- 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

1. Stability Flashcards by Casi Jones

Disperse system

emulsion and suspension

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If particles are less than 1 um

Colloidal system

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Continuous phase

usually in water

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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

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Why physical instability can be problematic?

not mixed properly
uneven distribution
inadequate suspension

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Why must drugs be homogenous before administration?

mixed properly
e.g in a vigle

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HETEROGENOUS

drug not disbursed well

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Second approach: Enabling re-dispersion

shake ; re-embursed

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Instability phenomena

1) Aggregation
2) Coagulation
3) Flocculation
4) Sedimentation
5) Caking
6) Ostwald ripening

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Aggregation

Particles in groups

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Coagulation

Closely aggregated and difficult to redisperse

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Flocculation

Aggregates have an open structure with particles a small distance apart, attracted by weak forces to form flocs or flakes

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Sedimentation

Process of settling or being deposited as a sediment

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Caking

Deflocculated particles (fine separate particles) form cakes which are difficult to re-suspend

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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

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Stability

Physical instability results in poor dosing reproducibility

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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

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Brownian motion and diffusion

Particles diffuse from a high concentration to a low concentration

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Diffusion rate is based on Fick’s first law:

𝑑𝑚/𝑑𝑡=−𝐷𝐴 𝑑𝐶 / 𝑑𝑥

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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

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Diffusion coefficient, D(Stokes-Einstein equation)

𝐷=(𝑘_𝐵 𝑇) / 6𝜋𝜂𝑟

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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

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Bigger the solute molecule…

The less of diffusion rate because bigger particles cannot move as freely as smaller particles

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Collision&raquo_space;> Aggregation

particles collide and come together (clusters)

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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 with nutrients - Areas rich in sediments are often also rich in biodiversity > Sedimentary soil is usually better for farming - Deltas and river banks, where much sediment is deposited, are often the most fertile agricultural 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 thought of 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 by Derjaguin, 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