Introduction and theories of pharmaceutical dispersion with manufacturing approaches and their stabilities.

1. Theory of Dispersion
Mr. Sachin Aryal
M. Pharm, Pharmaceutics 1st Sem 2019
Subject: Modern Pharmaceutics
Karnataka College Of Pharmacy
Bangalore, India

2. Contents:
• Dispersion system- Suspension
– Introduction
– Types
– Theory of dispersion
– Formulation
– Evaluation
– Stability
• Emulsions
-Emulsification
- Instability

3. Dispersion system: Suspensions
Introduction:
• Consist of dispersed phase and continuous
phase is known as dispersion system.
• Dispersed phase: Drug particles.
• Continuous phase: External phase/vehicles.

4. Introduction:
Dispersed phase:
• The substance that is dispersed known as the dispersed
phase.
• Example: drug substances
Continuous phase:
• External phase or vehicle where drug get dispersed.
• Example: water, sorbitol, glycerine, propylene glycol
• Viscosity enhancer: sodium CMC, Xanthum gum etc

5. 1. Based on General Classes
• Oral suspension
• Externally applied suspension
• Parenteral suspension
2. Based on Proportion of Solid Particles
• Dilute suspension (2 to10%w/v solid)
• Concentrated suspension (50%w/v solid)
3. Based on Electro Kinetic Nature of Solid
• Flocculated suspension
• Deflocculated suspension
4. Based on Size of Solid Particles
• Colloidal suspension (< 1 micron)
• Coarse suspension (>1 micron)
• Nano suspension (10 ng)
Dispersion system: Suspensions
Classification

6. Advantages of suspension dosage
forms:
• Pharmaceutical 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

7. • 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
Advantages of suspension dosage
forms:

8. THEORY OF DISPERSION:
Theory of Brownian movement:
• Random movement of particles in the system
• Prevents sedimentation.
• Observed if the particle size is about 2 µ -5 µ.
• Viscosity of the medium are favorable.
• Theory of Brownian movement proposes particle
size and viscosity as the major factors.

9. • Sedimentation Behaviour
Sedimentation means settling of particle or floccules
occur under gravitational force in liquid dosage form.
THEORY OF DISPERSION:

10. Theory of sedimentation:
• The rate of sedimentation of particles can be
expressed by the stokes’ Law using equation
as;
THEORY OF DISPERSION:

11. Factors affecting suspensions:
Particle size:
• If particle size reduced, the rate of sedimentation decreased.
• Smaller particle facilitate rapid absorption.
• Reducing the particle to extreme degree of fineness is not advisable
because it may causes cake formation.

12. Viscosity of the medium:
• The viscosity of the suspension should be optimum.
• Higher the viscosity lower is the rate of
sedimentation.
• Enhances the physical stability because sedimentation
is retarded.
• Inhibits the crystal growth because movement of
particles is diminished.
• Prevents the transformation of metastable crystal to
stable crystals.
Factors affecting suspensions:

13. Density of the medium:
• If the density of the medium equals to the density of
particles/solids then rate of settling becomes zero.
• It is possible to increase the vehicle density by including the
ingredients such as polyvenylpyrrolidone (PVP), sugars
(sorbitol, dextrose), polyethylene glycols, glycerine etc.
Factors affecting suspensions:

14. Formulation aspects of dispersion:
Suspensions:
• Finely divided solid is dispersed uniformly in a
liquid dispersion medium
• Depending on their intended route of delivery
– Parenteral suspension,
– Topical suspensions, and
– Oral suspensions
• Oral suspensions generally have high viscosity
• Low viscosity and contains less than 5% solids.

15. IMPORTANT CONSIDERATIONS FOR
FORMULATION OF SUSPENSIONS:
• Nature of suspended material:
• Interfacial properties of the suspended material are an
important consideration
• Particles that have low interfacial tension are easily wetted
• Surfactants increase wettability

16. • Size of suspended particles:
• Reduction of particle size leads to a decrease in the
rate of sedimentation.
• Particle size also affects rate and extent of absorption.
• Reducing particle size beyond a certain limit may
lead to formation of a compact cake upon
sedimentation.
IMPORTANT CONSIDERATIONS FOR
FORMULATION OF SUSPENSIONS:

17. • Viscosity of the dispersion medium:
• Greater viscosity of dispersion medium offers the advantage of
slower sedimentation.
• The property of shear thinning is highly desirable so that the
suspension is highly viscous during storage.
IMPORTANT CONSIDERATIONS FOR
FORMULATION OF SUSPENSIONS:

18. • Electrokinetic Properties:
– Zeta Potential
Difference in potential between the surface of the
tightly bound layer (shear plane) and electro-
neutral region of the solution.
Zeta potential has practical application in stability
of systems containing dispersed particles.
If zeta potential is reduced below certain value
then flocculation occurs.
IMPORTANT CONSIDERATIONS FOR
FORMULATION OF SUSPENSIONS:

19. • Flocculating Agents:
• Flocculating agents decreases zeta potential of
the suspended charged particle and thus cause
aggregation (floc formation) of the particles.
• Examples:
– Neutral electrolytes such as KCl, NaCl.
– Calcium salts
– Aluminium salts
– Sulfate, citrates, phosphates salts
IMPORTANT CONSIDERATIONS FOR
FORMULATION OF SUSPENSIONS:

20. Flocculated Suspension:Method of
Floccules Formation:
1. Electrolytes:
• Electrolytes decrease electrical barrier between the
particles and bring them together to form floccules.
• Decrease in zeta potential and the formation of a
bridge between adjacent particles

21. 2. Surfactants:
• Both ionic and non-ionic surfactants can be used to
bring about flocculation of suspended particles.
• Optimum concentration of surfactants.
Flocculated suspension:Method of
Floccules Formation:

22. 3. Polymers:
• Polymers possess long chain in their structures.
• The part of the long chain is adsorbed on the surface
of the particles and remaining part projecting out into
the dispersed medium.
Flocculated suspension:Method of
Floccules Formation:

24. Deflocculated suspension
• Stays dispersed for a longer time.
• Sedimentation occurs; it leads to formation of a close-
packed arrangement resulting in caking.
• Redispersion of this type of emulsion is difficult.

25. Fig 2. Deflocculated and Flocculated system

26. Fig 2.1 Sedimentation Behaviour of Flocculated and Deflocculated Suspensions

27. Rheological Behaviour:
• Viscosity of Suspension:
• Should be in optimum range for stability and
pourability.
• Thixotropy:
• The isothermal slow reversible conversion of
gel to sol.
• Thixotropic substances solve the problems,
stability and pourability.

28. Different Approaches to Increase the
Viscosity of Suspensions:
Viscosity Enhancers:
• gums (acacia, tragacanth), polymers, cellulose
derivatives (sodium CMC, methyl cellulose),
clays(bentonite) and sugars (glucose, fructose)
Co-solvents:
• Propylene glycol, PEG 400 etc.

29. Formulation of Pharmaceutical
Suspensions:
Preparation of Structured Vehicle:
• Structured vehicles are prepared with the help of
Hydrocolloids.
• It can act as a 'Protective colloid' and stabilize
charge.
• Density increased by:
– Polyvinylpyrrolidone
– Polyethylene glycols
– Glycerin

30. Other Formulation Aspects:
• A perfect suspension is one, which provides
content uniformity.
• Choice of pH, particle size, viscosity,
flocculation, taste, color and odour are some of
the most important factors.
Formulation of Pharmaceutical
Suspensions:

31. 1. Suspending agents:
• Alginates
• Methylcellulose
• Hydroxyethylcellulose
• Carboxymethylcellulose
• Sodium Carboxymethylcellulose
• Microcrystalline cellulose
• Acacia
• Tragacanth
• Xanthan gum
• Bentonite
• Carbomer
 Preferred suspending are those that gives thixotropy to the media eg.
Xanthan gum.
Formulation of Pharmaceutical
Suspensions:

32. Suspending agent:
• The selection of amount of suspending agent is
dependent on the presence of other suspending agent.
• Stability of the suspensions depends on the types of
suspending agents rather than the physical properties
of the drugs.
Formulation of Pharmaceutical
Suspensions:

33. • Suspending agent: Stability pH Range and
Concentrations of Most Commonly used
Suspending Agents
Formulation of Pharmaceutical
Suspensions:
Suspending Agent Stability pH Range Concentration used
Na CMC 5-1o 0.1-5%
Hydroxyethylcellulose 2-12 1-2%
Methyl cellulose 3-11 1-2%
Sodium alginate 4-10 1-5%
Hydroxy
propylcellulose
6-8 1-2%

34. • Some important characteristics of most
commonly used suspending agent:
Alginates:
– Alginate solution looses its viscosity when heated
above 600C due to depolymerization.
– Fresh solution has highest viscosity, after which
viscosity gradually decreases.
– Maximum viscosity is observed at a pH range of 5-9
Formulation of Pharmaceutical
Suspensions:

35. • Methyl Cellulose:
– Methylcellulose is more soluble in cold water than
hot water.
– Methyl Cellulose is stable at pH range of 3- 11.
– As methyl Cellulose is non-ionic, it is compatible
with many ionic adjuvants.
– On heating to 50oC, solution of Methyl Cellulose
is converted to gel form.
Formulation of Pharmaceutical
Suspensions:

36. • Carboxymethyl Cellulose (CMC):
– To improve viscosity and stability of suspension
Middle Viscosity-CMC is widely accepted.
• Sodium Carboxymethylcellulose(NaCMC):
– It is soluble in both hot and cold water.
– It is stable over a pH range of 5-10.
– As it is anionic, it is incompatible with polyvalent
cations.
Formulation of Pharmaceutical
Suspensions:

37. • Wetting Agents:
– Non-ionic surfactants having HLB value between
7-10 are best as wetting agents.
– Ionic surfactants are not generally used because
they are not compatible with many adjuvant and
causes change in pH.
• Surfactants:
– Some surfactants such as polysorbate 80 interact
with preservatives such as methyl paraben and
reduce antimicrobial activity.
– Polysorbate 80 is also adsorbed on drug particle
and decreases its zeta potential.
Formulation of Pharmaceutical
Suspensions:

38. • Solvents:
– alcohol, glycerin, polyethylene glycol and
polypropylene glycol.
• Buffers:
– Resist any change in pH when an acid or base is
added.
– Buffers used should be compatible with other
additives and simultaneously they should have less
toxicity.
– citric acid and its pharmaceutically acceptable salts,
phosphoric acid and its pharmaceutically acceptable
Formulation of Pharmaceutical
Suspensions:

39. • Preservatives:
– Parabens are unstable at high pH value so parabens
are used effectively when pH is below 8.2.
• Flavoring and Coloring Agents:
– Added to increase patient acceptance.
– Titanium, carmine etc
• Sweetening Agents:
– Sodium saccharine, sorbitol, mannitol, aspartamine
etc
• Antioxidant:
– BHA, BHT etc
Formulation of Pharmaceutical
Suspensions:

40. In Process Quality Control (IPQC)
of Suspensions:
• Monitoring critical variables of manufacturing process
to ensure a quality of the final product.
• Appearance of Phases:
– The particle size distribution, clarity of syrup, the viscosity of
gum dispersion, quality control of water is monitored
• Viscosity of Phases:
– Optimum viscosity of the medium so a stable, redispersible
suspension can be formed.
– Brooke field viscometer.

41. • Particle Size of Dispersed Phase
– Microscopically analyze and find out particle size
range of drug.
• pH Test:
– pH of the different vehicles, phases of suspension,
before mixing and after mixing are monitored.
• Pourability:
– Ensure that the final preparation is pourable.
In Process Quality Control (IPQC)
of Suspensions:

42. • Final Product Assay:
– Assayed to find out degree of homogeneity.
• Zeta Potential Measurement
– Value of Zeta potential reflects the future stability of
suspensions.
– It monitored time to time to ensure optimum zeta
potential.
– Measured by either Zeta meter or micro-
electrophoresis.
• Centrifugation Test:
– Uniform distribution of color.
In Process Quality Control (IPQC)
of Suspensions:

43. Final Quality Control of Suspensions
• Appearance
• Color, odor and taste.
• Physical characteristics such as particle size
determination and microscopic photography for crystal
growth.
• Sedimentation rate and Zeta Potential measurement.
• Sedimentation volume.
• Redispersibility and Centrifugation tests
• Rheological measurement
• pH

44. Stability of Suspensions:
• Pharmaceutical suspensions are thermodynamically unstable
system .
• Stability of suspension can be considered in two ways:
– Physical
– Chemical
• Physical stability:
• The particles do not sediment for a specific time period and if
they sediment, do not form a hard cake.

45. • Particle-Particle Interaction and its Behaviour:
– DLVO theory
– The potential energy curves may be used to explain the
sedimentation behaviour.
– Deflocculated system- primary minimum
– Flocculated System- secondary minimum
– Electrolytes serve to reduce the effective range of the
repulsion forces operating on the suspended particles, as
evidenced by the decrease in Zeta Potential.
Stability of Suspensions:

46. Particle-particle interaction:
(+)
(-)
Secondary minimum(attraction)
Fig. 3 Potential energy versus interparticular distance
•Chemical nature and
size of particles
•Density, surface charge and
thickness of the double layer

47. Emulsions:
• Dispersion of at least two immiscible liquids.
• Oil-in-water (O/W) and water-in-oil (W/O)
emulsion.
• The emulsions are thermodynamically unstable.
• Surfactants reduce the interfacial tension between
the immiscible phases
– Oral
– Topical, and
– Parenteral routes

48. Mechanism of emulsification:
• Emulsifying agents are employed to reduce
the interfacial tension.
• The emulsifying agents can be ionic, non-ionic
or zwitterionic surfactants and proteins or
amphiphilic polymers.
• The polar group is often an ammonium,
carboxylate, sulfate, or sulfonate group.
• The non-polar group is generally a linear
hydrocarbon chain.

50. Stability of emulsions:
Flocculation:
• Form colonies in the external phase.
• The extent of flocculation depends on globular
size, charge in the globular surface and viscosity
of the external medium.

51. Creaming:
• Concentration of the globules at the top or bottom of
the emulsion.
– Upward creaming
– Downward creaming
Influenced by
– Globular size
– Viscosity of the dispersion medium
– Difference in the densities of dispersed and dispersion
phase.

52. Coalescence:
• It involves the fuse of globules each other and
form bigger globules.
Phase inversion
Involves the change of emulsion type from o/w to w/o or
vice versa

53. Instability in emulsion:

54. References:
• CVS subrahmanyam, Text book of physical pharmaceutical
pharmaceutics, 3rd edition 4th reprint, 2018 AD, page 420-422.
• T.yangesh, Pharmaceutical Suspensions-patient compliance
oral dosage forms,research gate, 2016