Suspensions

1
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

2
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

3
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

4
Ophthalmics

• used to increase corneal contact time (provide a
  more sustained action)

5
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

6
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

7
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
• specific to lotions
• spreads over surface but doesnt 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

8
Settling
Fbuoyancy
Ffriction
9
Settling Contd

• eventually Ff Fb and reach terminal velocity
• Stokes Law
• 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

• How fast will a 50 mm particle of density 1.3
  g/cm3 settle in water (h 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?

11
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

12
Interfacial Phenomena

• flocculation or caking
• determined by forces of attraction (van der
  Waals) versus forces of repulsion (electrostatic)
• deflocculated
• repulsiongt attraction
• affected by electrolytes
• flocculated
• attraction gt repulsion

13
Electrical Properties

• particles may become charged by
• adsorption of ionic species present in soln or
  preferential adsorption of OH-
• ionization of -COOH or -NH2 group

-

-

-

-

-

hydroxyl ion
-
solid
14
Electric Double Layer
tightly bound
diffuse

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-


-


-
electroneutral bulk


-
-
-


-



-


-
-

-
-
-


gegenion
zeta potential
Nernst potential
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Electrical Props contd

• 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

16
DLVO Theory
repulsion

total potential energy of interaction
0
distance between particles
-
attraction
17
repulsion

total potential energy of interaction
0
distance between particles
-
electrolyte?
attraction
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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

19
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

20
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.

21
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

22
Thixotropy

• slow recovery of viscosity lost through shearing
• applies only to shear thinning materials
• gel-sol-gel transformation (hysteresis)
• thixotropy is desirable because
• gel state resists particle settling
• becomes fluid on shaking and then readily
  dispensed

stress, s
shear rate
23
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

24
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

25
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

26
Controlled Flocculation

• polymers
• adsorb to particle surface
• bridging
• viscosity, thixotropy
• protective colloid action
• most effective

27
Structured Vehicles

• pseudoplastic or plastic dispersion medium
• examples
• methylcellulose, bentonite
• negatively charged
• increase viscosity

28
Combined Approach

• possibility of incompatibilities of suspending
  agent and flocculating agent
• structured vehicles have negative charge
• incompatible if particle carries a negative
  charge

29
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

31
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
• allow suspension stored in fridge to come to room
  T before redispersing
• dont dilute
• reduces palatability, effectiveness of
  flocculating suspending agents
• change in pH (stability)
• manufacturer will no longer accept legal
  responsibility for consequences