Coarse Dispersions 1 Flashcards
Dispersed Systems
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
What is a Dispersed System?
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”
Suspension Requirements?
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
Properties of a Stable Suspension
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
Suspension advantages
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
Suspension disadvantages
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
Desired physical properties of suspensions
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
Interfacial properties of suspended particles
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
Surface forces that affect the degree of flocculation and
agglomeration in a suspension
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
Electric properties of Interfaces
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)
Electric Double Layers
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
Nernst and Zeta Potential
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
Zeta potential and effects of electrolytes
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
Properties of flocculated particles
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
Properties of deflocculated particles
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
What is flocculation?
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)
What is Stokes’ Equation?
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
How to decrease the sedimentation rate?
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
Approaches to formulate suspensions
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
Suspension Formulation Strategies
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
Preparing Suspensions
The dispersed phase :
Particles size (good range: 1-50m)
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)
What is a suspending agent?
Suspending agents: thickening agents (viscosity modifiers)
Slow down settlements
Promote flocculation
Be cautious with drug-excipients interactions
Examples of suspending agents
Examples: Carboxymethylcellulose, methylcellulose, microcrystalline cellulose Polyvinyl pyrrolidone Xanthan gum, Veegum, Tragacanth, Carbopol Bentonite (hydrocolloids)
What are wetting agents?
Surfactants
Hygroscopic substances: glycerin, alcohol, propylene glycol
Mechanism:
Lower the surface tension and contact angle
Replace air in the crevices and cracks of particles
Suspension preparation procedures
Particle preparation: Small scale: grinding, levigating, Large scale: colloid Mill,… Wetting Blending Mixing to homogenous Washing
Sustained Release Suspensions
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
Other Suspension Examples
Oral suspensions
Rectal suspension
(Dry powders) for oral suspensions
