Introduction Wetting phenomenon, Particle‐particle interactions, DLVO theory, Flocculated and deflocculated systems, Schulze Hardy rule, Sedimentation process, Ostwald ripening and crystal factors

1. Biphasic
Systems:
Suspension
Mr. Mirza Salman Baig
Assistant Professor (Pharmaceutics)
AIKTC, School of Pharmacy, New Panvel
Affiliated to University of Mumbai (INDIA)

2. Content
• Introduction
• Wetting phenomenon,
• Particle‐particle interactions,
• DLVO theory,
• Flocculated and deflocculated systems,
• Schulze Hardy rule,
• Sedimentation process,
• Ostwald ripening and crystal factors

3. Definition
• Suspension is heterogeneous system and Suspension is
biphasic liquid dosage form.
• Dispersion medium is liquid and dispersion medium is solid
(suspension)
3

4. Features desired in Pharmaceutical Suspension
• Particles should settle slowly and should be readily
re-dispersed upon shaking of the container.
• The particle size of the suspensoid should remain
fairly constant throughout long periods of
undisturbed standing.
• The suspension should pour readily and evenly
from its container.
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5. Applications of suspensions
• Drugs which degrade in aqueous solution may be suspended in a
non-aqueous phase. eg. Tetracycline hydrochloride is suspended
in a fractionated coconut oil for ophthalmic use.
• Lotions containing insoluble solids are formulated to leave a thin
coating of medicament on the skin. As the vehicle evaporates, it
gives a cooling effect and leaves the solid behind.eg calamine
lotion and sulphur lotion compound.
• Bulky, insoluble powders can be formulated as a suspension so
that they are easier to take eg Kaolin or chalk.
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6. Advantages of suspensions
• Suspension can improve chemical stability of certain drug. E.g.
Procaine penicillin G
• Drug in suspension exhibits higher rate of bioavailability than
other dosage forms. bioavailability is in following order,
•
Solution > Suspension > Capsule > Compressed Tablet > Coated
tablet
• Duration and onset of action can be controlled. E.g. Protamine
Zinc-Insulin suspension
• Suspension can mask the unpleasant/ bitter taste of drug. E.g.
Chloramphenicol palmitate
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7. Disadvantages of suspension
• Physical stability, sedimentation and compaction can causes
problems.
• It is bulky, therefore sufficient care must be taken during
handling and transport.
• It is difficult to formulate
• Uniform and accurate dose can not be achieved unless
suspension are packed in unit dosage form
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8. Diffusible / in diffusible solid
1.DIFFUSIBLE SOLIDS– these sediment sufficiently slowly to enable
satisfactory dose removal after redispersion. eg. Light kaoline,
magnesium tricilicate
2.INDIFFUSIBLE SOLIDS- eg. sulphadimidine and chalk. These sediment
too rapidly and require the addition of other materials to reduce
sedimentation rate to an acceptable level.
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9. Wetting phenomenon
• Force of attraction between solid and liquid play important role
• Angle of contact range (0° to 180 °)

10. Wetting phenomenon
• Contact angle is the angle between liquid droplet and surface over which it
spreads.
• Important action of wetting is to reduce angle of contact

11. Wetting phenomenon
Two types of solids
Lyophilic (wetting)
• Not sensitive to electrolytes in
medium
• Readily wettable
Lyophobic (non-wetting)
• Sensitive to electrolytes in
medium
• No aggregation
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12. Steps of wetting
• Adhesional Wetting
• Immersional
• Spreading
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13. Strategies for wetting of hydrophobic solids
• Surfactant
• Hydrophilic polymers
• Water insoluble hydrophilic material (bentonite)
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14. Methods to evaluate wetting property of
wetting agent
• Wet point method
• Amount of vehicle needed to just wet given amount of solid powder
• Flow point method
• Amount of liquid needed to produce pourability
• Unit (mL/100gm)
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15. Methods to evaluate wetting property of
wetting agent
• Low wet point and low flow point
• Also, small difference between wet point and flow point
• This indicate good dispersion of solid particles in liquid medium.
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16. 16

17. Particle-particle interactions
(Zeta Potential)
Zeta potential is defined as the
difference in potential between the
surface of the tightly bound layer
(shear plane) and electroneutral
region of the solution.
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18. Particle-particle interactions
• Thus electrostatic repulsion set up between adjacent particles
preventing them from adhering to one another.
• Accordingly deflocculation occurs.
• Solvation of particle surfaces also helps to prevent particles
coming together (Physical Barrier)
• Flocculation and deflocculation mechanism dependent on
the presence of surface electrical charges and the distribution
of ions around the particles
18

19. • At high electrolyte conc → Attractive force
predominate and cause coagulation
• At low electrolyte conc → Repulsive force
predominate
Particle-particle interactions
(Attractive forces vs Repulsive forces)
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20. Particle-particle
interactions
• Interparticle forces
• Electric double layer
• Nerst Potential/Zeta Potential
• DLVO Theory
• Schulze Hardy rule

21. Interparticle forces
• Van der Waals attractive forces
• Electrostatic repulsive force → Overlapping of diffusion layer.
• Repulsive forces due to hydration → Structuring of water at interface
(Physical barrier)
• Steric repulsive force → Because of adsorbent (Physical barrier)
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22. Electric double layer
• Regardless of the specific mechanism, the particles will bear either
positive or negative charges.
• Source of the charge on particle may arise from
- ionizable groups on the surfaces or
- adsorption of ions from the surrounding solution

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Electric double layer
• Consider solid surface in contact with solution of electrolyte containing ions
• Some cations (+) adsorb on solid surface
• Adsorb ions that give charge to surface aa' (in this case cations +) known as
potential determining ions.
• Anions attracted to positive charge by electrical force of attraction known as
counter ions or gegenions .
• Shear plane is bb' rather than aa' because of tightly bound layer (next figure)
• First layer is aa' to bb'
• Second layer is bb' to cc'... more negative charge is present in this layer in this
case.

24. 2424
Electric double layer

25. 2020/9/19
Nerst potential
• It is defined as potential difference between actual surface and
electro neutral region
• Potential at solid surface aa’ (above figure) due to potential
determining ions is known as Nerst potential

26. 2020/9/19
Zeta potential
• The zeta potential is defined as the difference in potential between
the surface of the tightly bound layer bb’ (shear plane) and electro-
neutral region of the solution.
• Zeta potential has practical application in the stability of systems
containing dispersed particles .

27. 2727
• If the zeta potential is reduced below a certain value, the attractive
forces exceed the repulsive forces, and the particles come together.
This phenomenon is known as flocculation
• The flocculated suspension is one in which zeta potential of particle
is -20 to +20 mV
• Thus the phenomenon of flocculation and deflocculation depends
on zeta potential carried by particles.
Zeta potential

28. 2020/9/19
• At low electrolyte conc → Repulsive
force predominate
• At high electrolyte conc → Repulsive
force reduce and cause coagulation
Effect of electrolytes

29. 2020/9/19
DLVO theory
• DLVO theory was developed in the 1940s and named after the
• Russian scientists
• B. Derjaguin
• L. Landau,
• Dutch scientists
• E. Verwey
• J. Overbeek

30. DLVO Theory
• It proposed that an energy barrier resulting from the electrostatic
repulsive force prevents two particles approaching one another and
adhering together.
• If the particles collide with sufficient energy to overcome the barrier, the
Van der Waals attractive force will attract them strongly and cause
them adhere together irreversibly.
• If the particles repel each other strongly, the dispersion will resist
coagulation and the dispersed system will be stable.
• If the repulsion is not sufficient then coagulation will take place.

31. DLVO theory: Flocculation curve/Secondary minimum
Force of
repulsion
Force of
attraction
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32. Inter-particular forces
• Attractive → Van der Waals/London force

33. Factors affecting repulsion between particles
which influences hydration of particles
• Electric (diffuse) double layer and its thickness
• Ionic strength (ionic concentration)
• Valency, size of ion on surface and in electric double layer
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34. Swamping
• Increase in ionic strength (concentration of electrolytes) decreases
thickness of electric double layer .. This effect is known as swamping
• Swamping encourage aggregation
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35. Schulze Hardy rule
• Specific adsorption of ion on solid neutralize surface charge and
allow aggregation
• Concentration of ion need to attain optimum aggregation of particles
depend upon type of interacting ion.
• Addition of more concentration beyond limit causes reversal of
charge → aggregation→ causes caking
• This effect is explained by ‘Schulze Hardy rule’

36. Schulze Hardy Rule
• Statement "valency of ion having charge opposit to that of
hydrophobic particle appears to determine the effectiveness
of the electrolyte in aggregating the particle"
• Aggregating value of ion increase with valency of ion
• Al+++ >> Fe++ >> Na+
• 1000 >>> 10 >> 1
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37. Schulze Hardy Rule
• This rule is valid only for system in which there is no interaction
between electrolyte and ion of double layer of particle surface.
• Influence of valency of ion on aggregation of lyophobic particle can
be correlated to → Zeta potential and Sedimentation volume
• Hofmeister of lyotropic rule apply to hydrophilic particle
37

38. Flocculation and
Sedimentation
Deflocculated vs Flocculated Suspension
Sedimentation volume (F)
Controlled Flocculation
Physical stability of suspensions
Oswald ripening & crystal factors

39. Classification of suspensions
• Based On General Classes
Oral suspension
Externally applied suspension
Parenteral suspension
• Based On Proportion Of Solid Particles
Dilute suspension (2 to10%w/v solid)
Concentrated suspension (50%w/v solid)
• Based On Electrokinetic Nature Of Solid Particles
Flocculated suspension
Deflocculated suspension
• Based On Size Of Solid Particles
Colloidal suspension (< 1 micron)
Coarse suspension (>1 micron)
Nano suspension (10 ng)
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40. Deflocculated vs Flocculated Suspension
40

41. Types of suspension aggregates
Open Network
aggregate Close network aggregate
Deflocculated 41

42. 42
• In flocculated suspension, formed flocs (loose
aggregates) will cause increase in sedimentation rate
due to increase in size of sedimenting particles.
• Hence, flocculated suspensions sediment more
rapidly.
• Here, the sedimentation depends not only on the
size of the flocs but also on the porosity of flocs.
Flocculated Suspensions

43. Deflocculated suspensions
• In deflocculated suspension, individual particles
are settling.
• Rate of sedimentation is slow , which prevents
entrapping of liquid medium which makes it
difficult to re-disperse by agitation.
• This phenomenon called ‘caking’
• In deflocculated suspension larger particles settle
fast and smaller remain in supernatant liquid so
supernatant appears cloudy.
4343

44. Sedimentation
• This is a phenomenon which occurs in dispersed system where the
dispersed particles settle to the bottom of the container because of
gravitational force.
• This occurs because the particles are too large to remain
permanently suspended in the vehicle.
• Therefore suitable suspending agents are added to retard this
process.
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45. Velocity of sedimentation
(Stoke’s Law of sedimentation)
V = D2 (ρ1-ρ2)/18η
• V= Velocity of sedimentation
• D= Diameter of particle
• ρ1 and ρ2 =Density of particle and liquid
• η = viscosity of liquid
• Pharmaceutical suspension containing less than 2% (w/v) of solid follow
Stoke’s Law.
• If solid content increase viscosity increases
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46. Sedimentation Volume (F)
• Sedimentation volume is ratio of
ultimate height (height at time t) of
sediment to total height of suspension
when sedimentation occur in standard
condition
• F=Hu/Ho
• Higher value is desirable
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47. 47
The sedimentation volume is used to measure flocculation

48. F has values ranging from less than one to greater than one.
When F < 1 Vu < Vo
When F =1 Vu = Vo
The system (F =1) is said to be in flocculation equilibrium and
show no clear supernatant on standing.
When F > 1 Vu > Vo
Sediment volume is greater than the original volume due to the
network of flocs formed in the suspension and so loose and fluffy
sediment and extra vehicle is needed (added) to contain sediment

49. 49
Degree of flocculation (β)
"It is the ratio of the sedimentation volume of the flocculated
suspension ,F , to the sedimentation volume of the
deflocculated suspension, F∞ "
β = F / F∞
(Vu/Vo) flocculated
β = --------------------
(V∞/Vo) deflocculated
Vu
β = ------
V∞
The value of β is 1,when
flocculated suspension’s
sedimentation volume is
equal to the sedimentation
volume of deflocculated
suspension.

50. Need of Controlled Flocculation
• Assume powder is properly wetted and dispersed
• In order to prevent compact sediment (hard cake) we need
controlled flocculation

51. Controlled Flocculation
Controlled Flocculation can be achieved through following methods
• Effect of Electrolytes (ionic substance): It act as flocculating agents by
reducing electrical barrier between particles... by decresing zeta
potential and forming bridge between adjacent particles
• Effect of Surfactant
• Effect of Polymer

52. • At low electrolyte conc --Repulsive
force predominate
• At high electrolyte conc --
Repulsive force reduce and cause
coagulation
Effect of electrolytes

53. Effect of electrolytes
(Bismuth subnitrate suspension)
• Bismuth sub nitrate particles posses
+ve charge
• If we add monobasic potassium
phosphate (KH2PO4) then positive zeta
potential decrease to zero because of
adsorption of -ve phosphate ions then
increase in negative direction
• At certain +ve zeta potential, maximum
flocculation occur
• Onset of flocculation coincide with
maximum sedimentation volume
• When zeta potential become
sufficiently -ve repeptization
(deflocculation) occur once again and
sedimentation volume(F) falls

54. Effect of Surfactant
• Concentration of (cationic/anionic) surfactant as flocculating agent is
critical because--
• Act as wetting and deflocculating agent
• Surfactant improve dispersion by reducing surface tension
• Ionic surfactant (SLS) sometime cause flocculation

55. Effect of Polymers
• Hydrophilic polymer act as
protective colloids
• Act as flocculating agent
• Chain of polymer adsorb on
multiple particles
• Ex. Xanthan gum increase
sedimentation volume by
polymer-bridging phenomenon
for bismuth sub-carbonate
Fig. Dissolution and crystallization of drug in presence of polymer

56. Physical stability of suspensions
• Raising temperature leads to flocculation of sterically stabilized (by
non-ionic surfactant) suspension
• Repulsion force depend upon amount of surfactant adsorbed on
particles
• On heating, energy of repulsion reduces because of dehydration of
surfactant, attraction increases and particles flocculate

57. Physical stability of suspensions
• During freezing processes particle overcome repulsive barrier due to
ice formation.
• Particles come close enough and experience attractive force like in
primary minimum and form aggregates as per DLVO theory
• When ice melts, particles remain as aggregates unless work is applied
to overcome the primary energy peak
• Aggregate size is directly proportional to rate of freezing

58. Particle size distribution representation (example)

59. Oswald Ripening
• Solubility of large crystal is less than that of smaller crystals
• It is because of more surface energy per unit mass on smaller
crystals.
• Smaller crystals are in a state of unstable equilibrium in a
supersaturated solution.
• As a result larger crystals grow on expense of the small crystals
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60. What is Ostwald ripening?
• This is a spontaneous process that occurs because larger crystals are
more energetically (thermodynamically) favored than smaller
crystals.
• Large crystals, have lower energy state.
• While the formation of many small crystals is kinetically favored.
• Small crystals have a larger specific surface area (surface area to
volume ratio)
• Thus, many small crystals will attain a lower energy state by getting
transformed into large crystals and this is Ostwald ripening.
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61. Ostwald ripening and crystal factors
• Fluctuation changes particle size
distribution in suspension.
• Particle growth is common if
solubility is temperature dependent.
• When temperature is high, small
particles dissolve to form saturated
solution.
• When temperature decreases, solute
deposit on large crystals hence →
crystal size increases for large size
crystals

62. Ostwald ripening and crystal factors
• Oswald ripening can be reduced by adding polymer or surfactant
• Polymer (PVP) segment adsorb on drug (e.g. acetaminophen)
• Hydration sheath present around polymer molecule
• Polymer inhibit approach of drug molecule from solution to crystal
surface for deposition
• High molecular wt. polymer (PVA) are more effective because of firm
adsorption on particle surface

63. Crystal structure factors
• No change in crystal habit (physical shape)
• Drug decomposition & Salting out
• pH change & change in particle size distribution
• Effect of temperature
• Change in crystal habit
• Solvation
• polymorphism
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64. Effect of excipients on suspension stability
• Flocculation by sorbitol depend cloud point, thus lower the cloud point
less sorbitol needed to induce flocculation (cloud point can be lowered
by methyl paraben)
• (Cloud point is the temperature above which an aqueous solution of a
water-soluble surfactant becomes turbid)
• If low cloud point surfactant (low solubility) is used then less amount of
sorbitol is needed to induce flocculation
• Stability of suspension decrease because of interaction with excipients,
(preservative adsorption on particle)
• Amount of preservative (Benzalkonium Cl ) can change zeta potential

65. Rheology
• Viscosity is a measure of a fluid's resistance to flow.
• It describes the internal friction of a moving fluid.
• A fluid with large viscosity resists motion because its molecular
makeup gives it a lot of internal friction.
• A fluid with low viscosity flows easily because its molecular makeup
results in very little friction when it is in motion.
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66. Rheograms
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67. Rheology
Desirable
• Thixotrophy is a phenomenon or property exhibited by highly
floculated preparation in which a preparation is sem-solid at rest
(in the absence of shearing forces) but becomes fluid when
tapped or shaken and resumes its original structure after only a
few minutes of rest.
• A thixotropic suspension is the one which 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.
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68. Rheology
Undesirable
• Pseudo plastic (shear thinning with no yield value)
• Dilatant
• Rheopexy (viscosity increases with time)
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69. Rheology method
• To study structure achieved on
storage
• T-bar spindle with helipath
• T-bar continually descend to study
undisturbed sample
• Dial reading vs no. of turns of
spindle
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70. Preparation of suspension
• Dispersion
• Precipitation
70