Suspensions rheology by mikeholy


• 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
• 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

B. Amsden                     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

B. Amsden                      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%

B. Amsden                      CHEE 440
used to increase corneal contact time (provide a more sustained

B. Amsden                     CHEE 440
• 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

B. Amsden                     CHEE 440
• uniformity and accuracy of dose - not as good as tablet or
     adequate particle dispersion
• sedimentation, cake formation
• product is liquid and bulky
• formulation of an effective suspension is more difficult than for
  tablet or capsule

B. Amsden                       CHEE 440
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

B. Amsden                      CHEE 440

                   4 3
            Fb      ro gs  o 

            Ff  6ro o v


B. Amsden                              CHEE 440
Settling Cont’d
eventually Ff = Fb and reach terminal velocity
Stokes’ Law

v = terminal velocity (cm/s)
                                                d 2 s  o g
d = diameter (cm)                            v
s = density of dispersed phase                      18o
o = density of continuous phase
o = viscosity of continuous phase (Pa s)

B. Amsden                         CHEE 440
How 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?

B. Amsden                      CHEE 440
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

B. Amsden                     CHEE 440
Interfacial Phenomena
flocculation or caking
     determined by forces of attraction (van der Waals)
      versus forces of repulsion (electrostatic)
     repulsion> attraction
     affected by [electrolytes]
     attraction > repulsion

B. Amsden                CHEE 440
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

B. Amsden                         CHEE 440
Electric Double Layer

            tightly       diffuse

            +   -    +   -
            +   -          +              - -    +
            +   -     -             +                electroneutral
                -           +
            +   -    + +            -      +   +
                                             - +
            +   -      +   -         -


                          zeta potential

                        Nernst potential
B. Amsden                      CHEE 440
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
    governs electrostatic force of repulsion between solid

B. Amsden                     CHEE 440
total potential energy of interaction   DLVO Theory


                                           -                           particles

                                        B. Amsden           CHEE 440
total potential energy of interaction   DLVO Theory


                                           -                                 particles

                                        B. Amsden              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

B. Amsden                CHEE 440
   Flocculated Condition
• weakly bonded to form fluffy conglomerates
• 3-D structure (gel-like)
• settle rapidly but will not form a cake - resist close-
• easily re-suspended
• forms a clear supernatant

B. Amsden                  CHEE 440
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.

B. Amsden                     CHEE 440
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

B. Amsden                          CHEE 440
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

B. Amsden                      CHEE 440
other considerations :
    increasing viscosity decreases rate of drug
    extent of absorption is unaffected, but may reduce
     effectiveness of drugs with a low therapeutic

B. Amsden                CHEE 440
   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

B. Amsden                        CHEE 440
Controlled Flocculation
     most widely used
     reduce zeta potential
         • decrease force of repulsion
     change pH
     bridge formation
     reduction in zeta potential
     form adsorbed monolayers on particle surface
     efficacy is dependent on charge, concentration

B. Amsden                     CHEE 440
Controlled Flocculation
    adsorb to particle surface
    bridging
    viscosity, thixotropy
    protective colloid action
    most effective

B. Amsden                CHEE 440
Structured Vehicles
• pseudoplastic or plastic dispersion medium
• examples
     methylcellulose, bentonite
• negatively charged
• increase viscosity

B. Amsden                CHEE 440
Combined Approach
possibility of incompatibilities of suspending agent and
flocculating agent
     structured vehicles have negative charge
     incompatible if particle carries a negative charge

B. Amsden                 CHEE 440
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

B. Amsden                     CHEE 440
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
other parameters :
    redispersibility, particle size, zeta potential,

B. Amsden                 CHEE 440
Other Considerations
    raising T often causes flocculation of sterically stabilised
    freezing may result in cake formation
    fluctuations in T may cause crystal growth

B. Amsden                      CHEE 440

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