Download Suspensions - Chemical Engineering

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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CHEE 440
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
 antacids, tetracycline HCl, indomethacin
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CHEE 440
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 :
 calamine lotion (8% ZnO, 8% ZnOFeO)
 hydrocortisone 1 - 2.5 %
 betamethasone 0.1%
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Ophthalmics
used to increase corneal contact time (provide a more sustained
action)
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Intramuscular
• formation of drug depots (sustained action)
examples :
 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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CHEE 440
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
1. slow settling and readily dispersed when shaken
2. constant particle size throughout long periods of standing
3. pours readily and easily OR flows easily through a needle
specific to lotions :
1. spreads over surface but doesn’t run off
2. dry quickly, remain on skin, provide an elastic protective film
containing the drug
3. acceptable odor and color
common : therapeutic efficacy, chemical stability, esthetic appeal
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CHEE 440
Settling
eventually Ff = Fb and reach terminal velocity
Stokes’ Law
d 2 (rs - ro )g
v=
18ho
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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4 3
F
=
Fbuoyancy b 3 pro g(rs - ro )
CHEE 440
Ffriction
Ff = 6pro ho v
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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CHEE 440
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
 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 OH ionization of -COOH or -NH2 group
+
+
+
+
+
+
- hydroxyl ion
solid
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Electric Double Layer
tightly
bound
+
+ +
+ +
+ -
diffuse
- - +
- + +
+
+
+ - + - + +
zeta potential
Nernst potential
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+
+
electroneutral
bulk
Electrical Prop’s cont’d
Nernst potential
 potential difference between the actual solid surface and the
electroneutral bulk
Zeta potential
 potential difference between the tightly bound layer and the
bulk
 governs electrostatic force of repulsion between solid
particles
Debye-Huckel length:
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æ
ee RT
=ç 2 o
k ç F å ci Zi
è
1
(
CHEE 440
)
ö
÷
÷
ø
1
2
total potential energy of interaction
DLVO Theory
repulsion
+
0
VT = VA +VR
-
VA = -
attraction
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Aa
12H
VR = 2p aeeoyo2 exp (-k H )
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Distance (H)
between
particles
total potential energy of interaction
DLVO Theory
repulsion
+
0
distance
between
particles
attraction
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[electrolyte]
CHEE 440
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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CHEE 440
Flocculated Condition
• weakly bonded to form fluffy conglomerates
• 3-D structure (gel-like)
• settle rapidly but will not form a cake - resist closepacking
• easily re-suspended
• forms a clear supernatant
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Gels
2-phase gels
 ex. bentonite (hydrated aluminum silicate)
single phase gels
 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)
stress, s
thixotropy is desirable because :
 gel state resists particle settling
 becomes fluid on shaking and then readily dispensed
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 :
1. use of a structured vehicle
 caking still a problem
2. flocculation
 no cake formation
less common approach is to combine above
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CHEE 440
Controlled Flocculation
electrolytes
 most widely used
 reduce zeta potential
• decrease force of repulsion
 change pH
 bridge formation
alcohol
 reduction in zeta potential
surfactants
 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 parameters :
 redispersibility, particle size, zeta potential,
rheology
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Other Considerations
temperature
 raising T often causes flocculation of sterically stabilised
suspensions
 freezing may result in cake formation
 fluctuations in T may cause crystal growth
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