Workshop on Suspensions

Question 1

What is a suspension?

Answer 1

• A coarse disperse system where an insoluble solid is
  dispersed in a liquid medium
• Disperse phase: Solid particles, usually > 0.1µm
• Disperse medium: For most pharmaceutical applications, this is usually an aqueous media.However, it may infrequently be an organic or oily material

Question 2

What decisions govern the use a pharmaceutical oral suspension?

Answer 2

• Compliance:
• Easy to swallow (children, elderly)
• Easy to divide the dose and to control the dose
• Can mask unpleasant tastes (i.e. chlorampenicol, where the ester form has a more acceptable taste, and is given as a suspension)
• Fast pharmaceutical “action” (i.e. fast onset, absorption, etc.)
• Stability is an issue – consider use only if necessary?
• Onset times:
• The speed at which the drug action commences will vary according to the route of administration.
  The right drug
  The right dose
  The right route
  The right time
  The right patient

Question 3

List three key properties of suspensions, and describe why these properties are of clinical relevance.

Answer 3

• The dispersed particles should settle slowly:
• This allows an accurate and uniform dose to be taken from the medicine
• The suspended particles should not settle rapidly and sediment produced must be easily re-suspended by the use of moderate amount of shaking.
• The particles should remain flocculated (evenly distributed throughout the liquid media) and should be readily dispersed upon shaking:
• i.e. use of oleic acid in preventing caking (coalescence) and flocculation (Yamaguchi et al. Physicochemical characterisation of parenteral lipid emulsion: influence of co-surfactants on flocculation and coalescence, 1995: 12, 1273-1278).
• Ease of use
• Particle size:
• It should be easy to pour yet not watery and exhibit no grittiness.
• It should have suitable organoleptic properties (i.e odour, colour and palatability).
• Good syringeability.
• It should be physically, chemically and microbiologically stable.
• Parenteral/Ophthalmic suspension should be sterilizable.

Question 4

Use Stoke’s law to describe the relationship between media viscosity and the rate of particle
settlement. How effective is viscosity modification as a long-term formulation strategy for suspensions?

Answer 4

There is an inverse relationship between media viscosity and particle settlement:

v = 2a2 g (σ - ρ)/ 9η

a – particle radius
σ - density
ρ - vehicle density
η- viscosity
g – gravity
ν - velocity

Question 5

Why is particle wetting an issue for the formulation of pharmaceutical suspensions?

Answer 5

• Powders may often float on top of a liquid. This is often due to:
• The presence of an absorbed layer of air
• The lipophilic nature of certain materials or contaminants
• Poor properties of “wettability” – this generally refers to
  the contact angle of the particle and the surface.

Question 6

List two excipients that can be added to a suspension to improve “wettability”, and describe briefly
how each of these excipients works.

Answer 6

Note: Choice of material depends on the route of administration

1. Surfactants

Oral route:
- Surfactants, such as polysorbates sorbitan esters, are commonly used (Tweens and Spans, respectively)

i. v.:
- Lecithin, polysorbates and poloxamers and related materials

2. Solvents (alcohols, glycols, glycerol):
   - Different solvents may exert a range of effects, including the ability to penetrate into loose aggregations of particles, and in doing so displacing the air adsorbed within such structures

Question 7

Define flocculation

Answer 7

IUPAC: “a process of contact and adhesion whereby the particles of a dispersion form larger-size clusters”

Question 8

What are the advantages of a flocculated system, compared to a deflocculated system?

Answer 8

Deflocculation system:

• Particles remain independent
• Particles settle at different rate but overall slowly
• Supernatant remain turbid for a long time (small particles settle slowly)
• Settled particles may form hard cake which is difficult to re-disperse

Flocculated system:

• Particles link together to form a loose structure
• Big and small particles settle together in the loose structure
• Supernatant quickly become clear (different sizes link and settle together)
• The sediment remains loose, easy to re-disperse

Question 9

Which is preferable for a pharmaceutical suspension, and why?

Answer 9

i.e. ease of resuspension, reduction of caking, uniformity of dosing

Question 10

Describe three types of excipients that can be used to control flocculation in pharmaceutical
suspensions.

Answer 10

• Electrolytes
• Polymers
• Viscosity modifiers

Question 11

How is Ostwald ripening influenced by particle size?

Answer 11

IUPAC: The change of an inhomogeneous structure over time. Over time, small crystals (or sol particles) dissolve, and redeposit onto larger crystals or sol particles

In S/S0 = 2 gamma M / 2.303 RT pr

• As size (r) decreases, solubility increases

Question 12

With reference to Ostwald ripening, if one extends the logic describing this process, what would be the ultimate result for a pharmaceutical, or similar, product?

Answer 12

What is polymorphism?

“Many shapes”: the potential for a material to exist in more than one physical form i.e. paracetamol has two, the monoclinic and orthorhombic arrangements
They have significantly different compaction properties,
affecting tablet manufacture and, subsequently,
bioavailability

Question 13

Using a relevant example, illustrate how it may influence the stability, quality and bioavailability of
pharmaceutical suspensions.

Answer 13

• To prepare the material for pharmaceutical use, it must be in the correct crystal form only; factors that will affect a material’s properties include temperature, the presence of water and the application of shear stress (i.e. by grinding) in water

Question 14

Taking calamine lotion BP as an example, list all its ingredients and describe what role each of them plays in the formulation. What are the active ingredient(s)?

Answer 14

• Calamine 30g
• Zinc oxide 10g
• Bentonite 6g (thickening agent)
• Sodium citrate 1g (controls flocculation)
• Liquefied phenol 0.5mL (preservative)
• Glycerol 5mL (thickening agent; also helps the product
  adhere better to the skin)
• Water to 200mL

Question 15

Typical time to onset
of action - Minutes to hours
Which dosage form?

Answer 15

Short-term depot injections, solutions,

suspensions, powders, granules, capsules, tablets and modified release tablets

Question 16

Typical time to onset
of action - Minutes
Which dosage form?

Answer 16

i.m and s.c. injections, buccal tablets, aerosols, gases

Question 17

Typical time to onset
of action - Several hours
Which dosage form?

Answer 17

Enteric-coated formulations

Question 18

Typical time to onset
of action - Seconds
Which dosage form?

Answer 18

i.v. injections

Question 19

Typical time to onset
of action - Days
Which dosage form?

Answer 19

Depot injections

Question 20

Typical time to onset
of action - Varies
Which dosage form?

Answer 20

Topical preparations