Kinetics and Stability Studies: Stability of Suspensions I Flashcards
Dr. Ilomuanya
Mention 5 factors affecting the physical stability of a suspension.
i. Sedimentation
ii. Crystal growth
iii. Caking
iv. Loss of volatile constituents
v. Absorption or loss of water
CALCS
Mention 7 factors affecting the chemical stability of a suspension.
i. Hydrolysis
ii. Oxidation
iii. Photochemical degradation
iv. Racemization
v. Polymerization
vi. Enzymatic decomposition
vii. Changes involving other drug components and formulation additives
CHOPPER
What considerations are necessary to obtain a chemically and physically stable suspension?
1.Settling/Sedimentation rate of the suspended particles
2. Limitations of Stokes’ Law
3. Sedimentation in flocculated and deflocculated systems
4. Controlled flocculation
5. Effects of particle size on suspension stability
6. Crystal growth
7. Use of Structured vehicles
State Stokes’ law
V = (d^2(Ps - Po)g)/18n
Where V is the terminal velocity in cm/sec,
d is the diameter of the
particles in cm,
ps and po are the densities of the dispersed phase
and dispersion medium respectively,
g is the acceleration due to gravity, and
n is the viscosity of the dispersion medium in poise
Discuss the limitations of Stokes’ law.
Stokes’ law is based upon several assumptions, which may not always hold true for pharmaceutical suspensions.
The law is valid for diluted pharmaceutical suspensions that are composed of no more than 2% solids.
In a diluted suspension, the solid particles settle without interference from one another in what is termed “free settling”.
In a concentrated suspension, this interference may occur and may hinder the settling results.
Particle shape and size are also important in Stokes’ equation.
The equation assumes spherical and monodisperse particles, which may not be encountered in real systems.
The limitations to Stokes’ law include:
* Negative density difference in Stokes’ equation
* High content of dispersed solids
* Dielectric constant
* Brownian movement
What are the two approaches used in preparing stable suspensions?
- Use of structured vehicle to maintain deflocculated particles
in suspensions - Application of principles of flocculation to produce flocs that
are easily redispersed by minimal agitation.
What are structured vehicles?
These are plastic or pseudoplastic viscosity-imparting agents which reduce the rate of sedimentation in dispersed systems.
They are generally aqueous solutions of natural and synthetic polymers.
Give 5 examples of structured vehicles.
i. Methylcellulose
ii. Carboxymethylcellulose
iii. Sodium Carboxymethylcellulose
iv. Acacia
v. Gelatin
vi. Carbopol
vii. Tragacanth
viii. Bentonite
Explain why flocculated systems are favoured over deflocculated systems.
For a deflocculated suspension, the shear-thinning property of the
structured vehicle will allow easy redistribution of the particles from the
small sediment. However, they may form a compact cake, which will not be re-dispersible by agitation. Its for this reason that formulation of flocculated systems are advocated for.
Therefore a flocculated suspension in a structured vehicle is preferred. When the shaking is discontinued, the vehicle goes
back to its original higher consistency, and that keeps the particles
suspended.
** Flocculated suspensions sediment more rapidly, but are easy to redisperse.
Deflocculated suspensions sediment slowly, but form compact cakes that may be difficult to redisperse.
What are the ideal properties or requirement of a suspension product?
Product must:
1. Flow readily from the container and
2. Possess a uniform distribution of particles in each dose
Mention 3 methods of controlled flocculation.
- Electrolytes: They act by reducing the zeta potential, which brings the particles together to form loosely arranged structures. The
flocculating power increases with the valency of the ions. - Surfactant: Both ionic and nonionic surfactants can be used as flocculating agents.
Ionic surfactants cause flocculation by neutralising the charge on particles.
Because of their long structure, nonionic surfactants are
adsorbed onto more than one particle, thereby, forming a
loose flocculated structure. - Polymers: Linear and branched-chain polymer form a gel-like network that adsorbs onto the surface of dispersed
particles, holding them in a flocculated state. Moreover, hydrophilic polymers can also function as protective
colloids.
Linear polymers (e.g., sodium carboxymethylcellulose) serve better as flocculating agents. However, coiled polymers (e.g.,
polyvinylpyrrolidone) are not conducive to flocculation, due to their
shape and so they produce steric stability.
How are surfactants used to promote deflocculation?
By reducing the interfacial tension between the solid particles and the vehicle. Due to the lowered interfacial tension and advancing contact angle, wetting and deflocculation is promoted.
Discuss the effects of particle size on suspension stability.
The particle size of any suspension is critical and must be reduced within the optimal range determined during pre-formulation. It is
necessary to ensure that the drug to be suspended is of a fine
particle size prior to formulation as this will ensure a slow rate of
sedimentation of the suspended particles.
Large particles, if greater than about 5µm diameter, will also impart
a gritty texture to the product, and may cause irritation if injected or
instilled into the eyes
Discuss crystal growth as a factor affecting the physical stability of suspensions.
Crystal/particle growth is a destabilization process resulting from temperature fluctuations or Ostwald ripening during storage.
Ostwald ripening (or disproportionation) is the process of disappearance of small particles or droplets by
dissolution and deposition on the larger particles or
droplets. The driving force for Ostwald ripening is the
difference in solubility between the small and the large particles.
The smaller particles (with higher radius of
curvature) are more soluble than the larger ones (with lower radius of curvature). With time, the smaller particles or droplets dissolve, and their molecules diffuse in the bulk and become deposited on the larger
ones. This results in a shift of the particle or droplet size distribution to larger values.
Fluctuations of temperature may change the particle size
distribution and polymorphic form of a drug altering the
absorption rate and drug bioavailability. Particle growth is crucial when the solubility of the drug is dependent on the temperature. When the temperature is increased, crystals of the drug may dissolve and form supersaturated solution which favour crystal growth. The surface free energy on smaller particles is comparatively more than
that on larger particles, so they are more soluble in the dispersion medium. If the temperature rises, more materials are dissolved from the smaller particles, decreasing their size even more.
When the temperature goes down, the drug attempts to recrystallize on the surface of existing particles. The larger particles will increase gradually in size as the smaller
particles decrease in size.
How can crystal growth be prevented?
i. By using a narrow particle size range
ii. Use of polymeric colloids
iii. Use of surfactants
