Excipients are sub-divided into various functional classifications, depending on the role that they play in the resultant formulation.
In Liquid/Suspension products, the possible types of excipients include:
- Solvents/co-solvents e.g. Aqueous Vehicle, Propylene Glycol, Glycerol
- Buffering agents, e.g. Citrate, Gluconates, Lactates
- Preservatives, e.g. Na Benzoate, Parabens (Me, Pr and Bu), BKC
- Anti-oxidants, e.g. BHT, BHA, Ascorbic acid
- Wetting agents, e.g. Polysorbates, Sorbitan esters
- Anti-foaming agents, e.g. Simethicone
- Thickening agents, e.g. Methylcellulose or Hydroxyethylcellulose
- Sweetening agents, e.g. Sorbitol, Saccharin, Aspartame, Acesulfame
- Flavouring agents, e.g. Peppermint, Lemon oils, Butterscotch, etc.
- Humectants, e.g. Propylene Glycol, Glycerol, Sorbitol
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Solvents/Co-Solvents
Water is the solvent most widely used as a vehicle due to:
- Lack of toxicity, physiological compatibility, and good solubilising power (high dielectric constant), but
- Likely to cause instability of hydrolytically unstable drugs
- Good vehicle for microbial growth
Sorbitol, dextrose, etc. are often added as solubilisers, as well as base sweeteners
- Similar pros and cons to water alone
Water-miscible co-solvents are used to:
- Enhance solubility, taste, anti-microbial effectiveness or stability
- Reduce dose volume (e.g. oral, injections)
- Or, conversely, optimise insolubility (if taste of API is an issue)
- Examples: propylene glycol, glycerol, ethanol, low molecular weight PEGs
Water-immiscible co-solvents, e.g.
- Emulsions / microemulsions using fractionated coconut oils
Buffering Agents
Can be necessary to maintain pH of the formulation to:
- Ensure physiological compatibility
- Maintaining/optimising chemical stability
- Maintaining/optimising anti-microbial effectiveness
- Optimise solubility (or insolubility if taste is an issue)
- But, optimum pH for chemical stability, preservative effectiveness and solubility (or insolubility) may not be the same
➡️ Compromises need to be made
Preservatives
Preservatives used in multi-use cosmetic/pharmaceutical products (including paediatric formulations)
- prevents an increased risk of contamination by opportunistic microbial pathogens (from excipients or introduced externally), resulting in potential health consequences
Ideally targeted for microbial cells - showing no toxicity/irritancy towards mammalian cells
- In reality, the majority of effective GRAS preservatives are active against both microbial and mammalian cells (non-specific cytoplasmic poisons)
There is a limited number of approved preservatives available for multi-use oral products, and options are even more limited for other routes of administration.
This restricted number can be further reduced by dose, pH-solubility profiles, incompatibilities, adsorption, toxicity and other relevant physico-chemical factors.
Anti-Oxidants
Used to control oxidation of:
- API, e.g. lovastatin
- Preservative, e.g. potassium sorbate
- Vehicle, e.g. oils or fats susceptible to β-oxidation
Sacrificial (more oxidisable than API, preservative, etc). Levels will reduce with time…. need to be monitored by specific assay
Need to assess regulatory acceptability (differs in different countries)
Efficacy can be affected by:
- Compatibility with other excipients
- Partitioning into micelles (from surfactants)
- Adsorption onto surfaces (container, thickening agent and suspended particles)
- Incompatibilities, e.g. with metal ions
Wetting Agents
To aid ‘wetting’ and dispersion of a hydrophobic API, preservative or antioxidant
- Reduce interfacial tension between solid and liquid during manufacture or reconstitution of a suspension
- Not all are suitable for oral administration
Examples include:
- Surface active agents, e.g.
- Oral: polysorbates (Tweens), sorbitan esters (Spans)
- Parenteral: polysorbates, poloxamers, lecithin
- External: sodium lauryl sulphate
- ….but these can cause excessive foaming (see anti-foaming agents) and can lead to deflocculation and undesirable physical instability (sedimentation) if levels too high
Hydrophilic colloids that coat hydrophobic particles, e.g. bentonite, tragacanth, alginates, cellulose derivatives. Also used as suspending agents, these can encourage deflocculation if levels are too low.
Anti-Foaming Agents
The formation of foams during manufacturing processes or when reconstituting liquid dosage forms can be undesirable and disruptive.
Anti-foaming agents are effective at discouraging the formation of stable foams by lowering surface tension and cohesive binding of the liquid phase.
A typical example is Simethicone (polydimethylsiloxane-silicon dioxide), which is used at levels of 1-50ppm.
Of course, a foam is also a very valid dosage form option for certain situations, e.g. for topical administration and in wound dressings.
In addition, granulation using a foam rather than aqueous granulation fluid is gaining popularity.
Thickening Agents
Suspension stabilisers: prevent settling/sedimentation (particularly if a wetting agent present)
They usually modify viscosity and are often thixotropic (where viscosity is dependent on applied shear and exhibits ‘shear thinning’)
- Easily poured when shaken
- Quickly reforms ‘gel-like’ structure
- They can impact on flocculation at low levels
Work by entrapment of solid particles, e.g. API, in a viscous or even ‘gel-like’ structure
- Can be either water-soluble, e.g. methylcellulose or hydroxyethylcellulose
- Or water-insoluble, e.g. microcrystalline cellulose
Sweetening Agents
Natural sweeteners
- Sucrose; soluble in water (vehicle), colourless, stable (pH 4-8), increases viscosity; Arguably the best taste/mouthfeel overall but cariogenic & calorific → avoid in paediatrics?
- Sorbitol (non-cariogenic, non-calorific - appropriate for paediatric formulations), but lower sweetness intensity than sucrose (so you need more) & can cause diarrhoea
Artificial sweeteners
- Regulatory review required – often restricted territories
- Much more intense sweeteners compared with sucrose
- As a consequence the levels are much lower (<0.2%)
- Can impart a bitter or metallic after-taste (hence used in combination with natural sweeteners), e.g.
- Saccharin, and it’s salts
- Aspartame
- Acesulfam –K
- Sucralose – excellent sweetness, non-cariogenic, low calorie, wide & growing regulatory acceptability but relatively expensive
Flavouring Agents
Supplement and complement a sweetening agent
- Ensures patient compliance (especially in paediatric formulations – a big issue)
- Can be natural, e.g. peppermint, lemon oils,
- Or artificial e.g. butterscotch, ‘tutti-frutti’ flavour
- Instability can be an issue – combinations can be used to cover intended product shelf-life
Taste appreciation is not globally consistent…
- Genetic element: one person’s acceptable taste is another’s unacceptable taste
- Territorial (cultural?) differences in preference; e.g. US vs. Japan vs. Europe
Regulatory acceptability of flavours needs to be checked
- Different sources, different compositions, different flavour, e.g. there are >30 different “strawberry flavours”!
Humectants
Hygroscopic excipients used at ~5% in aqueous suspensions and emulsions for external application.
Their function is to retard evaporation of aqueous vehicle of dosage form:
- To prevent drying of the product after application to the skin
- To prevent drying of product from the container after first opening
- To prevent cap-locking caused by condensation onto neck of container-closure of a container after first opening
Examples include:
- propylene glycol
- glycerol
- PEG
Any questions?
