Download SUSPENSIONS

 Dispersion system consist of (1)- particulate matter (dispersed phase)
(2)- continuous medium (dispersion medium)
 Classification of dispersed systems (based on particle size)
1 Molecular
dispersion
2 Colloidal
dispersion
3 Coarse
dispersion
< 1 nm
1nm- 0.5 mm
> 0.5 mm
Oxygen molecules,
glucose solution
Natural polymers
Suspension and
emulsion
 Definition of suspension: Pharmaceutical suspensions are uniform
dispersions of solid drug particles in a vehicle in which the drug has
minimum solubility. Particle size of the drugs may vary from one
formulation to the other depending on the physicochemical
characteristics of the drug and the rheological properties of the
formulation.
 A suspension containing particles between 1 nm to 0.5 µm in size is
called colloidal suspension. When the particle size is between 1 to 100
µm, the suspension is called coarse suspension. Most of the
pharmaceutical suspensions are coarse suspension.
 Majority of the marketed suspensions are available as dry powders
that must be reconstituted before administration but occasionally some
products in the market are ready-to-use. The first products are not
very stable once reconstituted; must be used within 7 to 10 days.
Examples of Pharmaceutical Suspensions:
A. Antacid oral suspensions Antibacterial oral suspension
B. Dry powders for oral suspension (antibiotic)
C. Analgesic oral suspension
D. Anthelmentic oral suspension
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E. Anticonvulsant oral suspension
F. Antifungal oral suspension
Pharmaceutical applications of suspensions:
1) Insoluble drug or poorly soluble drugs which required to be given
orally in liquid dosage forms ( in case of children, elderly, and
patients have difficulty in swallowing solids dosage forms)
2) To over come the instability of certain drug in aqueous solution:
a. Insoluble derivative formulated as suspension
An example is oxytetracycline HCL  calcium salt
(instable)
(stable)
b. Reduce the contact time between solid drug particles and
dispersion media  increase the stability of drug like Ampicillin
by making it as reconstituted powder.
c. A drug that degraded in the presence of water  suspended in
non-aqueous vehicles. Examples are phenoxymethypencillin/
coconut oil and tetracycline HCL/ oil
3) To mask the taste:
Examples are paracetamol suspension (more palatable) and
chloramphenicol palmitate.
4) Some materials are needed to be present as finely divided forms to
increase the surface area. Fore example, Mg carbonate and Mg
trisilcate are used to adsorb some toxins
5) Suspension can be used topical applications:
An example is calamine lotion Bp  after evaporation of dispersing
media; the active agent will be left as light deposit
6) Can be used for parentral administration  intramuscular (i.m.) to
control arte of absorption
7) In vaccines
Absorbed antigen
Aluminum hydroxide
e.g. Diphtheria and Tetanus
vaccines
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8) X-ray contrast media: an example is oral and rectal administration of
propyliodone
9) In aerosol  suspension of active agents in mixture of propellants
Qualities of ideal suspension: A well-formulated suspension should have
the following properties:
1) The dispersed particles should not settle readily and the settle should
redispersed immediately on shacking. Ideally, the particles in a
suspension should not sediment at any time during the storage period.
Unfortunately, the present technology does not allow us to prepare
such a suspension. Since one cannot completely avoid the
sedimentation of particles, it is desirable that the particles should
settle slowly. The easy redispersion of sedimented particles in a
suspension is important for the uniformity of dose.
2) The particle should not form a cake on settling
3) The viscosity should be such that the preparation can be easily poured.
A highly viscous suspension would make pouring difficult.
4) It should be chemically and physically stable
5) It should be palatable (orally)
6) It should be free from gritting particles (external use)
FACTORS TO BE CONSIDERED
A- Wetting of the particles:
Solid
particles
Hydrophilic can be
dispersed easily
Suspending
media
Difficult to disperse and
float on the surface due to
hydrophobic surface or
entrapped air
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 It is difficult to disperse solid particles in a liquid vehicle due to the
layer of adsorbed air on the surface. Thus, the particles, even high
density, float on the surface of the liquid until the layer of air is
displaced completely. The use of wetting agent allows removing this
air from the surface and to easy penetration of the vehicle into the
pores. Alcohol, glycerin, and propylene glycol are frequently used to
remove adsorbed air from the surface of particles when aqueous
vehicle is used to disperse the solids. When the particles are
dispersed in a non-aqueous vehicle, mineral oil is used as wetting
agent. Irrespective of the method of preparation, the solid particles
must be wetted using any of the suitable wetting agents before the
dispersion in the vehicle.
 Solid particles that are not easily wetted by aqueous vehicle after the
removable of the adsorbed air are referred to as hydrophobic
particles. It is necessary to reduce the interfacial tension between the
particles and the vehicle by using surface-active agents to improve
the wettibility. Sodium lauryl sulfate is one of the most commonly
used surface-active agents. Hydrophilic particles are easy to disperse
in the aqueous vehicle once the adsorbed air is removed.
Hydrophilic particles do not require the use of surface-active agents.
 The main function of wetting agents: (1)- to reduce the contact angle
between surface of solid particles and wetting liquid via displace the
air in the voids (2)- surfactant
 Examples of wetting agents are tragcanth mucilage, glycerin,
glycols, bentonite and polysorbates.
 Excessive amounts of wetting agents can cause foaming or
undesirable taste or odor.
 Contact angle can be used to measure wettibility, if the angle
approximately equal or more than 90 0, particles are floating well out
of fluid.
B-Particle size:
 Particle size of any suspension is critical and must be reduced within
the range as determined during the preformulation study.
 Too large or too small particles should be avoided. Larger particles
will settle faster at the bottom of the container and too fine particles
will easily form hard cake at the bottom of the container.
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 The particle size can be reduced by using mortar and pastel but in
large-scale preparation different milling and pulverization equipments
are used.
 Limitation in particle size reduction (after reaching a certain particle
size):
1. Expensive and time consuming
2. Movement of small particles due to brownian motion cause
particles to aggregate, settle, form hard cake that it is
difficult to redispersed
C-Sedimentation:
 Sedimentation of particles in a suspension is governed by several
factors: particle size, density of the particles, density of the vehicle,
and viscosity of the vehicle. The velocity of sedimentation of particles
in a suspension can be determined by using the Stoke's law:
v =
d2 (p1-p2) g
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Where:
v = velocity of sedimentation
d = diameter of the particle
g = acceleration of gravity
1 = density of the particle
 = density of the vehicle
 = viscosity of the vehicle
 According to the Stoke's equation, the velocity of sedimentation of
particles in a suspension can be reduced by decreasing the particle
size and also by minimizing the difference between the densities of
the particles and the vehicle. Since the density of the particles is
constant for a particular substance and cannot be changed, the
changing of the density of the vehicle close to the density of the
particle would minimize the difference between the densities of the
particles and the vehicle. The density of the vehicle of a suspension
can be increased by adding the following substances either alone or in
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combination: polyethylene glycol, polyvinyl pyrolidone, glycerin,
sorbitol, and sugar.
 The viscosity of the vehicle also affects the velocity of sedimentation.
It decreases as the viscosity of the vehicle increases. The viscosity and
density of any vehicle are related to each other, so any attempt to
change one of these parameters will also change the other one.
D-Electrokinetic Properties
 Dispersed solid particles in a suspension may have charge in relation
to their surrounding vehicle. These solid particles may become
charged through one of two situations.
1. Selective adsorption of a particular ionic species present in the
vehicle. This may be due to the addition of some ionic species
in a polar solvent. Consider a solid particle in contact with an
electrolyte solution. The particle may become positively or
negatively charged by selective adsorption of either cations or
anions from the solution.
2. Ionization of functional group of the particle. In this situation,
the total charge is a function of the pH of the surrounding
vehicle.
Surface
Counterion
Shear plan
b-
c-
a-











     -
-
a
   b
 





  
 c
Tightly
bound
layer
Diffusion
layer
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d-
 - 
 
 - 
 d
Electro-neutral
region
 In the above figure, the particle is positively charged and the anions
present in the surrounding vehicle are attracted to the positively
charged particle by electric forces that also serve to repel the approach
of any cations. The ions that gave the particle its charge, cations in
this example, are called potential-determining ions. Immediately
adjacent to the surface of the particle is a layer of tightly bound
solvent molecules, together with some ions oppositely charged to the
potential-determining ions, anions in this example. These ions,
oppositely charged to the potential-determining ions, are called
counterions or gegenions. These two layers of ions at the interface
constitute a double layer of electric charge. The intensity of the
electric force decreases with distance from the surface of the particle.
Thus, the distribution of ions is uniform at this region and a zone of
electrolneutrality is achieved.
E-Nernst and zeta potential The difference in electric potential between the actual surface of the
particle and the electroneutral region is referred to as Nernst potential.
Thus, Nernst potential is controlled by the electrical potential at the
surface of the particle due to the potential determining ions. Nernst
potential has little effect in the formulation of stable suspension.
 The potential difference between the ions in the tightly bound layer
and the electroneutral region, referred to as zeta potential (see the
figure), has significant effect in the formulation of stable suspension.
Zeta potential governs the degree of repulsion between adjacent,
similar charged, solid dispersed particles.
 If the zeta potential is reduced below a critical value, the force of
attraction between particles succeed the force of repulsion, and the
particles come together. This phenomenon is referred to as
flocculation and the loosely packed particles are called floccule.
F-Deflocculation and flocculation:
 Deflocculation of particles is obtained when the zeta potential is
higher than the critical value and the repulsive forces supersede the
attractive forces.
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 The addition of a small amount of electrolyte reduces the zeta
potential. When this zeta potential goes below the critical value, the
attractive forces supersede the repulsive forces and flocculation
occurs.
 The following table illustrates the relative properties of flocculated
and Non-flocculated suspension
Flocculated
Non-flocculated
1. Particles forms loose aggregates
and form a network like structure
2. Rate of sedimentation is high
3. Sediment is rapidly formed
4. Sediment is loosely packed and
doesn’t form a hard cake
5. Sediment is easy to redisperse
6. Suspension is not pleasing in
appearance
7. The floccules stick to the sides of
the bottle
1.
2.
3.
4.
Particles exist as separate entities
Rate of sedimentation is slow
Sediment is slowly formed
Sediment is very closely packed and a
hard cake is formed
5. Sediment is difficult to redisperse
6. Suspension is pleasing in appearance
7. They don’t stick to the sides of the
bottle
 It should be noted that the deflocculated suspensions should be
avoided because of the formation of irreversible solid hard cake.
Although flocculated suspensions sediment faster and form a clear
supernatant, these are easy to redisperse.
 The following figure shows the effect of period of standing on
flocculated and deflocculated suspension:
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G-Thixotropic suspension-A thixotropic suspension is the one that is
viscous during storage but loses consistency and become fluid upon shaking.
A well-formulated thixotropic suspension would remain fluid long enough
for the easy dispense of a dose but would slowly regain its original viscosity
within a short time.
Method of preparation
The preparation of suspension includes three methods: (1) use of controlled
flocculation and (2) use of structured vehicle (3)- combination of both of the
two pervious methods. The following is the general guidelines to suspension
formulation:
Particles
Addition of wetting agent and dispersion medium
Uniform dispersion of deflocculated particles
A
Incorporation of
structured vehicle
B
C
Addition of
flocculating agent
Flocculated suspension
as final product
Deflocculated suspension
in structured vehicle
as final product
Addition of
flocculating agent
Flocculated suspension
Incorporation of
structured vehicle
Flocculated suspension
in structured vehicle as
final product
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A-Structured vehicle
 Structured vehicles called also thickening or suspending agents. They
are aqueous solutions of natural and synthetic gums. These are used to
increase the viscosity of the suspension.
 Methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl
cellulose, acacia, gelatin and tragacanth are the most commonly used
structured vehicle in the pharmaceutical suspensions. These are nontoxic, pharmacologically inert, and compatible with a wide range of
active and inactive ingredients.
 These structured vehicles entrapped the particle and reduces the
sedimentation of particles. Although, these structured vehicles
reduces the sedimentation of particles, not necessarily completely
eliminate the particle settling. Thus, the use of deflocculated particles
in a structure vehicle may form solid hard cake upon long storage.
 The risk of caking may be eliminated by forming flocculated particles
in a structured vehicle.
 Note that too high viscosity isn’t desirable and it causes difficulty in
pouring and administration. Also, it may affect drug absorption since
they adsorb on the surface of particle and suppress the dissolution
rate.
 Structured vehicles are pseudoplastic or plastic in their rheological
behaviors
 In the following table is summary of suspending agents
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Table summary of suspending agent
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B-Controlled flocculation
 Controlled flocculation of particles is obtained by adding flocculating
agents, which are (1)-electrolytes (2)- surfactants (3)- polymers
Typical Flocculation agents
1-Addition of electrolyte to control flocculation
 Most frequently used flocculating agents are electrolytes, which
reduce the zeta potential surrounding the solid particles. This leads to
decrease in repulsion potential and makes the particle come together
to from loosely arrange structure (floccules).
 The flocculating power increases with the valency of the ions. As for
example, calcium ions are more powerful than sodium ions because
the velency of calcium is two whereas sodium has valency of one.
 The following figure shows the flocculation of a bismuth subnitrate
suspension by means of monobasic potassium phosphate (flocculating
agents).
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The particles of bismuth subnitrate are positively charged originally. By
addition of electrolyte (phosphate, -ve) the zeta potential fell down near zero.
At this neutralization value noted absence of caking. Continuing adding of
negatively charged electrolyte resulted in changing the overall zeta potential of
particles to negative and formation of cake.
2-Addition of surfactant to control flocculation
 Both ionic and non-ionic surfactants could be used to control
flocculation
 Surfactant adsorbed on the surface of solid particle leading to
neutralization or reversing the surface charge
 Since most of surfactants act as wetting agents and flocculating
agents, the amount of surfactant to be added should be calculated
based on this fact.
Example of surfactant used as flocculating agents
3- Addition of polymers to control flocculation
 Polymers are long-chained, high molecular-weight compounds
containing active groups spaced along their length.
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 These agents promote flocculation through adsorption of part of the
chain on the surface of particle and the remaining part project out into
the dispersion medium. Formation of bridge between the projected
parts leads to formation of floccules (see the following figure)
Projection out into
dispersion medium
Adsorption on the
surface of particles
Solid particle
Solid particle
Formation of bridge between particles
 Hydrophilic polymers also act as protective colloids resulting in
coated particles have fewer tendencies to form cake.
 Polymers exhibits pseudoplastic flow in solution that promotes the
physical stability of suspension
 Some polymers like gelatin stabilize the suspension based on the pH
and ionic strength of dispersion medium (carry charge)
 An example of polymer is xanthan gum
 Positively charged Liposomes (vesicles of phospholipids) adsorbed on
negatively charged particles to prevent caking formation.
B- Flocculation in structured vehicles
 Sometimes suspending agents can be added to flocculated suspension
to retard sedimentation
 Examples of these agents are Carboxymethylcellulose (CMC),
Carbopol 934, Veegum, and bentonite
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 It should be noted that physical incompatibility can limit the addition
of suspending agent
Most of hydrophilic colloids are negatively charged
Positively charged
particles
_
Negatively charged
particles

Addition of
electrolyte
- - - -
_
_
-

- - _
+
Addition of
suspending
agent
+
-+
_
+
+
_ +
_
Compatible
+
_
-
_
+
+
+ _
_
Incompatible
Particle settle rapidly
 Under this circumstance, the formulator can protect particle by
changing sign of particle from negative to positive using protective
colloids. This is illustrated by the following figure:
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Ready to use suspension and extemporaneous preparation
 Ready to use suspension is manufactured as you learn in this class
 Extemporaneous suspension is unordinary preparation that pharmacist
wants to prepare to a water-insoluble drug that exists in tablet or
capsule for situations when liquid dosage from is needed. The
following steps could be done to prepare extemporaneous suspension:
1.
2.
3.
4.
Put the tablet or capsule content in mortar and crush it
Add the suspending vehicle slowly with mixing
You could add any flavoring agent or coloring agent available
Example of ready available suspending agents are Roxanes diluent
and Cologel
Evaluation of suspensions
Suspensions are evaluated by determining their physical stability. Two
useful parameters for the evaluation of suspensions are sedimentation
volume and degree of flocculation. The determination of sedimentation
volume provides a qualitative means of evaluation. A quantitative
knowledge is obtained by determining the degree of flocculation.
1. Sedimentation volume: (F), sedimentation volume of a suspension is
expressed by the ratio of the equilibrium volume of the sediment, Vu, to
the total volume, Vo of the suspension.
F = Vu/Vo
The value of F normally lies between 0 to 1 for any pharmaceutical
suspension. The value of F provides a qualitative knowledge about the
physical stability of the suspension.
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F= 1
F =0.5
F>1
No sedimentation, no clear
supernatant
50% of the total volume is occupied
by sediment
Sediment volume is greater than the
original volume due to formation of
floccules which are fluffy and loose
2. Degree of flocculation: (ß), degree of flocculation is the ratio of the
sedimentation volume of the flocculated suspension, F, to the
sedimentation volume of the deflocculated suspension, F
ß = F / F
(Vu/Vo) flocculated
ß = -------------------(Vu/Vo) deflocculated
When the total volume of both the flocculated and the deflocculated
suspensions are same; the degree of flocculation, ß = (Vu)floc/(Vu)defloc .The
minimum value of ß is 1; this is the case when the sedimentation volume of
the flocculated suspension is equal to the sedimentation volume of
deflocculated suspension. ß is more fundamental parameter than F since it
relates the volume of flocculated sediment to that in a deflocculated system
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Rheological consideration: viscosity of suspension affects and controls the
settling of dispersed particle. It, also, affects pouring the product from bottle
and spreading qualities in case of lotion. Best viscosity for suspension is to
be high during storage to prevent sedimentation and to be low at high shear
to ease the administration. Thus, pseudoplastic/ thixotrpic and plastic/
thixotropic suspending agents could be use for this purpose. Combination of
two suspending agents can enhance the stability of suspension
Ingredients of suspension:
1.
2.
3.
4.
5.
6.
Active ingredient
Wetting agent
Suspending agent
Flocculated agent
Protective colloid
Sweetener
7. Preservative
8. Buffer system
9. Color agent
10.Flavor agent
11.Antifoaming agent
12.Preservative
Typical buffering agents, flavors, colorants, and preservative used in
suspensions:
Class
Agent
Buffer
Ammonia solution
Citric acid
Fumaric acid
Sodium citrate
Flavor
Cherry
Grape
Methyl salicylatte
Orange
Peppermint
Colorant
D &C Red No. 33
FD &C Red No. 3
D &C Yellow No. 33
Preservative
Butylparaben
Methylparaben
Propylparaben
Sodium benzoate
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Packaging and Storage of Suspensions:
1) Should be packaged in wide mouth containers having adequate air space
above the liquid.
2) Should be stored in tight containers protected from: freezing, excessive
heat & light
3) Label: "Shake Before Use" to ensure uniform distribution of solid
particles and thereby uniform and proper dosage.
4) Stored in room temperature if it is dry powder (25 0C). It should be stored
in the refrigerator after opening or reconstitute (freezing should be avoided
to prevent aggregation)
Stability of suspension
A-Physical stability:
1. Appearance, color, odor and taste
2. pH
3. Specific gravity
4. Sedimentation arte
5. Sedimentation volume
6. Zeta potential measurement
7. Compatibility with container
8. Compatibility with cap liner
9. Microscopic examination
10.Determination crystal size
11.Determination uniform drug distribution
B-Chemical stability:
1. Degradation of active ingredient
2. Viscosity change
3. antimicrobial activity:
a. Incompatibility with preservative
b. Degradation of preservative
c. Adsorption of preservative onto drug particle
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