Transcript week09.1.suspensions

Suspensions
 coarse
dispersion in which insoluble
solid particles (10-50 µm) are
dispersed in a liquid medium
 routes of administration :

oral, topical (lotions), parenteral
(intramuscular), some ophthalmics
 used
for drugs that are unstable in
solution (ex. antibiotics).
 allow for the development of a liquid
dosage form containing sufficient
drug in a reasonably small volume
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Oral Suspensions
 for
elderly, children etc., liquid drug
form is easier to swallow
 liquid form gives flexibility in dose
range
 majority are aqueous with the
vehicle flavored and sweetened.
 supplies insoluble, distasteful
substance in form that is pleasant to
taste
 examples
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antacids, tetracycline HCl,
indomethacin
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Topical Suspension (Lotions)
 most
often are aqueous
 intended to dry on skin after
application (thin coat of medicianl
component on skin surface)
 label stating “to be shaken before
use” and “for external use only”
 examples :
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calamine lotion (8% ZnO, 8%
ZnOFeO)
hydrocortisone 1 - 2.5 %
betamethasone 0.1%
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Opthalmics
 used
to increase corneal contact time
(provide a more sustained action)
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Intramuscular
 formation
of drug depots (sustained
action)
 examples :
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Procaine penicillin G
Insulin Zinc Suspension
» addition of ZnCl2
» suspended particles consist of a
mixture of crystalline and
amorphous zinc insulin
(intermediate action)
Extended Insulin Zinc Suspension
» solely zinc insulin crystals  longer
action
contraceptive steroids
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Disadvantages
 uniformity
and accuracy of dose not as good as tablet or capsule

adequate particle dispersion
 sedimentation,
cake formation
 product is liquid and bulky
 formulation of an effective
suspension is more difficult than for
tablet or capsule
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Formulation Criteria



slow settling and readily dispersed when
shaken
constant particle size throughout long
periods of standing
pours readily and easily OR flows easily
through a needle
lotions :
 spreads over surface but doesn’t run off
 dry quickly, remain on skin, provide an
elastic protective film containing the drug
 acceptable odor and color
common : therapeutic efficacy, chemical
stability, esthetic appeal
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Settling
4
Fb  ro3gs  o 
3
Fbuoyancy
Ff  6ro o v
Ffriction
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Settling Cont’d
 eventually
Ff = Fb and reach terminal
velocity
 Stokes’ Law
d 2 s  o g
v
18o


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v = terminal velocity (cm/s)
d = diameter (cm)
s = density of dispersed phase
o = density of continuous phase
o = viscosity of continuous phase (Pa s)
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Example
fast will a 50 mm particle of
density 1.3 g/cm3 settle in water ( =
1.0 cP)? How fast will it settle in a 2
w/v% methylcellulose solution of
viscosity = 120 cP? How fast will it
settle if you reduce its particle size to
10 mm?
 How
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Physical Stability
 the
large surface area of dispersed
particles results in high surface free
energy DG = SL DA
 thermodynamically unstable
 can reduce SL by using surfactants
but not often can one reach DG = 0
 particles tend to come together
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Interfacial Phenomena
 flocculation

or caking
determined by forces of attraction
(van der Waals) versus forces of
repulsion (electrostatic)
 deflocculated
repulsion> attraction
 affected by [electrolytes]

 flocculated
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attraction > repulsion
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Electrical Properties
 particles


may become charged by
adsorption of ionic species present in
sol’n or preferential adsorption of OHionization of -COOH or -NH2 group
++++++ - hydroxyl ion
solid
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Electric Double Layer
tightly
bound
diffuse
+- +
++
- - +
+
+- ++ + - + +
+- +
++
+
electroneutral
bulk
gegenion
zeta potential
Nernst potential
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Electrical Prop’s cont’d
 Nernst

potential difference between the actual
solid surface and the electroneutral bulk
 Zeta

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potential
potential
potential difference between the tightly
bound layer and the bulk
governs electrostatic force of repulsion
between solid particles
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DLVO Theory
total potential energy of interaction
repulsion
+
0
distance
between
particles
-
attraction
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total potential energy of interaction
repulsion
+
0
distance
between
particles
-
attraction
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[electrolyte]
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Deflocculated Condition
 repulsion
energy is high
 particles settle slowly
 particles in sediment compressed
over time to form a cake
(aggregation)
 difficult to re-suspend caked
sediment by agitation
 forms a turbid supernatant
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Flocculated Condition
 weakly
bonded to form fluffy
conglomerates
 3-D structure (gel-like)
 settle rapidly but will not form a
cake - resist close-packing
 easily re-suspended
 forms a clear supernatant
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Gels

2-phase gels


single phase gels
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ex. bentonite (hydrated aluminum silicate)
entangled polymer chains in solution
if increase concentration or decrease hydration
of polymer chain, then form a gel
factors influencing gel formation
» temp., concentration, mol. wt.
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Rheology of Suspensions
 flocculated
particles in concentrated
suspensions

exhibit pseudoplastic or plastic flow
» system resists flow until a yield
stress is reached
» below s substance is a solid
 deflocculated
systems exhibit
Newtonian behavior
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Thixotropy
 slow
recovery of viscosity lost
through shearing


applies only to shear thinning materials
gel-sol-gel transformation (hysteresis)
 thixotropy

gel state resists particle settling
becomes fluid on shaking and then
readily dispensed
stress, s

is desirable because :
shear rate
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Viscosity
 other
considerations :
increasing viscosity decreases rate
of drug absorption
 extent of absorption is unaffected,
but may reduce effectiveness of
drugs with a low therapeutic
window

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Formulation of Suspensions
2 common approaches :
 use of a structured vehicle

caking still a problem
 flocculation

no cake formation
less common approach is to combine
above
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Controlled Flocculation
 electrolytes


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most widely used
reduce zeta potential
» decrease force of repulsion
change pH
bridge formation
 alcohol

reduction in zeta potential
 surfactants
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form adsorbed monolayers on particle
surface
efficacy is dependent on charge,
concentration
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Controlled Flocculation
 polymers
adsorb to particle surface
 bridging
 viscosity, thixotropy
 protective colloid action
 most effective

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Structured Vehicles
 pseudoplastic
or plastic
dispersion medium
 examples

methylcellulose, bentonite
 negatively
charged
 increase viscosity
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Combined Approach
 possibility
of incompatibilities
of suspending agent and
flocculating agent
structured vehicles have negative
charge
 incompatible if particle carries a
negative charge
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Preparation of
Suspensions
 reduce
drug powder to desired size
 add drug and wetting agent to
solution
 prepare solution of suspending
agent
 add other ingredients

electrolytes, color, flavor
 homogenize
medium
 package
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Evaluating Suspensions
 two
parameters
sedimentation volume, F = Vu/Vo
» Vu = final sediment volume
» Vo = initial dispersion volume
» want F =1
 degree of flocculation,  = Vu/Vu
» Vufinal sediment volume of
deflocculated suspension

 other
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parameters :
redispersibility, particle size, zeta
potential, rheology
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Other Considerations
 temperature

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raising T often causes flocculation of
sterically stabilised suspensions
freezing may result in cake formation
fluctuations in T may cause crystal
growth
allow suspension stored in fridge to
come to room T before redispersing
 don’t
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dilute
reduces palatability, effectiveness of
flocculating & suspending agents
change in pH (stability)
manufacturer will no longer accept legal
responsibility for consequences
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