can result in a change in particle
size and a change from one polymorphic form
to another more stable form. As changes in
temperature occur, the solubility of the drug
changes; drug continually dissolves and
recrystallizes.
The term Ostwalt ripening refers to the growth
of large particles at the expense of smaller ones
in a suspension composed of a relatively wide
particle size distribution. The net result is that
the size distribution narrows. In a suspension
with a relatively narrow size distribution to begin
with, the size distribution tends to broaden.
These changes will occur until an equilibrium
condition is established.
Nash2 offers some guidelines for limiting these
types of changes.

Select particles with a narrow range of sizes.

Use the most stable crystalline form of the
drug.
Avoid the use of high energy milling.
Use a wetting agent to reduce the interfacial
tension between the solid and suspending
vehicle.

15

Use a protective colloid to inhibit dissolution.

Increase the viscosity of the vehicle to retard
dissolution.
Avoid temperature extremes during product
storage.

Controlling the Properties of a Suspension

Figure 5: Rheological Flow Curves:
A - Newtonian, B - Pseudoplastic
C - Plastic, D - Plastic with Thixotropy

Sedimentation

Suspending agents and type of flow

Pseudoplastic vs. thixotropic
Yield value

a =

Shear Stress

As discussed with Stoke's Law, one of the most

readily available ways to control sedimentation
is to increase the viscosity of the suspension
vehicle. This can be done either by the selection
of the suspending agent or by increasing the
concentration of the suspending agent.
Viscosity behavior of a suspending agent is
described by a flow curve constructed by
plotting shear stress as a function of shear
rate from any viscometer depicted in Figure 5.
A Newtonian fluid (Figure 5A), e.g., most pure
liquids, is characterized by a linear flow curve.
These liquids have a constant viscosity
calculated as the ratio of the shear stress
over shear rate or the slope of the flow curve
defined as the apparent (a) and differential
viscosity (d), respectively.

Shear Rate

Almost all suspending agents have a flow

behavior described as non-Newtonian. Cellulose
derivatives and soluble polymers have a flow
behavior described by the term pseudoplastic.
With either definition of viscosity, it can be seen
from the flow curve in Figure 5B that viscosity
decreases with shear rate for a pseudoplastic
fluid as illustrated by the upper curve in Figure 6.

Shear Stress

Figure 6: Viscosity vs Shear Rate

Shear Rate

70
60

d = d (Shear Stress)

50

Viscosity

d (Shear Rate)

40
30
20
10
0

400

500

Shear Rate

16

600

700

This behavior is advantageous for suspensions

since during sedimentation the settling particle
generates a low shear rate, the corresponding
viscosity is high, and sedimentation is inhibited.
Conversely, when the suspension is shaken
vigorously, a high shear rate is generated, the
viscosity is decreased, and the suspension
flows or pours easily. This is in contrast to a
Newtonian fluid which has a constant viscosity
regardless of the amount of shear applied to
the fluid.

being shear thinning and may have a yield value,

the slower structure buildup allows the fluid to
be processed easily for a period of time.

Other suspending agents, particularly carbomer,

clays, and Avicel RC, have a plastic flow
behavior. This flow is shear thinning like the
pseudoplastic fluids but is also characterized
by a yield value. This yield value is seen as an
intercept on the shear stress axis and corresponds to the stress that must be placed on
the fluid to cause it to flow (Figure 5C).

Martin3 has shown that the flocculation of a

suspension can be controlled by adjusting the
surface charge of a suspension as measured by
the zeta potential. Figure 7 summarizes these
observations by illustrating the interrelationship
between sedimentation volume, caking, and
zeta potential.In water, bismuth subnitrate
has a positively charged surface with a zeta
potential high enough so that the particles
repel each other. At this point the suspension
is deflocculated and will eventually produce
a caked sediment.

The viscosity relationship for a thixotropic fluid

is depicted in Figure 6 where the upper curve
corresponds to the viscosity measured at
increasing shear rate and the lower curve to
viscosity measured at decreasing shear rate.

Electrostatic Flocculation

If the yield value of the suspending agent is

greater than the stress exerted on the fluid
by the suspension particle, the suspension
particle cannot move through the suspension
and sedimentation cannot take place. The
theoretical minimum yield value required to
permanently suspend a particle can be
calculated from the following equation:

YVt =

Figure 7: Caking Diagram Shows the

Flocculation of a Bismuth Subnitrate
Suspension by Means of the Flocculating
Agent, Monobasic Potassium Phosphate2

Vp ( 2 - 1 ) g

Caking Zone

_
100

+
+

Apparent zeta potential

where:
YVt = is the calculated or theoretical yield
value
Vp = is the particle volume given by d3/6
A = is the cross sectional area of the
particle, d2/4 and the other terms are
as defined in Stoke's Law
Some suspending agents have a time dependent
flow behavior (Figure 5D), called thixotropy, which
is characterized by ahysteresis loop in the flow
curve. A thixotropic fluid has a structure that is
broken down by shear as in a plastic or pseudoplastic fluid; however, the rebuilding of structure
after shearing is stopped takes a finite time. This
is advantageous in that, in addition to the fluid

+
+

_+
+

Noncaking Zone
+

_
_
+

_
+

Caking Zone

_+

_
_

_
_

_ 0.04

V3/V4 Curve

_ 0.03

zeta potential
Curve

_
Caked
50

17

V1 - V2
Ratio

Not Caked
ConcentrationKH
KH22PO
PO44
Concentration

Caked

As the electrolyte is added, the HPO42- ion is

attracted to the positively charged surface thus
shielding and lowering the zeta potential. The
surface charge is not sufficient for the particles
to repel each other and the suspension
flocculates. The sediment produced is loose
and fluffy and can be redispersed easily by
shaking. Further addition of electrolyte produces
a negative surface charge, the suspension
becomes deflocculated, and will eventually
produce a caked sediment. Martin's experiments
were carried out in dilute suspensions of bismuth
subnitrate in water with added electrolyte. In a
real suspension, concentrations of drug are
much higher and the suspension contains many
other ingredients that can affect surface charge
and characteristics. Nevertheless, one can in
practice produce either a flocculated or

deflocculated suspension by controlling the

electrolyte concentration of the suspension.

Deflocculated vs. Flocculated

Formulations: A Structured Vehicle
Approach
Swarbrick4 describes a scheme for alternative
approaches for preparing suspensions. In this
scheme, the suspension can be either
flocculated or deflocculated as long as a
structured vehicle is used. The structured
vehicle is characterized by having a yield
value and thixotropic flow which prevents
sedimentation regardless of the state of
flocculation so that a caked sediment
cannot be formed.

Figure 8: Alternative Approaches to the Formulation of Suspensions

Particles
Addition of wetting and dispersion medium
Uniform dispersion of
deflocculated particles
A

Incorporation of
structured vehicle

Addition of flocculating agent

Addition of
flocculating
agent

Flocculated suspension
as final product

Flocculated
suspension
Deflocculated suspension
in succeeding vehicle as
final product

Incorporation of
structured vehicle
Flocculated suspension
in structured vehicle as
final product

18

A Universal Approach
Figure 9: Sedimentation Behavior of
a Bismuth Subcarbonate Suspension
in Water and in 3% Avicel RC-581

Plaizier-Vercammen and Janssens5 have

proposed a universal method of formulating
suspensions. They acknowledge the effect of
a zeta potential or surface charge on the state
of flocculation but point out that zeta potentials
are measured in dilute dispersion and do not
reflect quantitatively the zeta potential in a real
suspension.

Relative Sediment
Volume

As pointed out in Figure 1, there are many

components in a suspension formulation that
affect the surface properties of each suspension
particle. While the zeta potential relates to the
relative surface charge in sign and magnitude, it
cannot be relied upon to describe the behavior
of a formulated suspension.

0.8

0.6

0.4

Caked
0.2

0.000

0.001

0.010

0.100

0.500

1.000

% Surfactant Concentration
Water
3% Avicel

Plaizier-Vercammen and Janssens suggest

that the suspension be formulated varying the
concentration of charged surfactant to vary the
zeta potential. All of the ingredients should be
included so that the overall effect can be seen.

Regardless of the mechanism of particle

interaction in this illustration, physically stable
and useful suspensions could be prepared
with 3% Avicel RC-581 with a surfactant
concentration ranging from 0 to 0.1%.

Such an approach is illustrated in Figure 9 for

a bismuth subcarbonate suspension prepared
in water and in 3% Avicel RC-581 as a
suspending agent and sodium dioctylsulfosuccinate as an anionic surfactant. In water, the
sediment volume decreases with increasing
surfactant concentration clearly suggesting
an increase in zeta potential with increasing
surfactant concentration. The last three samples
at the highest surfactant concentration are
caked, which is consistent with a deflocculated
suspension.

This universal method can be summarized and

extended as follows:

Prepare the suspension formulation with

reasonable ingredients at reasonable levels.
Vary the formulation composition to get a
subjectively suitable product regarding
appearance, viscosity, and sedimentation.

With Avicel RC-581, the sediment volume

stays relatively constant up to 0.1% surfactant
concentration, then decreases slightly. However,
none of the samples prepared with the suspending agent were caked, suggesting a flocculated
suspension, at least at the lower surfactant concentration. At higher surfactant concentrations,
the samples could be either flocculated or
deflocculated with the suspending agent
supplying a sufficient yield value to prevent
sedimentation and caking.

Select one formulation factor such as

electrolyte, surfactant, or solvent and vary
its concentration to obtain a variation in
the sedimentation rate or volume.
This systematic variation will produce
changes in all of the equilibria described
in Figure 1 so that changes represent a
composite effect of the entire formulation.

19

Select a concentration of this ingredient to

maximize sediment volume and minimize
sedimentation rate.

Experimental Suspension Parameters

Zeta Potential
Determined from the electrophoretic mobility in
dilute dispersion. Generally, reflects the relative
surface potential of the undiluted suspension
but not a quantitative measure.

Density
A measure of air incorporated into the
suspension during preparation.

Viscosity
Need to determine flow properties over a range
of shear rates to identify the type of flow, the
change in viscosity with shear rate, degree of
time dependency (thixotropy), and the presence
of a yield value.

Sedimentation
Rate of sedimentation, relative volume of
sediment, and quality of the sediment.

Redispersibility
Measured by the number of rotations of the
suspension container required to redisperse any
sediment. An indirect indicator of flocculation.

Particle Size
Measure as a function of time. Some change
can be expected over a period of time until
an equilibrium is established.

20

Reconstitutable Suspensions
Introduction

Preparation

Suspensions for reconstitution are dry

formulations which require mixing with water
prior to administration. Once reconstituted,
they must conform to all of the requirements
of a traditional suspension.

The preparation of suspensions for reconstitution

involves dry powder and granulation processes
that are described in other sections of this publication. In general, the products fall into one of
three classes; powder blends, granulations, or
a combination of the two.

This type of dosage form is usually used for

drugs that are not stable in the presence of
water but need to be dispensed in liquid form.
Oral and parenteral products are included in
this classification.

Powder Blends
Traditional powder mixing processes are involved
taking precautions when incorporating small
quantities of ingredients to ensure uniformity.

Formulations
Powder blends have the advantage of using
relatively simple equipment, are least likely to
have chemical and stability problems because
no heat or solvents are used, and normally
have a low moisture content.

In general, the number of ingredients should

be kept to a minimum in order to decrease the
possibility of problems. All ingredients should
disperse rapidly on reconstitution, this criterion
eliminates several suspending agents which
require special mixing procedures for complete
dispersion. Sodium carboxymethylcellulose
(NaCMC), microcrystalline cellulose with
NaCMC, carrageenans, and xanthan gum
are typical suspending agents capable of
dispersing readily by shaking.

They are, however, prone to uniformity problems,

poor flow and demixing.

Granulated Products
All of the ingredients are processed by
granulation, usually a wet granulation process.
They have the typical advantages of
granulations, i.e., improved appearance,
improved flow characteristics, less segregation
problems, and less dust generation during filling.

Typical Formulations
Two Commercial Amoxicillin Suspensions for
Reconstitution.
Ingredient Function
Active ingredient
Sweetener
Suspending agent
Dessicant
Buffer
Preservative
Colorant
Flavor

Product 1

Product 1

Disadvantages include increased cost due to

more processing steps, higher residual moisture
content, stability problems with ingredients
sensitive to water during granulation, e.g.,
flavors.

Amoxicillin trihydrate
Amoxicillin trihydrate
Sucrose
Sucrose, mannitol
Xanthan gum
Cellulose, Na CMC
Silica gel
Sodium citrate
Sodium citrate, citric acid
Sodium benzoate
FD&C Red No. 3
Red No. 28, Red No. 40
Flavors
Artificial flavors

Combination Products
These products take advantage of the positive
features of the first two methods. Less energy
is required if the majority of the diluent can
be added after granulation. Heat-sensitive
ingredients, such as flavors, can be added
after drying the granulation.

21

Care must be taken that the particle size

distribution of the granulation and
non-granulated fractions are controlled to
prevent segregation and nonuniformity.

Pharmaceutical Dosage Forms: Disperse

Systems, Vol. 2, ed, H. A. Lieberman, M. M.
Rieger, and G. S. Banker eds., Marcel Dekker,
Inc., 1996.

References

Pharmaceutical Dosage Forms: Disperse

Systems, Vol. 3, ed, H. A. Lieberman, M. M.
Rieger, and G. S. Banker eds., Marcel Dekker,
Inc., 1996.

1. United States Pharmacopeia, 24th Ed., 1999,

US Pharmacopeal Convention
2. R. A. Nash, Pharmaceutical Suspensions,
Chapter 1 in Pharmaceutical Dosage Forms:
Disperse Systems, Vol. 2, ed, H. A.
Lieberman, M M. Rieger, and G.S. Banker
eds., Marcel Dekker, Inc., 1996.
3. A.N. Martin and P. Bustamonte, Physical
Pharmacy, 4th ed., Williams & Wilkins, 1993.
4. J. Swarbrick, Coarse Dispersions, Chapter 21
in Remington: The Science and Practice of
Pharmacy, 19th ed, A. R. Gennaro ed, Mack
Publishing, 1995.
5. J. A. Plaizier-Vercammen and E. Janssens, A
Universal Method to Obtain Stable and Easily
Redispersible Suspensions, Labo-Pharma Probl. Tech. 32: 283-7, 1984.

Selected Readings
Remington: The Science and Practice of
Pharmacy, 19th ed, A. R. Gennaro ed, Mack
Publishing, 1995.
A.N. Martin and P. Bustamonte, Physical
Pharmacy, 4th ed., Williams & Wilkins, 1993.
Pharmaceutical Dosage Forms: Disperse
Systems, Vol. 1, ed, H. A. Lieberman, M. M.
Rieger, and G. S. Banker eds., Marcel Dekker,
Inc., 1996.

2000 FMC Corporation. All rights reserved. RS

22