Coarse Dispersions 1

Question 1

Dispersed Systems

Answer 1

Pharmaceutical dispersion systems (particulate systems) : one substance is dispersed within another substance.
Homogenous (one –phase system, molecular dispersion): true solutions, colloidal dispersion
Heterogeneous: coarse dispersion (e.g.. emulsions and suspensions), colloidal dispersion

Question 2

What is a Dispersed System?

Answer 2

A dispersion consist of:
Continuous media: external phase, dispersion media, dispersing vehicle
Dispersed phase: internal phase, particulate matter
Phase:
Distinct homogenous part of the system
Definite boundaries from other partsParticle size> 0.5 µm (usually between 1-200 µm)
Includes:
Suspensions: “Cloudy (Snowball) dosage forms”
Emulsions – The “Milky dosage Forms”

Question 3

Suspension Requirements?

Answer 3

Coarse dispersions
Common dosage forms
External phase is usually aqueous
Solid particles are suspended in a medium in which they are not solubleOften require specific particle size (e.g. in pulmonary inhalations desired particle size is 3-5 µm for deep lung penetration)
Inverse relationship between particle size and dissolution rate (e.g. ophthalmic suspensions are less than 10 µm in order to improve their dissolution before being removed by tear) .
Concentration of the suspended materials is normally related to the product application, for example:
Oral antibiotics, 125-500 mg/5 mL
Parenteral suspensions contain from 0.5-30 % of solid particles

Question 4

Properties of a Stable Suspension

Answer 4

Physical stability of a suspension means the particles:
retain their original size and do nor aggregate
remain uniformly distributed
regain their uniformity with simple agitation

Question 5

Suspension advantages

Answer 5

Better chemical stability than solution dosage forms
Increased delivery rate than solid dosage forms
Ease of adjusting dosage
Ease of swallowing
Allows liquid dosing of unpalatable drugs

Question 6

Suspension disadvantages

Answer 6

Problems typically encountered with suspensions and emulsions
Particles don’t disperse uniformly when placed in liquid
Particles tend to agglomerate (aggregate to cluster)
Particles tend to settle and forming cake due to gravitational effects
Dosage accuracy problems
Homogeneity problems
Stability problems
Compliance problems

Question 7

Desired physical properties of suspensions

Answer 7

Homogeneity: Mixtures must be uniform in order to insure dose consistency and can be spared evenly
Viscosity: The suspension should pour readily from its container, or spread easily on skin, or go easily through syringe needle.
Settlement: A suspension should settle slowly and reversibly and be resuspend easily on gentle shaking (without no caking)
Particle size: The particle size should remain fairly constant through long periods of undisturbed standing

Question 8

Interfacial properties of suspended particles

Answer 8

Dispersion of the small particles in a continuous medium, leads to large surface area.
Large surface area is associated with a surface free energy that make the system thermodynamically unstable.
In this system particles have a high energy and a tendency to regroup in order to decrease the total surface area and consequently the surface free energy.  Type of agglomerate to reach a more thermodynamically stable state:
Flocculate; 
- Light, fluffy conglomerate
- van der Waals forces
 Aggregate;
particles adhere by stronger forces
e.g. compacted cake
Caking;
growth and fusing of crystals 
Solid aggregate

Question 9

Surface forces that affect the degree of flocculation and

agglomeration in a suspension

Answer 9

Particle interactions forces (attractive and repulsive
forces modeled using DLVO theory)
Attraction: London-van der Waals
attraction
Repulsion: electrostatic repulsion; arise
from the interaction of the electric double layers
surrounding each particle

Question 10

Electric properties of Interfaces

Answer 10

Particles dispersed in liquid media may become charged:
Selective adsorption of a particular ionic species
Ionization of groups (e.g. COOH) at the surface of the particles (function of pH and pK)
Charges that arise from a difference in dielectric constants between particle and medium (less common)

Question 11

Electric Double Layers

Answer 11

1st layer: tightly bond layer
A dense layer of counter ions (e.g. negative ions) strongly attached to the solid surface
It is a relatively rigid layer
—-Shear Plane (bb’)—-
2nd layer: Diffusive
A diffusive layer of counter ions (e.g. negative ion) trying to approach the particle
Not rigid, approaching to overall neutralization

Question 12

Nernst and Zeta Potential

Answer 12

Electric potential at solid surface due to potential-determining ions: electro-thermodynamic (Nernst) potential
Electrical potential drops rapidly across the tightly bound layer, and drops more gradually across the diffuse layer
The potential located at the shear plan (the surface of tightly bond layer) is known as electro-kinetic (zeta) potential.
Zeta potential can be positive, zero, and negative.
Governs the degree of repulsion
If drops below a certain value, causes flocculation

Question 13

Zeta potential and effects of electrolytes

Answer 13

In aqueous suspension: Zeta potential is the electronic potential at the shear plane that separates the bound molecules (aqueous shell) and free molecules (in bulk)
The magnitude of zeta potential has implication for the stability of dispersed system
Zeta potential is related to the ionic environment of the liquid phase (e.g. electrolyte concentration)
Use the electrolytes to adjust the electrical barrier between the particles to form flocculated suspensions

Question 14

Properties of flocculated particles

Answer 14

Weakly bonded
Settle rapidly
Do not form a cake
Easily suspended
Clear boundary between the sediment and the supernatant liquid
The liquid above the sediment is clear

Question 15

Properties of deflocculated particles

Answer 15

Settle slowly
Eventually aggregate 
Form hard cake
Difficult to resuspend
No clear boundary between the sediment and the supernatant liquid
The liquid above the sediment is turbid

Question 16

What is flocculation?

Answer 16

Flocculated particles (flocs or floccules): light and fluffy conglomerates that are weakly held by van der Waals forces, and maintained a certain distance by repulsive forces (~1000-2000 Å)

Question 17

What is Stokes’ Equation?

Answer 17

Stokes’ equation describes the sedimentation rate of the particles in a diluted suspension (<2% w/v)

V (cm/sec) = sedimentation rate (dx/dt)
d (cm) = particle diameter (assuming sphere)
i = density of the particle (internal phase)
e = density of the medium (external phase)
g = the gravitational constant (980 cm/s2)
 (poise) = the viscosity of the continuous medium

Question 18

How to decrease the sedimentation rate?

Answer 18

The density of the particle in suspension should be close to the density of the medium
The size of the particles
The viscosity of the solution

Question 19

Approaches to formulate suspensions

Answer 19

The commonly used approaches:
The use of a structured vehicle to maintain deflocculated particles in suspension( disadvantage: formation of a compact cake)
The application of the principles of flocculation to produce flocs that, although they settle rapidly, are easily resuspended with a minimum of agitation. A flocculated suspension generally display the rheological behavior of either plastic or pseudo-plastic

Question 20

Suspension Formulation Strategies

Answer 20

Strategies to achieve optimum physical stability, and appearance for a suspension formulation (i.e. the product flow readily from the container and have a uniform distribution)
adjust the viscosity
Creating pseudoplastic thixotropic system by using suspending agent(s)(rheologic properties will be discussed in a later section) e.g. bentonite and carboxymethylcellulose combination)
Adjust the formulation to increase zeta potential to maximize repulsion
Creating weak particle aggregates (floccules) by reducing electrostatic repulsive barrier to keep them at the secondary minimum potential; can be achieve by increasing the salt content of the external phase.
Polymeric macro-molecules

Question 21

Preparing Suspensions

Answer 21

The dispersed phase :
Particles size (good range: 1-50m)
Particles size reduction methods (Large scale):
Milling
Micropulverization
Spray drying
Fluid energy grinding (jet milling, or micronizing) by compressed air stream
Dispersion medium (dispersing phase, dispersing vehicle, or continuous medium)
Suspending agents (thickening agents, viscosity modifiers)

Question 22

What is a suspending agent?

Answer 22

Suspending agents: thickening agents (viscosity modifiers)
Slow down settlements
Promote flocculation
Be cautious with drug-excipients interactions

Question 23

Examples of suspending agents

Answer 23

Examples: 
Carboxymethylcellulose, methylcellulose, microcrystalline cellulose
Polyvinyl pyrrolidone
Xanthan gum, Veegum, Tragacanth, 
Carbopol
Bentonite (hydrocolloids)

Question 24

What are wetting agents?

Answer 24

Surfactants
Hygroscopic substances: glycerin, alcohol, propylene glycol
Mechanism:
Lower the surface tension and contact angle
Replace air in the crevices and cracks of particles

Question 25

Suspension preparation procedures

Answer 25

Particle preparation: 
Small scale: grinding, levigating, 
Large scale: colloid Mill,…
Wetting
Blending
Mixing to homogenous
Washing

Question 26

Sustained Release Suspensions

Answer 26

It is difficult to prepare sustained release oral suspension and control the release rate
Successful oral suspension strategy:
Ion exchange resin complex with resin coating
e.g. Tussionex
12 hour dose

Question 27

Other Suspension Examples

Answer 27

Oral suspensions
Rectal suspension
(Dry powders) for oral suspensions