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Section 9
Suspensionsby Drs. Clyde M. Ofner and Roger l. Schnaare
Table of Contents
Suspensions
..................................................................................................................................1Table
of Contents
....................................................................................................................1
Introduction and
Background........................................................................................................3Definitions
................................................................................................................................3Uses
of
Suspensions................................................................................................................3
Formulations
..................................................................................................................................4Typical
Ingredients....................................................................................................................4
Drug
....................................................................................................................................4Wetting
Agent
....................................................................................................................4Suspending
Agent
..............................................................................................................4Protective
Colloid
..............................................................................................................5Flocculating
Agent..............................................................................................................5Sweetener
..........................................................................................................................5Preservative
........................................................................................................................6Buffer
..................................................................................................................................6Flavor
..................................................................................................................................6Color
..................................................................................................................................6Sequestering
Agent
............................................................................................................6
Typical Formulations
................................................................................................................7Antacid/Antiflatulent
Formula (cellulose gums and Avicel® suspending agents)
..............7Sulfamethazine Suspension (synthetic polymer
suspending agent)..................................7Sulfamethazine
Suspension (clay and cellulose gum suspending
agents)........................8Benzoyl Peroxide Suspension
(cellulose and natural gums suspending agents)
..............8Sterile Triamcinolone Diacetate Aqueous Suspension
(synthetic polymer) ......................9Prednisolone Acetate
Ophthalmic Suspension (cellulose gum suspending agent)
..........9
Steps in Suspension Preparation
................................................................................................10Wetting
of Drug
......................................................................................................................10
Surfactants
......................................................................................................................10Solvents
– Polar and Nonpolar
........................................................................................10Levigation
........................................................................................................................10
Dispersing Suspending
Agent................................................................................................10High
Shear
........................................................................................................................10Heat
..................................................................................................................................10Non-polar
Liquids
............................................................................................................10Water
Soluble Ingredients
................................................................................................10
Combined Drug and Suspending Agent
................................................................................11Other
Ingredients....................................................................................................................11
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Final Processing
....................................................................................................................11Published
Processing Guidelines
..........................................................................................11
DuPont Problem Solver, 1984 (excerpted)
......................................................................11Nash
(paraphrased)
..........................................................................................................11
How Suspensions Behave
..........................................................................................................12Sedimentation
........................................................................................................................12
Factors – Stoke’s Law
......................................................................................................12Particle
Size............................................................................................................................12Density
Difference
..................................................................................................................12The
Gravitational Constant, g
................................................................................................12Viscosity
................................................................................................................................12Dynamic
Suspension
Interactions..........................................................................................13Flocculation
............................................................................................................................13
Charge Repulsion – zeta potential
..................................................................................13Polymer
Adsorption
..........................................................................................................14Caking
..............................................................................................................................14
Crystal
Growth........................................................................................................................15Retardation
......................................................................................................................15Polymorphic
Changes
......................................................................................................15
Controlling the Properties of a Suspension
................................................................................16Sedimentation
........................................................................................................................16
Suspending Agents and Type of
Flow..............................................................................16Pseudoplastic
vs. Thixotropic
..........................................................................................16Yield
Value
........................................................................................................................16
Electrostatic Flocculation
......................................................................................................17Deflocculated
vs. Flocculated Formulations: A Structured Vehicle Approach
......................18
A Universal Approach
..................................................................................................................19Experimental
Suspension Parameters
........................................................................................20
Zeta Potential
........................................................................................................................20Density....................................................................................................................................20Viscosity
................................................................................................................................20Sedimentation
........................................................................................................................20Redispersibility
......................................................................................................................20Particle
Size............................................................................................................................20
Reconstitutable Suspensions
......................................................................................................21Introduction
............................................................................................................................21Formulations
..........................................................................................................................21Typical
Formulations
..............................................................................................................21Preparation
............................................................................................................................21
Powder Blends
................................................................................................................21Granulated
Products
........................................................................................................21Combination
Products......................................................................................................21
References
..................................................................................................................................22Selected
Readings
......................................................................................................................22
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3
Introduction and Background
Definitions
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 OralSuspension. 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.
The USP also defines several dosage forms thatare essentially
suspensions but historically arereferred to by other names. For
example;
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.” Thesecan be suspensions if
composed of “a two-phase 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
sucha manner that no apparent boundaries existbetween the dispersed
macromolecules and theliquid”, e.g., gelatin gel. These gels are
clearlynot 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,
magmasand milks is largely historical.
Today all of these preparations are referred to as
suspensions.
One other aspect needs to be clarified at thispoint and that is
the difference between a suspension and a colloid. Both can
bedispersions 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
theparticles uniformly dispersed and preventsedimentation.
Uses of Suspensions
Suspensions are basically used to prepareliquid 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 ofroutes of administration including
topical, oral,parenteral, ophthalmic, otic, and nasal. As adosage
form, they offer several advantages:
• Preferred for patients, geriatric and pediatric, who have
difficulty in swallowingsolid oral dosage forms such as tablets
andcapsules.
• Disagreeable tastes can be often overcomeby 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 inthe following
order for various oral dosageforms: solutions > suspensions >
capsules >tablets.
• Improved chemical stability compared tosolutions.
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Table 1. Typical Wetting Agents
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
ornegatively charged and generally effective in a concentration
range of 1 to 5%.
Being polymeric in nature, most suspendingagents have
hydrophilic and hydrophobicregions in their molecular structure
and, as such, can interact with a suspension particle surface. Some
adsorption of the suspendingagent to the particle surface almost
alwaysoccurs giving the particle surface the
solubilitycharacteristics of the suspending agent. As with
adsorption of wetting agents, the particlesurface, after adsorption
of a suspending agent, will be hydrophilic and either neutral or
negatively charged.
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Formulations
Typical Ingredients
Drug
Typically, the particle size distribution is between1 and 50 µm.
Ideally, one would prefer a uniformsize; however, in practice,
there is always a sizedistribution. With high-speed attrition
impactmills the distribution is usually between 10 to 50µm, while
fluid-energy mills, can reduce particle size below 5 µm.
The drug surface can be either hydrophilic orhydrophobic. Ionic
surfaces such as aluminumhydroxide, are readily wetted and
dispersed easily in aqueous vehicles. Most organic drugsform
particles with a hydrophobic surface andare difficult to disperse
in an aqueous medium.
Wetting Agent
Wetting agents are surfactants that reduce the surface tension
of an aqueous medium, coat the surface of suspension particles, and
therebyfacilitate the wetting of each particle. The goal is to
displace air from the particle surface and to separate each
particle from adjacent particlesusing the minimum concentration
necessary.
Since wetting agents are surfactants, theyadsorb onto the
particle surface and, dependingon 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
surfacewill be hydrophilic but not charged.
Wetting Agent Ionic Charge
Sodium Lauryl Sulfate AnionicDocisate Sodium AnionicPolysorbate
80 Nonionic
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Table 2. Typical Suspending Agents
Suspending Agent Rheologic Ionic ConcentrationBehavior Charge
Range (%)
Cellulose Derivatives
Methylcellulose Pseudoplastic/plastic Neutral 1-5Hydroxypropyl
Methylcellulose Pseudoplastic Neutral 0.3-2Sodium
Carboxymethylcellulose Pseudoplastic Anionic 1-2Microcrystalline
Cellulose with Plastic/thixotropic Anionic 0.5-2
Sodium Carboxymethylcellulose
ClaysBentonite Plastic/thixotropic Anionic 1-6Magnesium Aluminum
Silicate Plastic/thixotropic Anionic 0.5-5
Polymers
Carbomer Plastic Anionic 0.1-0.4Povidone Newtonian/Pseudoplastic
Neutral 5-10
GumsXanthan gum Plastic/thixotropic Anionic 0.3-3Carrageenan
Newtonian/Pseudoplastic Anionic 1-2
Protective Colloid
A protective colloid is a polymeric suspendingagent absorbed on
the surface of a hydrophobicsuspension particle giving the particle
ahydrophilic surface.
Flocculating Agent
Flocculating agents enable suspension particlesto link together
in loose aggregates or flocs.These flocs settle rapidly but form a
large fluffysediment which is easily redispersed.
Materials that function as flocculating agentsinclude
electrolytes, surfactants, and polymers;the same materials that
serve as wetting and suspending agents. The mechanism by whichthey
function is involved and will be discussed inmore detail later.
Sweetener
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
relatively high concentrations and also contribute to the
viscosity of the suspension.Other sweetening agents such as
saccharin,sodium and aspartame, used in relatively
lowconcentrations, do not affect the overall viscosity.
Table 3. Typical Sweetening Agents
Sweetener Comments
Saccharides
Sucrose Up to 80%
Polyols
MannitolCooling effect, considered noncaloric, fairly expensive,
can cause diarrhea.
SorbitolHalf as sweet as sucrose, considered noncaloric, can
cause diarrhea.
Synthetic
Sodium Saccharin500 times as sweet as sucrose, inexpensive.
AspartameGood acid stability
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Buffer
Many chemical buffer systems have been usedin suspensions to
control pH. The optimal pH ischosen to minimize solubility of the
drug, controlstability of the drug, and to ensure compatibilityand
stability of other ingredients.
Flavor
Flavoring agents enhance patient acceptanceof the product, which
is particularly importantin pediatric patients.
Color
Colorants are intended to provide a more aesthetic appearance to
the final product. As relatively large cations or anions,
theseagents may be chemically incompatible withother ingredients.
They also need approval by the FDA.
Sequestering Agent
Sequestering agents may be necessary to bindmetal ions to
control oxidative degradation ofeither the drug or other
ingredients.
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Preservative
Preservatives are required in most suspensionsbecause suspending
agents and sweeteners are good growth media for microorganisms.Many
preservatives are ionic, such as sodiumbenzoate, 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 pre-servatives at
concentrations approaching 10%.
Table 4. Typical PreservativesPreservative Concentration Range
(%)
Alcohols
Ethanol >20Propylene Glycol 15-30Benzyl Alcohol 0.5-3
Quaternary AminesBenzalkonium Chloride 0.004-0.02
Acids
Sorbic Acid 0.05-0.2Benzoic Acid 0.1-0.5
Parabens
Methylparaben 0.2Propylparaben 0.05
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Typical Formulations
Antacid/Antiflatulent Formula (cellulose gums and Avicel®
suspending agents)
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Ingredient % by Weight Use
Aluminum hydroxide gel (8.9%) 21.00 Drug
Magnesium hydroxide paste (29.5%) 12.90 Drug
Simethicone 0.37 Antiflatulant
Hydroxypropyl cellulose 0.33 Suspending agent
Methylcellulose 0.03 Suspending agent
Avicel® RC-591 0.11 Suspending agent
Sorbitol 6.00 Sweetener
Citric acid, anhydrous 0.06 Buffer
Methylparaben 0.16 Preservative
Propylparaben 0.03 Preservative
Saccharin sodium 0.02 Sweetener
Flavors 0.12 Flavor
Purified water qs 100.00 Solvent
Preparation
1. Charge the mixing tank with purified water at about 40% of
the total water required.
2. Separately disperse the methylcellulose in1.5% of the above
purified water, add thesimethicone and add to the mixing tank.
1. Mix the methyl and propyl parabens into a slurry with about
2% of the purified water and add to the mixing tank.
2. Add to the mixing tank in the followingorder; 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 withabout 13% of the
purified water and add tothe mixing tank.
5. Add the remainder of the purified water tothe desired volume
and mix until uniform.
Sulfamethazine Suspension (synthetic polymer suspending
agent)
Ingredients % by Weight Use
Sulfamethazine 10.1 Drug
Carbomer 934 0.5 Suspending agent
Sodium lauryl sulfate 0.02 Wetting agent
Sucrose 40.0 Sweetener
Saccharin sodium 0.08 Sweetener
Methylparaben 0.2 Preservative
Propylparaben 0.02 Preservative
Flavor mixture 1.0 Flavor
Citric acid 0.2 Buffer
0.1 N NaOH ~10 mL Adjust pH
Purified water qs 100 mL Solvent
Preparation
1. Hydrate the carbomer for 24 hours in a solution of the sodium
lauryl sulfate in 30 mLof water
2. Suspend the sulfamethazine in the abovevehicle with the aid
of a mixer.
3. Dissolve the preservatives and sucrose in 40 mL of water by
heating.
4. Cool the solution and add the saccharinsodium and citric
acid.
5. Add the solution to the suspension in step 2.
6. Add the flavor, adjust the pH to 5.5 and mixin a
homogenizer.
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Benzoyl Peroxide Suspension(cellulose and natural gum suspending
agents)
Sulfamethazine Suspension (clay and cellulose gum suspending
agents)
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Ingredient % by Weight Use
Sulfamethazine 10.0 Drug
Magnesium aluminum-silicate 0.6 Suspending agent
Sodiumcarboxymethylcellulose 1.3 Suspending agent
Sodium lauryl sulfate 0.02 Wetting agent
Saccharin sodium 0.08 Sweetener
Sucrose 40.0 Sweetener
Methylparaben 0.2 Preservative
Propylparaben 0.02 Preservative
Flavor 1.0 Flavor
Purified water qs 100 Solvent
Preparation
1. Hydrate the magnesium aluminum silicateand sodium
carboxymethylcellulose for 24hours in a solution of the sodium
lauryl sulfate in 30 mL of water.
2. Suspend the sulfamethazine in the abovevehicle with the aid
of a mixer.
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.
Ingredient % 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 10 Solvent
Phosphoric acid 0.03 pH adjustment
Purified water qs 100 Solvent
Preparation
1. Add the hydroxypropyl methylcellulose and xanthan gum to
water heated to approximately 70°C with stirring.
2. Cool to 50°C and add the polysorbate 20.
3. Cool to 35°C and successively add the isopropyl alcohol,
phosphoric acid, and benzoyl peroxide (as a 70% aqueous
slurry).
4. Mill to obtain a smooth suspension.
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Sterile Triamcinolone Diacetate AqueousSuspension (synthetic
polymer)
Ingredient % by Weight Use
Triamcinolone diacetate 4.0 Drug
Polyethylene glycol 3350 3.0 Suspending agent
Polysorbate 80 0.2 Wetting agent
Sodium chloride 0.85 Toxicity agent
Benzyl alcohol 0.9 Preservative
Water for injection qs 100 Solvent
Preparation
(Not considering sterility or presence of pyro-gens)
1. Dissolve the polysorbate 80 in a portion ofthe water for
injection.
2. Disperse the triamcinolone diacetate in thepolysorbate 80
solution.
3. Dissolve the polyethylene glycol 3350 in aportion of the
water for injection.
4. Add the triamcinolone diacetate dispersion to the
polyethylene glycol 3350 solution.
5. Successively add the sodium chloride andthe benzyl
alcohol.
6. Adjust to volume with water for injection.
Prednisolone Acetate Ophthalmic(cellulose gum suspending
agent)
Ingredient % by Weight Use
Prednisolone acetate 1.0 Drug
Hydroxypropyl methylcellulose qs Suspending agent
Polysorbate 80 qs Wetting agent
Sodium chloride qs Tonicity agent
Edetate disodium qs Chelating agent
Benzalkonium chloride 0.01 Preservative
Phosphate buffer qs Buffer
NaOH or HCl qs pH adjustment
Purified water qs 100 Solvent
Preparation
(sterilization not considered)
1. Dissolve the phosphate buffer, edetate disodium, sodium
chloride, and benzalkonium chloride in a portion of the water.
2. Disperse the hydroxypropyl methylcellulosein another portion
of water.
3. Disperse the prednisolone acetate in a solution of the
polysorbate 80 in water using a high-shear mixer.
4. Add the prednisolone acetate dispersion tothe aqueous
solution containing the buffer.
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.
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Wetting of Drug
• 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 solidon the surface of water and letting the
mixturestand overnight. Simple mixing of the hydratedmaterial will
disperse the solid uniformly.
Most drugs of organic origin, however, have ahydrophobic surface
and require some degreeof assistance to be thoroughly wetted.
Thewetting agent can be dissolved in approximatelyhalf the final
volume of aqueous vehicle and thedrug sprinkled on the surface of
the surfactantsolution and allowed to wet for a period of
timefollowed by a mixing step to uniformly dispersethe solid.
Alternately, the drug can be added to thesurfactant solution in
small portions withagitation or mixing. Using excessive or
highshear has the disadvantage of producing foamwhich may be
difficult to dissipate but may benecessary to wet the solid
thoroughly. Mixingthe drug with a solid, water soluble componentof
the suspension, i.e., sucrose, can often aidin preventing clumping
of the drug when addedto an aqueous vehicle.
Drugs may also be wetted by using a water-miscible liquid, such
as glycerin or propyleneglycol, to produce a thick, smooth paste
orslurry with the drug by levigation. The uniformslurry is then
added to the part of the aqueousvehicle or surfactant solution. The
wetting agentmay be dissolved in solution prior to adding theslurry
or may be mixed with the drug at thebeginning of the levigation
process.
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Steps in Suspension Preparation
Dispersing Suspending Agent
• High shear• Heat• Non-polar liquids• Water soluble
ingredients
Suspending agents also need to be uniformly dispersed to be
fully functional. Since they areall hydrophilic, i.e., clays,
simple hydration maybe sufficient for complete dispersion.
Those which are water soluble, i.e., cellulosederivatives,
present particular problems. Asthe water soluble suspending agents
are addedto water, the outer layer of particles or clumpsof
particles start to dissolve producing a thickrubbery gel with the
powdered, unhydratedpolymer inside. If this layer is not
dispersedquickly, the entire mass of particles will tendto stay as
a mass and complete dispersionwill be very slow or nearly
impossible. Thisis evident by the appearance of opaque
ortransparent fish eye-like clumps.
To avoid this problem, the suspending agentmust be dispersed in
the aqueous vehiclebefore the rubbery gel can form. This can bedone
by adding the suspending agent to theaqueous vehicle in small
portions with highshear, then letting the dispersion stand
todissipate the foam or air bubbles.
Alternately, the suspending agent can bedispersed in an organic
liquid, such as glycerinor propylene glycol, using the levigation
processdescribed above. The suspending agent willeventually solvate
in the organic liquid, but thisprocess is much slower than
hydration in water.Thus, the slurry must be added to the
aqueousvehicle with mixing before the solvation processoccurs in
the organic liquid.
The suspending agent can also be mixedwith a solid, water
soluble component of the suspension, i.e., sucrose, before being
addedto the aqueous vehicle with mixing.
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11
7. Most suspension vehicles can tolerate theaddition of flavors
in the form of oils as long asthe final batch is processed through
a colloid mill.
8. Process the batch through a colloid mill tocompletely
disperse the drug. The mill willefficiently disperse large, soft
agglomerates.
9. Process the batch through deaerating equipment.
10. Avoid excessive water losses, especially ifprolonged heating
is required.
11. Avoid excessive shearing and high temperatureswhich can
depolymerize colloids.
Nash2 (paraphrased)
1. Dry-grind insoluble particles to the smallest andmost uniform
size practical and maintain controlof the crystallographic form of
the drug duringbulk chemical manufacture.
2. Where practical, allow suspension particles towet completely,
without agitation, in a smallportion of the aqueous component of
thesuspending vehicle containing the wetting agentin order to
release entrapped air and reduce thenumber of non-wetted
agglomerates.
3. Dissolve or disperse the suspending agent in themain portion
of the liquid vehicle.
4. Slowly add the slurry of wetted suspensionparticles to the
main portion of the suspendingagent(s) with the aid of low shear
agitation.
5. Carefully control the addition of electrolytes,acids, bases,
buffers, and/or tonicity agents toprevent variations in particle
charge.
6. Colloid mills, homogenizers, ultrasonic devices, orpumps
should be used only after all additions andadjustments have been
completed as a finishingprocedure.
7. All finished aqueous suspensions must becarefully preserved
against microbial growth.
Combined Drug and Suspending Agent
Since the drug and suspending agent must be uniformly dispersed
during suspension prepara-tion, they can be combined in the dry
state anddispersed in the aqueous vehicle using anappropriate
method described above.
Other Ingredients
Other water soluble ingredients can be addedto the dispersion of
drug and suspending agentduring the stage of adding solvent to
finalvolume.
Final Processing
The final product is usually passed through ahomogenizer or
colloid mill to ensure an even distribution of all ingredients and
the break-upof clumps. Proper wetting of both drug and suspending
agents cannot depend on this finalstep. In addition, the suspending
agent clumpsand the fish eyes cannot be removed at thisstage.
Published Processing Guidelines
DuPont Problem Solver, 1984 (excerpted)
1. Disperse the drug by slow addition to a water, water-glycol
or glycol system containing the wetting agent.
2. Add all other excipients which require solutionin as dilute a
system as possible.
3. Make sure that the solvent system exceedssolubility limits of
dissolved ingredients.
4. Allow sufficient water for easy dispersion andhydration of
suspending agents(s) and protectivehydrocolloids.
5. If more than one drug compound is to beincorporated in the
formula, ascertain their compatibility.
6. Use sufficient drug overages to compensate forlosses during
manufacture and to maintain labelclaim for the shelf life of the
product.
deepikaTypewritten Text
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Density Difference
If the difference in density between the suspended particle and
suspension mediumcan be matched, the sedimentation rate couldbe
reduced to zero. Densities approaching 1.3can be obtained with high
concentrations ofsucrose, which is comparable to the crystaldensity
of 1.25 for many organic drugs. Thedisadvantage 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.
The Gravitational Constant, g
This parameter is not of much interest sinceit cannot be
controlled or changed unless in space flight.
Viscosity
Viscosity turns out to be the most readily controllable
parameter in affecting sedimentationrate. While the viscosity in
Stoke's Law refers to the viscosity of the fluid through which a
particle falls, in reality the viscosity that controlssedimentation
is the viscosity of the entire suspension. Thus, doubling the
viscosity of a suspension will decrease the sedimentationrate by a
factor of 2.
Sedimentation
Factors - Stoke’s Law
Sedimentation will potentially always occur in a pharmaceutical
suspension since the particlesize is generally greater than that of
a colloidal dispersion. The rate is described by Stoke's Lawfor a
single particle settling in an infinite containerunder the force of
gravity as follows:
where:
d�/dt = the sedimentation rate in distance/timed = particle
diameterρ
2= particle density
ρ1
= suspension medium densityg = acceleration due to gravityη =
viscosity of the suspension medium
While Stoke's Law does not quantitativelydescribe sedimentation
in a suspension, it doesprovide a clear collection of factors and
theirqualitative influence on sedimentation.
Particle size
Reducing particle size can have a significanteffect on
sedimentation rate. Since the diameteris squared in Stoke's Law, a
reduction in sizeby ¹⁄₂ will reduce the sedimentation rate by
(¹⁄₂)2
or a factor of 4.
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How Suspensions Behave
d�=
d2 (ρ2
- ρ1) g
dt 18η
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13
Since a suspension is composed of manyingredients, it must be
kept in mind that all theseingredients interact with each other.
Figure 1 isa simple representation of some of the
possibleinteractions that affect suspension behavior.
Although the drug in a suspension is describedas being
insoluble, there is always a finite solu-bility of a drug in water,
i.e., the aqueous vehiclesurrounding the suspension particle will
be asaturated solution of the drug. This equilibriumchanges with
changes in temperature and hasan influence on crystal growth,
polymorphicchanges and chemical degradation.
Figure 1: Dynamic Model of SuspensionInteractions
+ _
+ _
DrugSuspensionParticle
D (saturated solution)
(surfactant micelles)(surfactant monomers)
(polymer)
+ -
+ -
(electrolyte)
D
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, andsolvent polarity, will also promote adsorptionof
the surfactant onto the particle surface.
Likewise, polymers added as protective colloidsand suspending
agents will be in equilibriumbetween molecules adsorbed on the
suspensionparticle surface and molecules in solution inthe aqueous
vehicle. Changes that decreasepolymer solubility, i.e.,
electrolytes and solventpolarity, will also promote deposition of
thepolymer on the particle surface.
Electrolytes that affect the adsorption of surfactants and
polymers can themselves beadsorbed onto the suspension particle
surfacedirectly affecting the surface charge of the particle.
Flocculation
Charge Repulsion - zeta potential
Suspensions can exist in essentially two states,deflocculated or
flocculated, depending on howsuspension particles interact. The
deflocculatedstate is defined as the condition where eachsuspension
particle exists independently andbehaves as a single particle.
Flocculation is thestate where suspension particles attract
eachother and form loosely bound aggregates orflocs. These flocs
behave as a unit but are easilybroken up with shear.
Deflocculation occurs when the particles eitherrepel 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 theparticles repel, hence,
this condition would bedeflocculation. Adding negative ions, from a
soluble electrolyte, causes the positive charge of the original
suspension particles to be “neu-tralized” or “shielded” so that the
particles nolonger repel each other but rather aggregateproducing a
flocculated state (Figure 2B). Furtheraddition of negative ions can
reverse the originalparticle charge and produce negatively
particlesand if this negative charge is large enough, theparticles
will again repel each other and become deflocculated (Figure
2C).
Dynamic Suspension Interactions
-
Polymer Absorption
A suspension can also be deflocculated andflocculated by
polymers adsorbed on the particle surface as depicted in Figure
3.Polymers will almost always be adsorbedon the particle surface
and, if the suspensionvehicle provides a good solvent for the
polymer, the coated suspension particles will behave ashydrophilic
particles. Thus the particles have noreason to aggregate and will
be in a deflocculatedstate. The colloid literature calls this
condition stabilized, and the polymer functions as a protective
coating.
If the suspension vehicle is changed such thatit becomes a poor
solvent for the polymer, i.e.,by the addition of electrolyte or a
less polarsolvent, then the polymer will become less soluble,
polymer molecules will start to interactand, if the changes are
severe enough, thepolymer will precipitate. The polymer moleculeson
the particle surface will also start to interactcausing an
attraction between particles. Thisinteraction will produce a
flocculated state.
14
Figure 2: Electrostatic Model ofFlocculation
Figure 4: Sediment Volume of aDeflocculated (caked) and a
FlocculatedSuspension (not caked)
Figure 3: Polymer Model of Flocculation
+ _
+_
+_+
_+_
+_
+ _
_+
+ _
+_
+_+
_+_
+_
+ _
_+
+ _
+_
+_+
_+_
+_
+ _
_+
+ _
+_
+_+
_+_
+_
+ _
_+
__
_
_ _
_
_
_
__
_
_ _
_
_
_
+
+
++
+
+
+
+
+
+
++
+
+
+
+
–ions
–ions
A B CPositive Charge Neutral Charge Negative Charge
Deflocculated Flocculated Deflocculated
Caked Sediment Fluffy Sediment Caked Sediment
Good SolventDeflocculated
Poor Solvent/ElectrolyteFlocculated
Caking
The state of flocculation will have a profoundeffect on the
physical properties of the suspen-sion as summarized in the
following table andfigure. Agglomerations of flocculated
particles(flocs) act as large particles but are fluffy andeasily
broken up and redispersed. A deflocculat-ed suspension, while
settling more slowly thana flocculated suspension, will eventually
settlein a dense, hard cake which may be difficultor impossible to
redisperse.
0
50
100
0
50
100
Deflocculated Flocculated
-
15
A comparison of properties of flocculated and defloccuated
suspension particles follows:
Deflocculated
1. Particles exist as separate entities.2. Sedimentation is slow
- particles settle separately.3. Sediment is formed slowly from
bottom of container.4. Sediment eventually becomes caked due to
weight of succeeding layers of sediment.5. Pleasing appearance -
suspended material remains suspended for a relatively long
time.
Supernatant remains cloudy.
Flocculated
1. Particles are loose aggregates.2. Sedimentation is rapid -
particles settle as large flocs.3. Sediment is formed rapidly from
top of container.4. Sediment is loosely packed and easy to
redisperse.5. Somewhat unsightly - obvious, clear supernatant.
Crystal Growth
• Retardation• Polymorphic changes
The equilibrium solubility behavior of the drugin a suspension
can result in a change in particlesize and a change from one
polymorphic formto another more stable form. As changes
intemperature occur, the solubility of the drugchanges; drug
continually dissolves andrecrystallizes.
The term Ostwalt ripening refers to the growthof large particles
at the expense of smaller onesin a suspension composed of a
relatively wideparticle size distribution. The net result is
thatthe size distribution narrows. In a suspensionwith a relatively
narrow size distribution to beginwith, the size distribution tends
to broaden.These changes will occur until an equilibriumcondition
is established.
Nash2 offers some guidelines for limiting thesetypes 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 suspendingvehicle.
• Use a protective colloid to inhibit dissolution.• Increase the
viscosity of the vehicle to retard
dissolution.• Avoid temperature extremes during product
storage.
-
16
Controlling the Properties of a Suspension
Sedimentation
• Suspending agents and type of flow• Pseudoplastic vs.
thixotropic• Yield value
As discussed with Stoke's Law, one of the mostreadily available
ways to control sedimentationis to increase the viscosity of the
suspensionvehicle. This can be done either by the selectionof the
suspending agent or by increasing theconcentration of the
suspending agent.Viscosity behavior of a suspending agent
isdescribed by a flow curve constructed by plotting shear stress as
a function of shearrate 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 stressover shear
rate or the slope of the flow curvedefined as the apparent (ηa) and
differentialviscosity (ηd), respectively.
ηa =
Shear Stress
Shear Rate
=d (Shear Stress)η
d d (Shear Rate)
Figure 5: Rheological Flow Curves:A - Newtonian, B -
PseudoplasticC - Plastic, D - Plastic with Thixotropy
Figure 6: Viscosity vs Shear Rate
She
ar S
tres
s
Shear Rate
A B
DC
Almost all suspending agents have a flowbehavior described as
non-Newtonian. Cellulosederivatives and soluble polymers have a
flowbehavior described by the term pseudoplastic.With either
definition of viscosity, it can be seenfrom the flow curve in
Figure 5B that viscositydecreases with shear rate for a
pseudoplasticfluid as illustrated by the upper curve in Figure
6.
0
10
20
30
40
50
60
70
700500 600400
Shear Rate
Vis
cosi
ty
-
17
Electrostatic Flocculation
Martin3 has shown that the flocculation of a suspension can be
controlled by adjusting the surface charge of a suspension as
measured bythe zeta potential. Figure 7 summarizes
theseobservations by illustrating the interrelationshipbetween
sedimentation volume, caking, andzeta potential.In water, bismuth
subnitratehas a positively charged surface with a zetapotential
high enough so that the particlesrepel each other. At this point
the suspensionis deflocculated and will eventually producea caked
sediment.
This behavior is advantageous for suspensionssince during
sedimentation the settling particlegenerates a low shear rate, the
correspondingviscosity is high, and sedimentation is
inhibited.Conversely, when the suspension is shakenvigorously, a
high shear rate is generated, theviscosity is decreased, and the
suspensionflows or pours easily. This is in contrast to aNewtonian
fluid which has a constant viscosityregardless of the amount of
shear applied tothe fluid.
Other suspending agents, particularly carbomer,clays, and
Avicel® RC, have a plastic flowbehavior. This flow is shear
thinning like thepseudoplastic fluids but is also characterizedby a
yield value. This yield value is seen as anintercept on the shear
stress axis and corre-sponds to the stress that must be placed
onthe fluid to cause it to flow (Figure 5C).
If the yield value of the suspending agent isgreater than the
stress exerted on the fluidby the suspension particle, the
suspensionparticle cannot move through the suspensionand
sedimentation cannot take place. Thetheoretical minimum yield value
required topermanently suspend a particle can be calculated from
the following equation:
where:YV
t= is the calculated or theoretical yield
valueVp = is the particle volume given by π d3/6A = is the cross
sectional area of the
particle, π d2/4 and the other terms areas defined in Stoke's
Law
Some suspending agents have a time dependentflow behavior
(Figure 5D), called thixotropy, whichis characterized by
ahysteresis loop in the flowcurve. A thixotropic fluid has a
structure that isbroken down by shear as in a plastic or
pseudo-plastic fluid; however, the rebuilding of structureafter
shearing is stopped takes a finite time. Thisis advantageous in
that, in addition to the fluid
YVt
=Vp (ρ2 - ρ1 ) g
A
being shear thinning and may have a yield value,the slower
structure buildup allows the fluid tobe processed easily for a
period of time.
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.
Figure 7: Caking Diagram Shows theFlocculation of a Bismuth
SubnitrateSuspension by Means of the FlocculatingAgent, Monobasic
Potassium Phosphate2
+ _
+_
+_+
_+_
+_
+ _
_+ _
__
__
__
_+
+
++
+
+
+
+
Concentration KH PO2 4
_
+
_100
_
_
0.03
0.04
00
Caking Zone Noncaking Zone Caking Zone
App
aren
t zet
a po
tent
ial
zeta potential Curve
V3/V4 Curve
V1 - V2Ratio
Caked Not Caked Caked50 Concentration KH2PO4
-
deflocculated suspension by controlling the electrolyte
concentration of the suspension.
Deflocculated vs. FlocculatedFormulations: A Structured
VehicleApproach
Swarbrick4 describes a scheme for alternativeapproaches for
preparing suspensions. In thisscheme, 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.
18
Figure 8: Alternative Approaches to the Formulation of
Suspensions
As the electrolyte is added, the HPO42- ion isattracted to the
positively charged surface thusshielding and lowering the zeta
potential. Thesurface charge is not sufficient for the particlesto
repel each other and the suspension flocculates. The sediment
produced is looseand fluffy and can be redispersed easily
byshaking. Further addition of electrolyte producesa negative
surface charge, the suspensionbecomes deflocculated, and will
eventuallyproduce a caked sediment. Martin's experimentswere
carried out in dilute suspensions of bismuthsubnitrate in water
with added electrolyte. In areal suspension, concentrations of drug
aremuch higher and the suspension contains manyother ingredients
that can affect surface chargeand characteristics. Nevertheless,
one can in practice produce either a flocculated or
Particles
Addition of wetting and dispersion medium
Uniform dispersion ofdeflocculated particles
A B C
Incorporation of Addition of flocculating agent Addition
ofstructured vehicle flocculating
Flocculated suspension agentas final product
Flocculatedsuspension
Deflocculated suspensionin succeeding vehicle as Incorporation
of
final product structured vehicle
Flocculated suspensionin structured vehicle as
final product
-
19
A Universal ApproachPlaizier-Vercammen and Janssens5
haveproposed a universal method of formulating suspensions. They
acknowledge the effect ofa zeta potential or surface charge on the
stateof flocculation but point out that zeta potentialsare measured
in dilute dispersion and do notreflect quantitatively the zeta
potential in a realsuspension.
As pointed out in Figure 1, there are many components in a
suspension formulation thataffect the surface properties of each
suspensionparticle. While the zeta potential relates to therelative
surface charge in sign and magnitude, itcannot be relied upon to
describe the behaviorof a formulated suspension.
Plaizier-Vercammen and Janssens suggestthat the suspension be
formulated varying the concentration of charged surfactant to vary
thezeta potential. All of the ingredients should beincluded so that
the overall effect can be seen.
Such an approach is illustrated in Figure 9 fora bismuth
subcarbonate suspension preparedin water and in 3% Avicel® RC-581
as a suspending agent and sodium dioctylsulfosucci-nate as an
anionic surfactant. In water, thesediment volume decreases with
increasingsurfactant concentration clearly suggestingan increase in
zeta potential with increasingsurfactant concentration. The last
three samplesat the highest surfactant concentration arecaked,
which is consistent with a deflocculatedsuspension.
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 suspend-ing
agent were caked, suggesting a flocculatedsuspension, at least at
the lower surfactant con-centration. At higher surfactant
concentrations,the samples could be either flocculated
ordeflocculated with the suspending agent supplying a sufficient
yield value to prevent sedimentation and caking.
Figure 9: Sedimentation Behavior of a Bismuth Subcarbonate
Suspension in Water and in 3% Avicel® RC-581
0
0.2
0.4
0.6
0.8
1
0.000 0.001 0.010 0.100 0.500 1.000
Rel
ativ
e S
edim
ent
Volu
me
% Surfactant Concentration
Caked
Water3% Avicel®
Regardless of the mechanism of particle interaction in this
illustration, physically stableand useful suspensions could be
preparedwith 3% Avicel® RC-581 with a surfactant concentration
ranging from 0 to 0.1%.
This universal method can be summarized andextended 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.
• Select one formulation factor such as electrolyte, surfactant,
or solvent and varyits concentration to obtain a variation inthe
sedimentation rate or volume.
This systematic variation will producechanges in all of the
equilibria describedin Figure 1 so that changes represent
acomposite effect of the entire formulation.
• Select a concentration of this ingredient tomaximize sediment
volume and minimize sedimentation rate.
-
Zeta Potential
Determined from the electrophoretic mobility indilute
dispersion. Generally, reflects the relativesurface potential of
the undiluted suspensionbut not a quantitative measure.
Density
A measure of air incorporated into the suspension during
preparation.
Viscosity
Need to determine flow properties over a rangeof shear rates to
identify the type of flow, thechange in viscosity with shear rate,
degree oftime dependency (thixotropy), and the presenceof a yield
value.
Sedimentation
Rate of sedimentation, relative volume of sediment, and quality
of the sediment.
Redispersibility
Measured by the number of rotations of thesuspension container
required to redisperse anysediment. An indirect indicator of
flocculation.
Particle Size
Measure as a function of time. Some changecan be expected over a
period of time untilan equilibrium is established.
20
Experimental Suspension Parameters
-
21
Preparation
The preparation of suspensions for reconstitutioninvolves dry
powder and granulation processesthat are described in other
sections of this publi-cation. In general, the products fall into
one ofthree classes; powder blends, granulations, ora combination
of the two.
Powder Blends
Traditional powder mixing processes are involvedtaking
precautions when incorporating smallquantities of ingredients to
ensure uniformity.
Powder blends have the advantage of using relatively simple
equipment, are least likely tohave chemical and stability problems
becauseno heat or solvents are used, and normallyhave a low
moisture content.
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 segregationproblems, and less dust generation
during filling.
Disadvantages include increased cost due tomore processing
steps, higher residual moisturecontent, stability problems with
ingredientssensitive to water during granulation, e.g.,flavors.
Combination Products
These products take advantage of the positive features of the
first two methods. Less energyis required if the majority of the
diluent canbe added after granulation. Heat-sensitiveingredients,
such as flavors, can be addedafter drying the granulation.
Introduction
Suspensions for reconstitution are dry formulations which
require mixing with waterprior to administration. Once
reconstituted,they must conform to all of the requirementsof a
traditional suspension.
This type of dosage form is usually used fordrugs that are not
stable in the presence ofwater but need to be dispensed in liquid
form.Oral and parenteral products are included in this
classification.
Formulations
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
criterioneliminates several suspending agents whichrequire special
mixing procedures for complete dispersion. Sodium
carboxymethylcellulose(NaCMC), microcrystalline cellulose
withNaCMC, carrageenans, and xanthan gum are typical suspending
agents capable of dispersing readily by shaking.
Typical Formulations
Two Commercial Amoxicillin Suspensions forReconstitution.
Reconstitutable Suspensions
Ingredient Function Product 1 Product 1
Active ingredient Amoxicillin trihydrate Amoxicillin
trihydrate
Sweetener Sucrose Sucrose, mannitol
Suspending agent Xanthan gum Cellulose, Na CMC
Dessicant Silica gel
Buffer Sodium citrate Sodium citrate, citric acid
Preservative Sodium benzoate
Colorant FD&C Red No. 3 Red No. 28, Red No. 40
Flavor Flavors Artificial flavors
-
Care must be taken that the particle size distribution of the
granulation and non-granulated fractions are controlled to prevent
segregation and nonuniformity.
References
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. Bankereds., Marcel Dekker, Inc.,
1996.
3. A.N. Martin and P. Bustamonte, PhysicalPharmacy, 4th ed.,
Williams & Wilkins, 1993.
4. J. Swarbrick, Coarse Dispersions, Chapter 21in Remington: The
Science and Practice ofPharmacy, 19th ed, A. R. Gennaro ed,
MackPublishing, 1995.
5. J. A. Plaizier-Vercammen and E. Janssens, AUniversal Method
to Obtain Stable and EasilyRedispersible Suspensions, Labo-Pharma
-Probl. Tech. 32: 283-7, 1984.
Selected Readings
Remington: The Science and Practice ofPharmacy, 19th ed, A. R.
Gennaro ed, MackPublishing, 1995.
A.N. Martin and P. Bustamonte, PhysicalPharmacy, 4th ed.,
Williams & Wilkins, 1993.
Pharmaceutical Dosage Forms: DisperseSystems, Vol. 1, ed, H. A.
Lieberman, M. M.Rieger, and G. S. Banker eds., Marcel Dekker,Inc.,
1996.
22
Pharmaceutical Dosage Forms: DisperseSystems, Vol. 2, ed, H. A.
Lieberman, M. M.Rieger, and G. S. Banker eds., Marcel Dekker,Inc.,
1996.
Pharmaceutical Dosage Forms: DisperseSystems, Vol. 3, ed, H. A.
Lieberman, M. M.Rieger, and G. S. Banker eds., Marcel Dekker,Inc.,
1996.