4.3 Compounding – Emulsions and Suspensions
Learning Outcomes
Be able to:
- Define pharmaceutical emulsions and emulsifying agents, theory of emulsions.
- Describe the pharmaceutical application of emulsions and suspensions
- Identify the types of emulsions.
- List the classifications of emulsions instability
- Describe the HLB value and its application in emulsions
- Summarise the steps in the preparation of emulsions and prepare
- Describe the stability of emulsions.
Emulsions
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An emulsion is a thermodynamically unstable dispersion of at least two immiscible (or partially miscible) liquids. IMMISCIBLE: DOES NOT MIX – INCAPABLE OF ATTAINING HOMOGENEITY
One liquid phase is uniformly dispersed within the other.
- Dispersed phase (droplets) = internal phase
- Continuous phase = external phase
The immiscible liquids are described as “oil” and “water” as one liquid is nonpolar (oil/wax/lipid) and the other is polar (water/aqueous solution)
Simple Emulsions take on the following forms:
Aqueous emulsion: Oil in water (O/W)
- Water is external (continuous) phase.
- Oil is internal (dispersed) phase.
Oily emulsion: water in oil (W/O)
- Oil is external (continuous) phase.
- Water is internal (dispersed) phase.
Multiple emulsions can be formed from oil and water by the re-emulsification of an emulsion to form 2 dispersed phases.
These are known as:
- Oil-in-Water-in-Oil (O/W/O) or Water-in-Oil-in-Water (W/O/W) emulsions.
- Oil-in-Water-in-Oil (O/W/O) are O/W emulsions dispersed in an oil phase.
- Water-in-Oil-in-Water (W/O/W) are W/O emulsions dispersed in a water phase.
There are various advantages and disadvantages to emulsions
✔️Advantages: |
❌Disadvantages: |
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Where can we find emulsions?
The thermodynamically unstable system that is an emulsion, is stabilised by the addition of an emulsifying agent.
Surfactants/Emulgents/Emulsifying agents assist in the formation of emulsions. They adsorb at the interface between oil and water, creating droplets, also known as micelles, thereby decreasing the surface tension, and preventing coalescence. Thus, stabilising the emulsion.
Micelles are spherical structures that are formed when surfactants reach a certain concentration in water.
🎞️ Let’s watch a video the formation of a micelle:
Surfactants are classified into:
- Anionic surfactants e.g. sodium lauryl sulphate, sodium stearate, calcium oleate
- Cationic surfactants e.g. cetrimide, benzalkonium chloride
- Non-Ionic surfactants e.g. polysorbates, glyceryl monostearate, cetomacrogol
- What is surface tension and how do surfactants reduce surface tension?
🎞️ Let’s watch a video on Surfactants and Surface Tension ⏰ 7 Minutes
To ensure maximum stability
- Mixtures of surfactants with high and low HLB are always better
- The solubility of surfactants in both phases should be appropriate to maintain the stability of the product
- Emulsifier(s) should produce an optimum HLB which is required to produce stable emulsions
🎞️ Let’s watch a video on Surfaces Presented by Dr Martina Mylrea ⏰ 16 Minutes
🎞️ Let’s watch a video on Emulsions ⏰ 26 Minutes
Emulsion Formulation Excipients
- Vehicles for w/o or o/w emulsions (suitable solvents)
- Viscosity enhancer/Density modifiers: hydrophilic polymers
- Buffers for pH adjustment
- Humectants: glycerine
- Antioxidants: ascorbic acid, propyl gallate
- Flavours, colours for oral administration
- Sweetening agents for oral administration
- Preservatives: benzoic acid, phenol, benzalkonium chloride etc
- To increase the viscosity, emulsion thickeners may be used
🎞️ Let’s watch a video on Emulsion Preparation:
Suspensions
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Learning Outcomes
Be able to:
- Describe pharmaceutical suspensions and their application
- List the desirable quality of suspension
- Explain the interfacial properties of suspensions
- Summarise the factors that affect the stability of suspensions (flocculation and deflocculation)
- Describe the Theory of settling and sedimentation, Stokes Law.
- Explain the sedimentation parameters, sedimentation volume and degree of flocculation
- List the formulation and preparation of physically stable suspensions.
What is a suspension?
A suspension is a heterogeneous system consisting of two phases, a coarse dispersion (dispersed phase) which are finely divided insoluble particles (>0.5mm) are dispersed (suspended) uniformly in a liquid (the continuous phase OR dispersing medium)
- The concentration of dispersed phase/particles range from 0.5-30%
- As with emulsions, the dispersed systems are thermodynamically unstable as the small particles are highly energetic and tend to aggregate – floccule, or cake
- To get a stable product, the system needs to reduce surface free energy – reduce surface tension
Why do we need suspensions?
Suspensions are often used as a dosage form when the drug is insoluble in water and when use of solubilising agents are not possible.
- Certain drugs are chemically unstable in solution but are stable when suspended e.g., penicillin
- Dosage forms for people with swallowing difficulties such as children. e.g., Paracetamol or Ibuprofen Suspensions
- Products that are insoluble, such as minerals or inorganic salts. e.g., Calamine Lotion, salts in heartburn medication
- Flexibility in administration of a range of doses – especially when dosing is based on weight. e.g., antibiotics/ parenteral
- Used with medications that may be otherwise unpalatable unless in suspension and flavoured. e.g., antibiotics
Pharmaceutical applications of suspensions
Pharmaceutical, suspensions are used in a wide range of applications, although oral dosing is the most common.
- Oral administration: antibiotics (amoxicillin, Cephalexin oral suspension), antiacid suspensions, paracetamol & ibuprofen suspensions
- Topical administration: Calamine lotion
- Ocular administration: Suspensions for eyes e.g., Flarex eye drops
- Parenteral administration: antibiotics, vaccines
- Suspension for inhalation therapy: aerosols
There are advantages and disadvantages of suspensions
🎞️ Let’s watch a video: Suspensions RN⏰ 16:35 minutes
- Suspended material should not settle too rapidly. Small particles will settle slower than larger particles.
- Fine particles that settle to the bottom of the container should not form hard cake.
- Particles should be readily redispersed into a uniform mixture after gentle shaking.
- Suspension must not be too viscous and should pour readily, freely, and evenly from the opening of a bottle or to flow through a syringe needle.
Considerations when formulating a suspension.
The first thing we must consider when formulating a suspension is the size of the powder particles. Depending on the particle size of the disperse phase, disperse systems can be further categorised as:
- Colloidal (the dispersed particles are in the submicron range), and
- Coarse (dispersed particles are above colloidal size).
HOWEVER, no matter how small or large the particles they are, the particles will eventually begin to settle at the bottom of the bottle under gravity. This will form a sediment. The rate of settling of particles in a suspension is governed by Stokes law.
Stokes law for Dispersed Systems – Rate of Sedimentation
Stokes law says that as the size or density of the particles increases, they will settle faster, and as the viscosity or density of the continuous phase increases, they will settle slower.
Particles should be MORE DENSE than the vehicle – YES this would mean they settle faster BUT if they were less dense then the particles would float and you would not be able to get uniform distribution throughout the vehicle.
If we have a very small particle size, Stokes law says the rate of settling will be slow. HOWEVER – this does not mean that a small size is better.
🎞️ Let’s watch a video⏰ 8 minutes
📚 Read/Explore
- Question: Why do we need to “shake well before use”, what happens when we sell or dispense a suspension to a patient and why do we attach the ancillary label?”
- Answer: Shaking will uniformly distribute the API particles throughout the bottle. If the API particles were not uniformly distributed, then the patient would get the wrong dose. The dose will be either too low if the top of the product is used, or too high particles will be of a greater concentration of towards the bottom of the bottle if not shaken properly.
- Question: What happens to a suspension after it had been stored for a period of time, like on the shelf in the pharmacy?
- When particles settle, they form sediment. When a suspension contains small particles that settle slowly the sediment that forms will be small and closely packed so it will be fairly dense.
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- Dense, well packed sediment will be hard to redisperse on shaking. The consumer will have to shake the bottle very hard and may not even be able to fully redisperse the particles. To have a sediment that is easy to redisperse, we want it not well packed with lots of space between the particles. Larger particles will settle faster but won’t be as densely packed, and the sediment will be and the easier to redisperse.
- BUT REMEMBER – If the particles are too large, they may be easier to redisperse, but they will be gritty.
- How do I to get smaller particles to settle faster, but be easier to redisperse?
- By adding another excipient. Usual excipients of a suspension are the same as for a solution:
- API
- Flavourant
- Colourant
- Preservative
- Vehicle.
- By adding another excipient. Usual excipients of a suspension are the same as for a solution:
Suspending Agent
We know that suspensions come with the instructions “shake well before use.” This is so we can redistribute any settled particles throughout the suspension.
Settling can be due to low zeta potential. Zeta potential is used to measure the stability of a suspension. It is a physical property which is exhibited by any particle in suspension, macromolecule, or material surface. It can be used to optimise the formulations of suspensions, emulsions, and protein solutions.
It determines the degree of repulsion between adjacent, similarly charged dispersed particles.
Knowledge of the zeta potential can reduce the time needed to produce trial formulations. It can also be used as an aid in predicting long-term stability.
Low Zeta potential indicates that the particles in the suspension are likely to be attracted to each other and clump together, thus settling in lumps.
As Zeta potential reduces the suspension becomes less stable as the attractive forces exceed the repulsive forces and the particles come together- aggregation
Addition of flocculating and deflocculating agents is often monitored by measurement of the zeta potential of particles in a suspension.
Adjustment of zeta potential by the addition of flocculating agents, surfactants and other additives can be used to produce a more uniformly spread suspension and increases the stability of the system.
Most suspension particles dispersed in water have a charge acquired either by specific absorption of ions or by ionization of ionisable surface groups, if present. If the charge arises from ionization, the charge on the particle will depend on the pH of the environment.
Measuring a correct and appropriate zeta potential value is one of the keys to a quality product.
🎞️ Let’s watch a video on Suspensions⏰ 16 minutes
A well formulated suspension should be easy to shake and disperse the particles, but for the particles to settle fast to make sure a hard sediment. In other words, it exhibits the correct degree of flocculation.
Under flocculated systems tend to settle and sediment very rapidly although the compacts formed are loose and redispersion is possible.
Over flocculated systems settle slowly the sediment is tightly packed and redispersion is not possible.
Deflocculation
In deflocculation all individual particles exist as separate particles, these particles fall according to Stokes’ Law.
The rate of sedimentation is slow but does form a hard cake which cannot be redispersed on shaking. Larger particles will fall more rapidly than the smaller ones.
Caking is prevented by the addition of flocculating agents.
By controlling the degree of flocculation, it’s possible to reach a happy medium – in which there is a degree of flocculation and also deflocculation. Controlled flocculation can be achieved by:
1. PARTICLE SIZE CONTROL
2. CONTROLLING ZETA POTENTIAL by addition of electrolytes. The addition of inorganic electrolytes changes the zeta potential of the dispersed particles, and provided this is lowered sufficiently enough, will produce a flocculated system.
3. ADDITION OF SURFACTANTS to reduce surface tension
4. ADDITION OF POLYMERS (Structured Vehicles) Hydrophilic These are generally Aqueous solutions of polymers which form networks in disperse systems, adsorbing onto and trapping dispersed particles and holding them in a flocculated state. These materials are mainly hydrocolloids although not always, and include carboxymethylcellulose, methylcellulose, starches, alginates, carbomers, tragacanth.
These all REDUCE the rate of sedimentation.
In suspensions, electrolytes, ionic surfactants, and polymers are all known as FLOCCULATING AGENTS
All these factors bring together the best possible suspension.
You can now go into your compounding and produce a quality suspension!
📚 Read/Explore
- Aulton’s Pharmaceutics (Sixth Edition) 2022
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