Suspension and Emulsions - Shih

What are suspensions

Coarse dispersions where solid drug particles are suspended in a medium in which they are insoluble. Can be oral, topical, or injectable. Slower diffusion than solutions.

Suspension particle sizes

Coarse: >0.5-1 um dispersed

Nano: <0.5-1 um dispersed

What are emulsions

Two liquid phases immiscible with each other are stabilized using surfactants

Types of emulsions

Oil in water - oral and parenteral

Water in oil - topical

Multiple emulsions

Examples of pharmaceutical suspensions

Ready to use

Reconstituted

Suspension routes of administration

Oral - suspensions, liposomes, microspheres

External - pastes, concentrated suspensions

Injectable - microspheres, liposomes, nanoparticles

Ophthalmic - suspensions

Desired features of a suspension

Settle slowly and readily re-dispersed on gentle shaking (optimal density)

Particle size should remain fairly constant throughout shelf life

Suspension should pour readily and evenly from its container (optimal viscocity)

Advantages of suspension

Deliver insoluble drugs

Deliver unstable materials (more stable in solid state)

Controlled released (microspheres, liposomes)

Used in dermatologic and cosmetic applications (liposomes, ointments)

Disadvantages of suspension

Thermodynamically unstable (relative to solids)

Sedimentation

Agglomeration

Crystal growth

Change of crystalline state

Chemical instability

Stokes Law

V = [2r²(p1-p2)g] / 9 n

V

Velocity of sedimentation

r

Radius of dispersed particles

p1

Density of dispersed phase

*almost always greater than density of continuous phase, which is why dispersed particles tend to settle or aggregate

p2

Density of continuous phase

g

Acceleration due to gravity

n

Viscosity of continuous phase

What causes particle settling rate to increase

increase in particle size

Flocculation equation

Vu/Vo = Hu/Ho

Vu

Final volume of sediment

Vo

Original volume of suspension

Measuring flocculation

F < 0.1 = small, hard cake formation, difficult to redisperse

F 0.25-1.0 = large, re-dispersed more easily, do not cake

DLVO Theory

The primary forces that determine whether two particles in suspension will aggregate when they collide are:

• Van der Waal’s attraction potential (Va)

• Electrostatic repulsion potential (Vr)

• Total potential = Va + Vr

Stability of the system depends on balance between these two interactions

How is stabilization of colloidal or coarse dispersions accomplished

Providing the dispersed particles with a small amount of electrical charge

Surrounding each particle with a protective layer (like a polymer)

Ostwald Ripening

Seen in both suspension and emulsion

Crystal growth

Particles with a range of sizes.

Larger particles are more energetically (thermodynamically) favored than smaller particles

Smaller particles dissolve in solution can migrate towards and deposit on larger particles

This help them reach a thermodynamically stable state

Components of suspension formulation

Vehicle (water)

Surfactants - to reduce surface tension

Flocculating agents (electrolytes, bridge agents)

Viscosity enhancers, suspending agents (carboxymethylcellulose)

Buffers

Tonicity (sugars, NaCl)

Others (flavoring agents, preservatives)

Manufacturing of suspensions

Disperse drug in partial volume of dispersion medium

Add excipients

Combine in a homogenizing mixture

Be aware of foaming during mixture

Packaging and storage of suspensions

Wide-mouth containers with adequate air space

Most suspensions stored in tight containers protected from freezing, excessive heat, light

Always shake before use

Suspension quality control

Drug content

Particle size and size distribution over time

Solid state characterization

Suspensibility

Others (pH, viscosity, appearance, microbial load)

In vitro dissolution testing

Stability

Why choose an emulsion

To deliver insoluble drugs (solubilized in oil phase)

To deliver unstable materials (if drug is stable in oil and undergoes hydrolysis in water)

Controlled release

Parenteral nutrition

Vaccine adjuvants

Dermatological and cosmetic applications

Desired features of an emulsion

Globules retain similar size throughout shelf life

Emulsion is deliverable (uniform flow)

Suspended globules do not settle too quickly

We need a flocculated emulsion - droplets are at some distance from each other but still have some interactions so they don’t merge into one large droplet

Flow through syringe needle

Apply evenly to skin if topical

Disadvantages of emulsions

Thermodynamically unstable - tendency to form large particles

General instability issues

• creaming

• Coalescence

• phase inversion

• particle size increase

• Chemical instability

Creamering

Avoided by using thickening agents (increase viscosity), decreasing particle size, decreasing density difference between continuous and dispersed phase

Coalescence

When small droplets join together to form larger droplets. Leads to cracking (phase separation)

Once emulsion is cracked, it is no longer pharmaceutically useful as an emulsion

Avoided using surfactants, decreasing particle size, increasing velocity

Phase inversion causes

Change in temperature

Change in phase ratio

Addition of a second surfactant with a different HLB ratio

Components of emulsions

Liquid phases (water and oil)

Emulsifiers/surfactants - reduce surface tension and stabilizing droplets

Viscosity enhances - carboxymethylcellulose

Buffers - citrates, phosphates

Tonicity (if necessary) - sugar, NaCl

Others (flavoring agents, preservatives)

Dry gum methods of emulsion manufacturing

Triturating (grind) acacia gum with oil, add water

Wet gum method of emulsion manufacturing

Triturating acacia (gum) with water, add oil

Quality control of emulsions

Drug content

Particle size and size distribution over time

Aggregating over time - creaming, cracking

Others - pH, viscosity, appearance, and microbial load

In vitro dissolution testing

Stability