Liquid dosage forms for oral administration -Suspensions and Emulsions

Question 1

Characteristics of suspensions

Answer 1

dispersions in which the drug is dispersed in the external phase (vehicle)
solubility of drug in vehicle is low
Diameter of disperse phase: 0.5 to 100m.
when particle size < 0.5 m: colloidal.

Question 2

Physical stability of suspensions

Answer 2

Fundamentally unstable, leading to
sedimentation
particle-particle interactions and, ultimately,
caking (compaction).

understanding their physical stability :
electrical properties of dispersed particles and
effect of distance of separation between particles on their subsequent interaction.

Question 3

Electrical properties of dispersed particles

Answer 3

Following dispersion within an aqueous medium, particles may acquire a charge due to either:
ionisation of functional groups on the drug molecule and/or
adsorption of ions to the surface of the particle.
Following adsorption of ions on to the surface, a phenomenon referred to as the electrical double layer is established

The boundary of this second layer will possess a potential, referred to as the zeta (ζ) potential.
Zeta potential measures degree of electric charge on particles relative to bulk medium in which they are suspended
compression of the electrical double layer by increased concentration of electrolyte. This approach may be used to stabilise pharmaceutical suspensions.

Question 4

distance of separation and the interaction between particles

Answer 4

Three states of interaction are possible:
1. No interaction: particles sufficiently distant from one another. thermodynamically stable state (in absence of sedimentation).
2. Coagulation (agglomeration): particles form an intimate contact with each other; pharmaceutically unacceptable formulation- inability to redisperse the particles upon shaking.
3. Loose aggregation (termed floccules): loose reversible interaction between the particles; enabling the particles to be redispersed upon shaking.

Question 5

DLVO Theory

Answer 5

when dispersed in a liquid medium, particles will experience (electrical) repulsive forces and attractive (London/van der Waals) forces.

energies of attraction ( V a ) and repulsion ( V r )
V t= V a + V r
Where: Overall energy of interaction between the particles ( V t )

Question 6

Sedimentation

Answer 6

particles in a suspension will sediment under the influence of gravity and settle at the bottom of the container
larger particles reaching the bottom initially and the smaller particles occupying the space between the larger particles.
particles at the bottom of the container are gradually compressed by the weight of those above and, in so doing, sufficient energy is available to overcome the primary maximum (repulsive forces) and the particles become sufficiently close to form an irreversible interaction at the primary minimum. This is referred to as caking .

use stokes equation

Question 7

Controlled flocculation

Answer 7

For particles in which the zeta potential (and hence the primary maximum) is high, manipulation of the magnitude of the secondary minimum is required (controlled flocculation).

Flocculation controlled by addition of electrolyte or charged surfactants that reduce zeta potential (and hence VR) to give satisfactory 2ndary minimum in which flocs can be formed

Question 8

Acceptable suspension

Answer 8

low rate of sedimentation
disperse phase: easily redispersed with gentle shaking
flow properties: formulation easily removed from the container
aesthetically pleasing.
many potential routes of administration

Question 9

Advantages of pharmaceutical oral suspensions

Answer 9

delivery system for low solubility drugs
avoid large volume of solvent- solution of this drug
avoid precipitation upon storage; when co-solvent is used
taste masking of drugs
difficulty in swallowing solid-dosage forms
controlled drug delivery

Question 10

Disadvantages of pharmaceutical oral suspensions

Answer 10

Problems: correct dose of drug?
unstable; formulation to ensure stability over the period of the shelf-life
aesthetic suspension: difficult
bulky, difficult for patient to carry.

Question 11

Formulation considerations: Physical properties

Answer 11

Particle size: increase stability by modifying rate of particle sedimentation (Stokes law)
Particle size should be minimised
chemical methods (controlled precipitation)
physical methods (i.e. milling).
B. Wetting properties of drug
Insoluble drug particles: hydrophobic, not easily wetted
surface-active agents: decrease interfacial tension
particles poorly wetted: aggregation

Question 12

Crystal growth

Answer 12

Small particles > solubility/ dissolution rate than larger particles when dispersed in an aqueous vehicle
Change (increase) in storage temperature: smaller particles dissolve in the vehicle
Crystallisation of dissolved drug may occur on surface of larger particles (increase diameter of suspended drug particles).
Hydrophilic polymers decrease crystal growth: adsorption on to suspended drug particles (protection)
Control crystal growth: temperature cycling (repeated freeze-thaw cycles), monitor particle diameter, physical stability.

Question 13

Components of pharmaceutical oral suspensions

Answer 13

Vehicle: Purified Water USP, buffers (citrate commonly used).
Excipients: as for oral solutions.
Major difference: excipients to physically stabilise suspensions; control of rate of particle/floccule sedimentation.
Addition of electrolytes: (control flocculation)decreases zeta potential
Surface-active agents: wetting, facilitating flocculation; C< 0.5% w/v
non-ionic preferred: polyoxyethylene fatty acid sorbitan esters, sorbitan esters, lecithin
ionic surfactants: greater toxicity

3. Hydrophilic polymers: physical stability, affect flow properties
   adsorb on to surface of suspended drug particles. Due to large MW: 1 section of polymer chain adsorb on to particles, remainder of chain into aqueous vehicle.
   2 polymer-coated particles approach each other: prevent particles coming into close contact
   Ability to stabilise suspensions: C, Type of polymer
   increase viscosity ( decrease rate of sedimentation, increase physical stability - Stokes’ equation)
   flow properties (polymer C used in oral suspensions)

Question 14

Use of emulsions

Answer 14

cream formulations; emulsions that offer greater consistency (viscosity); applied topically
parenteral nutrition
oral administration
rectal administration of antiepileptic agents

Emulsions: disperse systems in which an insoluble liquid is dispersed in a second liquid phase
Disperse phase = phase that is sub-divided
Continuous phase = phase in which disperse phase is distributed

Question 15

Advantages of pharmaceutical emulsions

Answer 15

Delivery of drugs with low aqueous solubility:
drug dissolved in internal oil phase (o/w)
oral administration: oil droplets absorbed (mechanism for oils).
Taste masking: drug dissolved in internal phase (o/w); external phase may contain sweetening/ flavouring agents.
Administration of oils with therapeutic effect (cathartic effect , i.e. liquid paraffin; droplets in an o/w emulsion
reduction of irritation after topical administration: drug in internal phase (o/w)
difficulty swallowing solid-dosage forms
total parenteral nutrition

Question 16

Disadvantages of pharmaceutical emulsions

Answer 16

Thermodynamically unstable; appropriate formulation is needed to stabilise the emulsion from separation of the two phases.
Pharmaceutical emulsions may be difficult to manufacture

Question 17

oil-in-water emulsion (o/w

Answer 17

oil is the disperse phase and water the external phase

Question 18

water-in-oil emulsion (w/o)

Answer 18

water is the disperse phase and oil is the external phase.

Question 19

multiple emulsion (w/o/w )

Answer 19

emulsions whose disperse phase contains droplets of another phase

Question 20

Types of emulsions

Answer 20

oil-in-water emulsion (o/w): oil is the disperse phase and water the external phase

water-in-oil emulsion (w/o)
water is the disperse phase and oil is the external phase.

multiple emulsion (w/o/w ) emulsions whose disperse phase contains droplets of another phase

oil, water, emulsifying agents
Emulsion type: defined by stability of droplet phase: phase of lower stability coalesces to form external phase.
Determinants of type of emulsion produced
phase volume of internal phase (in practise phase volume ratio 50%- stability)
Chemical properties of film surrounding internal phase
viscosity of internal and external phases

Question 21

Acceptable emulsion/cream

Answer 21

Physical stability: no phase separation
Flow properties: enable formulation to be easily removed from container.
Formulation easily spread over affected area (external application)
Aesthetically and texturally pleasing.
Suitable flavour (emulsion for oral application)
Correct texture: emulsions externally applied

Question 22

Cracking (irreversible instability)

Answer 22

Cracking: complete coalescence of the internal phase, resulting in separation of emulsion into two layers
due to the destruction of the mono/multilayer film at the interface between the droplet and external phase.
If an emulsion has cracked it cannot be recovered.
may be due to:
Incorrect selection of emulsifying agents.
Presence of incompatible excipients
Temperature
Microbial spoilage.

Question 23

Flocculation

Answer 23

In flocculated state: secondary interactions (van der Waals forces) maintain droplets at a defined distance of separation (within the secondary minimum).
Application of i.e. shaking will redisperse these droplets to form a homogeneous formulation.
Although flocculation may stabilise formulation, there is also the possibility that the close location of the droplets (at the secondary minimum) would enable droplet coalescence to occur if the mechanical properties of the interfacial film are compromised.

Question 24

Creaming

Answer 24

result of density difference between the oil and water phases; involves either sedimentation or elevation of droplets of internal phase, producing a layer of concentrated emulsion either at top or bottom of container.
aesthetic problem (resulting emulsion is unsightly); upon shaking emulsion is rendered homogeneous.
Rate of creaming: Stoke’s equation
may be prevented if density difference between the two phases is zero (in practice, cannot be easily achieved).
methods by which the rate of creaming may be reduced are:
Reduce the average particle size of the disperse phase.
Increase the viscosity of the emulsion.

Question 25

Emulsion instability: Hydrophilic polymers

Answer 25

Ability to adsorb at the interface between the disperse phase and the external phase
Gel-like multilayers produced
NOTE!! Surface-active agents: monomolecular (not multimolecular) films

Question 26

Emulsion instability: Adsorbed particles

Answer 26

addition of finely divided solid particles sufficiently wetted by both phases (preferentially wetted by one of the phases)
type of emulsion: depends on preference of particles for each phase; if particles are wetted preferentially by aqueous phase: o/w.
o/w emulsions: aluminium hydroxide; magnesium hydroxide; bentonite; kaolin
w/o emulsions; talc; carbon black.

Question 27

Formulation of pharmaceutical emulsions

Answer 27

Oral, intravenous administration: o/w
Topical administration (creams):
o/w: generally used for water-soluble drugs for local effect; non-greasy
w/o; most moisturising formulations; greasy