1. Stability Flashcards
Disperse system
emulsion and suspension
If particles are less than 1 um
Colloidal system
Continuous phase
usually in water
Physical stability
- Lyophobic systems have a poor interaction with the solvent
- Suspensions are ‘coarse’ i.e. contain larger particles
- Large particles SEDIMENT
- Stokes’ law governs the sedimentation
Why physical instability can be problematic?
- not mixed properly
- uneven distribution
- inadequate suspension
Why must drugs be homogenous before administration?
- mixed properly
- e.g in a vigle
HETEROGENOUS
- drug not disbursed well
Second approach: Enabling re-dispersion
- shake ; re-embursed
Instability phenomena
1) Aggregation
2) Coagulation
3) Flocculation
4) Sedimentation
5) Caking
6) Ostwald ripening
Aggregation
Particles in groups
Coagulation
Closely aggregated and difficult to redisperse
Flocculation
Aggregates have an open structure with particles a small distance apart, attracted by weak forces to form flocs or flakes
Sedimentation
Process of settling or being deposited as a sediment
Caking
Deflocculated particles (fine separate particles) form cakes which are difficult to re-suspend
Ostwald ripening
Dissolution of small crystals or sol particles and the re-deposition of dissolved species on the surfaces of larger crystals or sol particles
Stability
Physical instability results in poor dosing reproducibility
Factors affecting stability (they are interconnected):
Kinetic properties (motion of the particles with respect to dispersion medium)
Brownian motion and diffusion
Sedimentation
Viscosity
Size/shape
Electrical properties
Brownian motion and diffusion
Particles diffuse from a high concentration to a low concentration
Diffusion rate is based on Fick’s first law:
𝑑𝑚/𝑑𝑡=−𝐷𝐴 𝑑𝐶 / 𝑑𝑥
What does each letter stand for (Fick’s first law)?
𝑑𝑚/𝑑𝑡 = mass of substance diffusing over time
D = diffusion coefficient
A = area
𝑑𝐶/𝑑𝑥 = concentration gradient
Diffusion coefficient, D(Stokes-Einstein equation)
𝐷=(𝑘_𝐵 𝑇) / 6𝜋𝜂𝑟
What does each letter stand for (Stokes-Einstein equation)?
kB = Boltzmann constant
T = Absolute temperature
η = Viscosity of medium
r = Radius of the solute molecule
Bigger the solute molecule…
The less of diffusion rate because bigger particles cannot move as freely as smaller particles
Collision»_space;> Aggregation
particles collide and come together (clusters)
Where else does aggregation happen outside of pharmacy?
Collisions of microscopic water droplets in clouds > macroscopic raindrops
Collisions of dust grains > dynamics of sand storms
Sedimentation
The rate of sedimentation is dependant on the combined forces of gravity and drag
Particle falling under the forces of gravity according to Stokes’ law
𝑉=(2𝑟^2×(𝜌−𝜌_o)×𝑔)/(9𝜂_o )
If Veodity is high
sedimentation will be low
What does each letter mean (Stokes’ law)?
v = sedimentation rate
r = particle radius
r = density of the disperse phase
ro = density of the continuous phase
g = gravity
ηo = viscosity of the continuous phase
What does this equation cover?
Only applies to > 0.5 μm
If 𝜌−𝜌_o < 0 then creaming rather than caking
Where else outside of pharmacy do we come accross sedimentation?
> Sediment enriches the soil withnutrients
- Areas rich in sediments are often also rich inbiodiversity
> Sedimentary soil is usually better forfarming
- Deltas and river banks, where much sediment is deposited, are often the mostfertileagricultural areas in a region
Viscosity - no flow
- Related to molecular weight of suspended particles/suspending agents
- Resistance to flow under an applied stress
Not just in pharmacy - Viscosity
- In some instances a thicker liquid being thoughtof as superior quality when compared to a thinner product
- Engine oil acts as a seal space between the piston & cylinder as they are not completely smooth
- Fill gaps to optimise engine performances and efficiency
e.g - honey
Factors influencing the rheology of suspensions
a) High volume fractions, f
b) Particle size
c) Particle size distribution
d) Particle shape
e) Electrostatic interactions
f) Steric hindrance
Shape
- Many suspended particles are spherical
- Several measurement techniques assume a sphere
- However, some are not spherical
Small deviation
Ellipsoidal model
Large deviation
Hydroxyapatite (rod-shaped)
Clay suspension (plate)
Polymers in solution (coil)
Prevention of Sedimentation
𝑉=(2𝑟^2×(𝜌−𝜌_o)×𝑔) / (9𝜂_o )
1) Form smaller particles
2) Decrease the density difference between the two phases
3) Increase viscosity of continuous phase
- Particles still collide, but less frequently
- Depends on the relative attractive and repulsive forces between particles
Electrical properties
Most surfaces acquire charge
Various charging mechanisms
Ion dissolution
(Ca2+10(PO43-)6(OH-)2) (solid) ⇌ 10Ca2+ (aq) + 6PO43- (aq) + 2OH- (aq)
Ionisation
Citrate COO-
Polystyrene latex COO-
Amino acids and proteins COO- and NH3+
Unequal ion adsorption
Give you a net charge on the surface
Electrical double layer of ions
Stern layer
Diffuse layer
Zeta potential = magnitude and type (+ or –) of the electrical potential at the slipping plane
- Low zeta potential (0 to 5 mV) are prone to aggregate
- Zeta potential > 30 mV tend to remain dispersed
Zeta potential
Measure how the particles react with each other
Magnitude of the zeta ^^^
REMAIN DISPERSED
Low magnitude of zeta
Might re-imburse
Factors affecting zeta potential
Ion concentration
pH of continuous phase
Ion concentration
Charge of ions determines magnitude
1 carboxylate group vs 3 carboxylate groups in citrate
pH of continuous phase
Alters the ionisation of ionic species in the continuous phase and the surface charge of ionisable groups
pKa - affects if they are single, double or triple charge:
H3PO4⇌ H++H2PO4− (pKa1≈ 2.12)
H2PO4−⇌ H++HPO42− (pKa2≈ 7.21)
HPO42−⇌ H++PO43− (pKa3≈ 12.67)
C6H8O7 ⇌ H++C6H7O7− (pKa1≈ 3.13)
C6H7O7− ⇌ H++C6H6O72− (pKa2≈ 4.76)
C6H6O72− ⇌ H++C6H5O73− (pKa3≈ 6.40)
DLVO (Established byDerjaguin, Landau, Verwey, and Overbeek in the 1940s)
VT = VA + VR
DLVO - definition
Quantitative approach to the stability of lyophobic systems
Assumes the only interactions involved are
Van der Waals forces of attraction (VA)
Electrostatic repulsive forces (VR)
recap - VDW
weak forces
Electrostatic repulsive forces (VR)
Repulsive forces from electrical charges on particles
Ionisation of surface groups
Adsorption of ions
EXAMPLE OF Electrical repulsion
A particle surface with a positive charge has a layer of negative ions attracted to its surface in the Stern layer
DLVO graph
- Secondary minimum is more important
- Very few coarse suspensions remain suspended
Where should you aim for to produce a redispersible coarse suspension?
flocculated suspnsions
Flocculation:
Low energy of attraction possible - ranging not a strong coloration
Coagulation
High energy of attraction possible
Dispersed
High energy of repulsion - particles may remain dispersed
