Routes of Administration: Oral Suspensions

Question 1

Define a disperse system

Answer 1

• A two phase heterogenous system in which an insoluble or immiscible dispersed phase is distributed through a continuous phase

Question 2

How are the disperse systems typically classified?

Answer 2

Based upon the size of the dispersed phase
1. Molecular dispersions < 1nm e.g. glucose solutions
2. Colloidal dispersions between 1 nm and 1 micrometer e.g. micro emulsions, nanoparticles, micelles
3. Corase dispersions > 1 micrometre e.g. suspensions, emulsions

Question 3

Define a pharmaceutical suspension.

Answer 3

• A liquid disperse system consisting of particles distributed within a liquid vehicle

Question 4

What are pharmaceutical suspensions classified as?

Answer 4

• As a coarse or colloidal dispersion

Question 5

How do suspensions appear as?

Answer 5

• They are not optically clear and appear cloudy

Question 6

What are the reasons for formulating an oral pharmaceutical suspension?

Answer 6

• To deliver poorly water-soluble drugs which cannot be formulated as
  aqueous solutions
• To mask the bitter taste of the drug
• To increase drug stability
• To achieve controlled/sustained drug release

Question 7

Which forces can particles dispersed in liquid exhibit?

Answer 7

Van der Waals
Electrostatic repulsion forces

Question 8

What determines the degree of flocculation and aggregation?

Answer 8

Forces at the surface of the particle

Question 9

Describe a flocculated system.

Answer 9

• Suspended particles are formed into floccules (Van der Waals forces) rather than separate particles.
• Sediment will be large and the redispersion is easy

Question 10

What is meant by controlled flocculation?

Answer 10

a mechanism to prevent particle caking in suspension formulations.

Question 11

How can we induce flocculation, and how can this be achieved?

Answer 11

• Reducing the surface charge of particles
• Can be achieved through the addition of surfactants and ionic salts.

Question 12

Describe a deflocculated system.

Answer 12

• A system in which particles are individually and uniformly dispersed throughout the liquid medium.
• It will remain deflocculated when repulsive energy
  between the suspended particles is high.

Question 13

Why is a deflocculated system not ideal as pharmaceutical suspensions?

Answer 13

Deflocculated particles may settle slowly over time results in the formation of a layer of particle sediment at the bottom of the suspension which will be difficult to re-suspend.

Question 14

Compare particles in a deflocculated suspension and a flocculated.

Answer 14

Deflocculated = exist in separate entities
Flocculated = From loose aggregates (flocs)

Question 15

Compare the sedimentation rate between a flocculated and deflocculated suspension.

Answer 15

Deflocculated = slow
Flocculated = Rapid

Question 16

Compare the sedimentation structure between deflocculated and flocculated.

Answer 16

Deflocculated = compact
Flocculated = scaffold-like loose

Question 17

Compare the redispersion of a flocculated and deflocculated suspensions.

Answer 17

Deflocculated = difficult
Flocculated = Easy

Question 18

Compare the supernatant liquid between a deflocculated and flocculated suspension.

Answer 18

Deflocculated = cloudy
Flocculated = generally clear

Question 19

What does an ideal suspension have?

Answer 19

• Solid materials mono dispersed as spheres and evenly suspended in 3D throughout the liquid vehicle for a prolonged period

Question 20

Describe the stability of suspensions.

Answer 20

• Inherently thermodynamically unstable and will over time through random motion of particles aggregate unless sufficient repulsive forces are present.

Question 21

What properties must a suspension have to ensure a uniform dose?

Answer 21

• Particles settle slowly.
• Particles are readily and uniformly re-dispersed upon shaking.
• Particle size remains consistent over time.
• Viscosity is high enough to ensure a uniform dose, but not so viscous that the
  suspension cannot be easily poured from the bottle.

Question 22

What can the movement of particles be caused by?

Answer 22

• Brownian motion
• Gravity
• External agitation e.g. shaking by patients

Question 23

What does particle motion affect?

Answer 23

The inter-particulate distance and thus the flocculation status of the suspension

Question 24

Describe how particles behave in a deflocculated system.

Answer 24

• Behave as individual small particles

Question 25

Describe how particles behave in a flocculated system.

Answer 25

- Clump together and behave as individual large particles with porous structure

Question 26

Which particles are subject to Brownian motion?

Answer 26

Small particles < 2 micrometers

Question 27

Describe brownian diffusion.

Answer 27

- irregular movement within the medium - diffusion from high to low conc - provides more homogenous particle distribution - smaller particles diffuse more rapidly - for particles > 2micrometres diffusion will be negligible - increasing medium viscosity will reduce diffusion

Question 28

What is sedimentation?

Answer 28

- It is the downward particle movement due to gravity - Particle movement is critical for successful suspension formulations

Question 29

Describe the optimal sedimentation pattern for a deflocculated system.

Answer 29

- A slow sedimentation rate

Question 30

Describe the relationship between particle size and sedimentation?

Answer 30

- Particle size has a direct effect on the ease of maintenance of a uniform suspended phase * Submicron suspension: Brownian motion helps to keep the particles in a dispersed state. * Larger particles: the effect of gravity becomes significant

Question 31

if reversibility is required to ensure dosing in reproducible which system would be better?

Answer 31

Flocculated

Question 32

What does stoke's law state?

Answer 32

The velocity of a suspended particle falling under gravity is directly proportional to the particle’s size

Question 33

State the ways to reduce sedimentation rate.

Answer 33

* Particle size reduction – increases diffusion. * Reduce particle density – but at the same time increases particle size thus may have adverse effects. * Increase medium density – e.g. adding dextrose. * Increase medium viscosity – e.g. adding polymers like hydroxypropyl methylcellulose, reduces both diffusion and sedimentation. * Increase temperature – increases diffusion constant, but effect is limited within normal range of temps.

Question 34

What is zeta potential?

Answer 34

Provides a measure of the magnitude of the electrostatic or charge repulsion between particles at the slipping plane between the particle and its associated double layer and the the solvent.

Question 35

How does an electrical double layer form?

Answer 35

* In an aqueous solution, the water molecules undergo self-ionisation reaction and produces ions/charges: – H2O ⇄ H+ (cations) + OH- (anions) * Solid/drug particle surface gives an apparent negative charge in liquid. * The system needs to maintain an overall neutral charge - Cations form a layer around the apparently ‘anionic’ solid particle form the “electrical double layer”.

Question 36

If the zeta potential is reduced below a certain value what happens?

Answer 36

The attractive forces between particles due to van der Waals’ force, overcome the forces of repulsion and the particles come together to form floccules.

Question 37

If a suspension has a large negative or positive zeta potential what happens?

Answer 37

The particles within it tend to successfully repel each other.

Question 38

Describe the effect of excipients on the electrical double layer.

Answer 38

- At low concentrations will only affect diffuse layer – easier to neutralise the particle charge, thinning diffuse layer. - At higher concentrations will also affect the fixed layer – charge on the particle surface will decrease.

Question 39

What is the critical micelle conc? (CMC)

Answer 39

the concentration of surfactants above which micelles form

Question 40

What happens above the CMC?

Answer 40

micelles form with a hydrophobic core in which hydrophobic drug may dissolve.

Question 41

What happens below the CMC?

Answer 41

surfactants will cover the particles surface

Question 42

Why are surfactants used at a concentration below the CMC?

Answer 42

To reduce interfacial tension between particle and liquid medium (i.e. enhance suspension stability)

Question 43

State the characteristics of an ideal suspension.

Answer 43

- Appropriate viscosity - Cake formation - no hard caking, forming of sediment, particles on standing - Sedimentation - particles settle down slowly - Dispersion - particle readily re-disperse on shaking container

Question 44

Which excipients are used to improve palatability?

Answer 44

Flavours, sweeteners and colourings

Question 45

Why are preservatives used?

Answer 45

Prevent microbial growth

Question 46

Why are buffers used?

Answer 46

To maintain the pH of the aqueous system

Question 47

Describe the nature of buffers and what this affects?

Answer 47

Ionic in nature so will affect flocculation behaviour

Question 48

What is a buffer?

Answer 48

A mixture of a weak acid/base and salts

Question 49

Why are suspending agents used?

Answer 49

Reduce particle sedimentation.

Question 50

Why are flocculating agents used?

Answer 50

Decreases zeta potential of the suspended charged particle - cause aggregation of the particles - The final excipient added to the formulation - For example ionic material NaCl, surfactants

Question 51

What is a chemical stabiliser?

Answer 51

– Improve chemical stability of the drug, this includes: – Antioxidants e.g. ascorbic acid at 0.2%w/v. – Chelators e.g. disodium salt of EDTA

Question 52

What is a wetting agent?

Answer 52

– Reduce interfacial tension between particle and liquid medium. – Improve homogeneity of drug particle distribution. – E.g. using surfactants below their critical micelle concentration.