Pharm 124 Module 6 Notes - Suspensions

Pharmaceutical suspension deifnition

Coarse suspension containing finely divided insoluble material suspended in a liquid medium

Suspensions are a 2 phase system:

1. dispersed phase

2. dispersion medium

The dispersion medium in suspensions, unlike colloids, consist of...

liquid or semisolid

Criteria for suspensions: (3)

1. particles are uniformly distributed

2. particles have minimal solubility

3. size is between 1-100 um

Fine dispersion size range in suspensions

1-50 um

Coarse dispersion size range in suspensions

50-100 um

Advantages of Suspensions: (6)

1. alternative to solid dosage form

2. solubility

3. palatability (why)

4. drug stability

5. improved bioavailability (compared to solid but not solutions)

6. sustained release

Disadvantages of Suspensions: (3)

1. sedimentation

2. manufacturing difficulties

3. bulk of final product

Why do suspensions have sustained release?

Because the drug has to go through a dissolution step

Desired properties of a suspension:

- fine uniform sized particles

- uniform distribution

- slow sedimentation rate

- easily redispersible

- appropriate viscosity

Major concerns with formulating suspensions: (3)

- adequate dispersion of particles in vehicle

- minimize settling

- prevent caking if/when a sediment forms

Types of suspensions according to Pharmaceutical use:

- oral

- topical

- parenteral

- sterile topical

- cosmetic

Sterile topical suspension example

Ophthalmic suspensions

Parenteral suspension [sterile] example

injections

The most common type of suspensions are _________ suspensions

Oral

Types of suspensions according to physical structure:

- deflocculated suspensions

- flocculated suspensions

Which one: flocculated or deflocculated?

Dispersed particles are small, discrete units because there is repulsion between particles.

Deflocculated

Which one: flocculated or deflocculated?

The smaller the particle size, the slower the gravitational settling. Because of slow settling, no liquid becomes trapped between particles.

Deflocculated

Which one: flocculated or deflocculated?

Sediment is compacted and very difficult to redisperse

Deflocculated

Which one: flocculated or deflocculated?

'Caking' occurs

Deflocculated

Which one: flocculated or deflocculated?

"Caking" is a serious physical stability problem for this type of suspension.

Deflocculated

Which one: flocculated or deflocculated?

The supernatant remains cloudy even after settling occurs.

Deflocculated

Which one: flocculated or deflocculated?

Dispersed particles form loose aggregates (flocs) since repulsive forces are low.

Flocculated

Which one: flocculated or deflocculated?

The rate of sedimentation is relatively rapid.

Flocculated

Which one: flocculated or deflocculated?

The sediment contains trapped liquid between flocs making the volume of sediment large and "fluffy". A cake doesn't form.

Flocculated

Which one: flocculated or deflocculated?

The loosely packed sediment is easily redispersed by moderate agitation.

Flocculated

Which one: flocculated or deflocculated?

The supernatant is relatively clear after settling occurs (due to rapid settling).

Flocculated

Formulation of Suspensions Factors to consider (5)

1. components

2. flocculation and deflocculation

3. particle size

4. wetting

5. stability

Suspension components: (2)

1. Internal phase (disperse phase)

2. External phase (dispersion medium)

In a suspension, hydrophobic solids are wetted by _________

oil

In a suspension, hydrophobic solids are wetted by ________

water

Most pharmaceutical substances are _____________ solids

Hydrophobic

The selection of the external phase in a suspension is based on: (5)

1. safety

2. density

3. viscosity

4. taste

5. stability

Suspension components: Excipients

Vehicle types: (3)

1. polar liquids

2. non-polar liquids

3. structured vehicles

Structed vehicles are used in large concentrations to ensure proper uniformity of the suspension. (T/F)

False, they are used in very low concentrations.

Non-polar liquid vehicles are mostly used for external formulations. (T/F)

True

Suspension components: Excipients

Additives: (6)

- Buffers, salts

- colors

- flavors

- fragrances

- preservatives

- suspending agents

Taste masking is easier in ___________ (solutions/suspensions)

suspensions

For a sweet taste, use... (3)

- vanilla

- grape

- bubblegum

For an acidic/sour taste, use... (6)

- lemon

- lime

- orange

- cherry

- grapefruit

- raspberry

For a salty taste, use... (5)

- nut

- butter

- butterscotch

- spice

- maple

For a bitter taste, use... (4)

- licorice

- coffee

- chocolate

- mint

Suspending agents: (4)

1. Wetting agents

2. Deflocculating agents

3. Flocculating agents

4. Thickeners

Wetting agents: (3)

1. surfactants

2. hydrophilic colloids

3. solvents

Surfactants purpose

Lower the interfacial tension and contact angle between solid particles and the liquid medium

We want surfactants to be slightly ____________ with the HLB (Hydrophilic Lipophilic Balance) range at:

- lipophilic

- 7-10

Surfactant concentrations are very ______ (high/low)

low

For surfactants, HLB range <10 is __________ (hydrophilic/lipophilic)

lipophilic

For surfactants, HLB range >10 is __________ (hydrophilic/lipophilic)

hydrophilic

Oral surfactants:

- polysorbates (Tweens)

- sorbitan esters (Spans)

Topical surfactants:

- sodium lauryl sulfate

- dioctyl sodium (or calcium) - sulfosuccinate

Parenteral:

- polysorbates

- lecithin (phospholipid)

Hydrophilic Colloids act by coating the solid particles. (T/F)

Hydrophilic colloids ________ (affect/don't affect) the interfacial tension.

- True

- don't affect

Hydrophilic colloid wetting agents examples: (5)

- acacia

- bentonite

- tragacanth

- alginates

- cellulose derivatives

If a suspension is caking and the supernatant appears cloudy, add this to increase the stability.

Deflocculating agents

Deflocculating agents make the electrical double layer _________ (large/small)

large

Which of these affects the interfacial tension?

a) surfactants

b) deflocculating agents

c) hydrophilic colloids

a) surfactants

What do deflocculating agents do?

Alter the surface charge by physical adsorption --> repulsion among particles

Flocculating agents examples

1. electrolytes

2. ionic surfactants

3. polymeric flocculating agents

Flocculating agents: Electrolytes

- what do they do?

- what concentration?

- reduce the zeta potential

- 0.01-1%

Flocculating agents: Ionic surfactants

- reduce the zeta potential

Electrolytes and ionic surfactants act by...

increasing the counter ion concentration in the formulation

Flocculating agents: Polymeric flocculating agents

- cross-link the suspended particles to create a fixed space between particles to cause flocculation

- increases viscosity

Example of a polymeric flocculating agent:

Methylcellulose

The degree of viscosity induced by thickeners is __________-dependent

Concentration

Increasing the viscosity __________ (increases/reduces) sedimentation.

reduces

Polysaccharides are _________ _________ (hydrophilic colloids)

viscosity modifiers

Viscosity modifiers examples: (5)

- polysaccharides

- water soluble cellulose derivatives

- Hydrated silicates

- Acrylic acid polymers

- Colloidal silicon dioxide (Aerosil)

Structured vehicles @ low vs high concentrations.

Low concentrations: protective colloids

High concentrations: viscosity-inducing

Structured vehicles ________ (increase/reduce) the sedimentation rate of dispersed particles according to Stoke's Law.

reduce

Structured vehicles are used for parenteral administration only. (T/F)

FALSE!!! THEY ARE NOT USED FOR PARENTERAL ADMINISTRATION! GET YOUR HEAD STRAIGHT

3 main strategies available to formulate a physically stable suspension. What are they?

1. Use of structured vehicles

2. Use of controlled flocculation

3. Combination of both

1. Particles

2. Wetting agent and dispersion medium

3. Uniform dispersion of deflocculated particles

4a) Incorporation of structured vehicle

4b) Addition of flocculating agent

4c) Addition of flocculating agent then incorporate structured vehicle

5a) deflocculated suspension in structured vehicle

5b) flocculated suspension

5c) flocculated suspension in structured vehicle

Summary

Formulation of suspensions considerations: (3)

1. Properties of well-formed suspensions

2. Properties of an ideal suspending agent

3. Stability of the suspension

When looking at the stability of the suspensions, look at these 3 things.

1. Physical stability

2. Rheological assessment (viscosity)

3. Assessment of crystal growth

Physicochemical aspects of suspensions: (3)

1. Wetting

2. Interfacial properties

- surface free energy

- zeta potential

3. Sediementation

What is the first step of a suspension preparation?

Wetting

The degree of wetting can be described by the ________ ________

contact angle

Contact angle describes the degree of __________

wetting

Wetting definition

The ability of a liquid excipient to displace the air and coat the surface of the solid particle

If the surface energy between the hydrophobic solid and hydrophilic solvent is high, the solid will wet ____ (well/poorly)

poorly

The surface of particles are typically hydrophobic. (T/F)

True

Contact angle:

Complete wetting

0 degrees

Contact angle:

no wetting

180 degrees

Contact angle:

0 degrees

complete wetting

Contact angle:

180 degrees

no wetting

Contact angle:

<90 degrees

suitable wetting

Contact angle:

90 degrees

partial wetting

Contact angle:

>90 degrees

poor wetting

Large contact angle corresponds to a ___________ (hydrophilic/hydrophobic) surface

Hydrophobic

Small contact angle corresponds to a ___________ (hydrophilic/hydrophobic) surface

Hydrophilic

Surface free energy equation components meaning:

ΔF =

ΔA =

Ysl =

- surface free energy

- total interfacial surface area (cm^2) [smaller particle = larger surface area]

- interfacial tension between liquid medium and solid particles

The smaller the particle, the __________ (bigger/smaller) the surface free energy, the __________ (bigger/smaller) the tendency of a system to aggregate into larger particles.

bigger, bigger

The _________ (larger/smaller) the ΔF, the more thermodynamically stable the suspension will be at equilibrium.

Smaller

For ΔF, surfactants lower the ______ which ________ (raises/lowers) the ΔF and ________ (raises/lowers) the stability of the suspension.

Ysl (interfacial tension between liquid and solid)

Lowers

Raises

Higher zeta potential:

- _________ (attractive/repulsive) forces are stronger

- system is _________ (flocculated/deflocculated)

- repulsive

- deflocculated

For suspensions, bigger particle sizes will ________ (increase/decrease) risk for cake formation

increase

Lower zeta potential:

- _________ (attractive/repulsive) forces are stronger

- system is _________ (flocculated/deflocculated)

- attractive

- flocculated

We want a _________ (high/low) zeta potential.

low

Stoke's law represents the _________ of particles.

- Sedimentation