Formulation of Emulsions
A typical emulsion consists of API (drug), oil, water and excipients (non-drug).
Type of drug depends on the internal phase. If internal phase is oil (in o/w emulsion) the drug is lipid soluble/ hydrophobic and vice versa.
Excipients include antioxidants, emulsifying agents (surfactants, those obtained from natural sources [gums] and finely divided solids) and preservatives (antimicrobial agents).
ANTIOXIDANTS
Role: to avoid degradation of oils and drugs due to oxidation. Oxidation may occur due to slight incorporation of air during mfg. Oils also may get rancid. Oxidising agents (metal impurities) may enter in emulsions through water source. Antioxidants prevent such spoilage by either blocking chain recation or oxidation of foreign bodies.
Types of oils used in emulsions: vegetable oils, mineral oils, vitamin oils.
Other: Steroidal materials.
Antioxidants: Alkyl gallates, Butylated hydroxy toluene (BHT), Butylated hydroxy anisole (BHA) and tocopherols.
PRESERVATIVES
An emulsion system containing high water content and carbohydrates, proteins or steroidal materials is prone to microbial contamination.
Sources of contamination: raw materials and equipments.
Steps where contamination may occur: during manufacturing, packaging or during the use of product.
It is possible that partitioning of preservatives between oil & water phases create problems. It is important to maintain adequate preservative concentration in aqueous phase. If preservative has high oil-water partition coefficient, the preservative amount added will be clinically unacceptable. Hence, choice of preservative is important.
Examples : Chloroform, hydroxybenzoate esters, chlorocresol, organic acids such as benzoic acid & sorbic acid, phenyl mercuric nitrate & phenyl mercuric acetate (organic mercury compounds), phenoxyethanol, cetrimide (quaternary ammonium compound) and aodium benzoate.
Emulsifying agents can interact with preservatives.
Phenolic preservatives - polysorbates/ polyoxyethylene group.
Hydroxybenzoate esters - polysorbates, povidone, macrogols, gelatin & methyl cellulose.
EMULSIFYING AGENTS
Emulsifying agents help to disperse the globules in emulsified system (and avoid coalescence) by forming barriers at the interface. They reduce interfacial tension between two phases. Strength and nature of the interfacial film determines the stability of emulsion.
Ideal properties of emulsifying agents:
Stable, inert, free from irritant and toxic properties. It should be odorless, colorless, tasteless and should be effective in low concentrations.
Emulsifying agents can be classified as three groups: surfactants, those derived from natural sources and finely divided solids.
SURFACTANTS
Molecular structure: hydrophilic and lipophilic regions.
Lipophilic/ non-polar groups: attracted to oil phase.
Hydrophilic/ polar groups: attract to water/aqueos phase.
Interfacial film serves as a mechanical barrier to coalescence by chemical or physical effects of emulsifier or by repulsive/electrically charged group effect or by combination of two.
Cationic, anionic & ampholytic surfactants provide surface charge by stabilization of globules.
Surfactants are of four types: anionic, cationic, non-ionic and ampholytic.
Anionic Surfactants:
Unsuitable for internal use due to unpleasant taste & irritant action on intestinal mucosa.
Stearic acid (fatty acid): useful emulsifying agents but are used after treatment (partial neutralisation) with inorganic bases.
Alkali metal & ammonium soaps:
Ammonium, potassium & sodium salts of long chain fatty acids. E.g. Sodium stearate (good for o/w emulsion). Unstable below pH 10.
Incompatible with acids and polyvalent inorganic & long chain organic cations.
Soaps of divalent & trivalent metals:
Calcium, zinc, magnesium, aluminium stearates. Good for w/o emulsions. E.g. Calcium stearate.
Amine soaps:
Forms o/w emulsions. Forms in situ upon reaction between amines (e.g. ethanolamine, diethanolamine, triethanolamine or isopropanolamine) & fatty acids (e.g. oleic acid)
More resistant to the pH change.
Alkyl sulphates:
These are the esters formed upon reaction of fatty alcohols with sulphuric acid. Example: sodium lauryl sulphate, sodium cetostearyl sulphate & triethanolamine lauryl sulphate. Form o/w emulsion but often need a secondary emulsifying agent. These are widely used as wetting agents.
Alkyl phosphates:
Esters formed upon reaction of fatty alcohols with phosphoric acid. Similar characteristics as alkyl sulphates.
Alkyl sulphonates: e.g. Docusate sodium. It forms o/w emulsion when used along with a secondary emulsifying agent.
Hydrolysis: Alkyl sulphates > Alkyl sulphonates
Carbomer:
Synthetic carboxyvinyl anionic polymer.
Forms o/w emulsions which are used for internal & external use.
Used with combination of other emulsifying agents.
Cationic Surfactants:
Examples: Quaternary ammonium compounds, cetrimide & benzalkonium chloride.
Used in combination with secondary emulsifiers.
Forms o/w emulsion- used for external application.
Such emulsions remain stable in the pH range 3 to 7.
Non-ionic Surfactants:
These are used to prepare o/w and w/o emulsions intended for external as well as internal administration.
Non-ionic surfactants remain compatible with other surfactants, stable in the presence if electrolytes & they are stable in pH between 4 to 9.
These are less irritant and can be used in the internal formulations.
These are compatible with phenolic or carboxylic acid group containing preservatives.
Type of the emulsion produced depends on the hydrophilic- lipophilic balance of surfactant (represented by HLB number)
Polysorbates:
(polyoxyethylene sorbitan fatty acid esters)
Formation of polysorbates takes place by copolymerisation of 20 moles of ethylene oxide with 1 mole of mixture of partial fatty acid esters of sorbitol & its mono and di- anhydrates.
To obtain different polysorbates, type of fatty acids and the number of oxyethylene group contained in molecule are changed/altered.
Examples:
Polysorbate 20 (polyoxyethylene 20 sorbitan mono-laurate), polysorbate 60 (polyoxyethylene 20 sorbitan mono- stearate), polysorbate 80 (polyoxyethylene 20 sorbitan mono- oleate).
Polysorbates yield o/w emulsions with good stability. These are resistant to electrolytes & pH changes.
Macrogol:
i) Ethers: (Polyoxyethylene alkyl ethers) produce stable emulsions which can withstand the contact of acids and alkalies.
These are often used in the combination with long chain alcohols.
Examples: polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, cetomacrogol 1000.
ii) Long chain alcohols:
These are weak w/o emulsifying agents.
Main function: stabilization of o/w system (acts as stabilizing agents)
Examples: cetostearyl alcohol, stearyl alcohol, oleyl alcohol, cetyl alcohol.
Poloxamers:
(Macrogol- Polyoxypropylene - macrogol copolymers)
Present in various grades and represented by three digit numbers.
Example: Poloxamer 188
First two digits: approx. average molecular weight of Polyoxypropylene portion of the molecule divided by 10.
Last digit: percentage by weight of polyoxyethylene portions divided by 10.
Water solubility of Poloxamers increases with increase in the number of polyoxyethylene content of the molecule.
Polyvinyl alcohol:
Obtained by the hydrolysis of polyvinyl acetate.
Used as emulsion stabilizers.
Different range of PVA are available with difference in the viscosities.
Ampholytic Surfactants
Not used widely as emulsifying agents.
These are used as bactericidal detergents or in shampoos.
Whether these surfactants act as cationic or anionic depends on the system's pH. Below defined acidic pH, these are cationic & above a defined alkaline pH, these are anionic. An intermediate pH value causes them to act as zwitterion (+ve and -ve charge is present on the molecule at the same time).
Examples: Fatty acid derivatives, amino acids & long chain betains.
How Surfactants are selected?
A surfactant with large hydrophilic group compared with lipophilic (non-polar) group of the molecule helps the formation of o/w emulsion. A surfactant with large lipophilic group helps to form w/o emulsion. The degree of solubility of surfactant in each phase will determine the type of emulsion it will produce.
Other factors such as viscosity & phase volume ratio are also important while deciding the type of emulsion.
HLB Values:
Surfactants with HLB value 4- 6: used for w/o emulsion preparation,
8-18: used for o/w emulsion preparation.
Emulsifying agents derived from natural products
These are derived from the plant & animal sources. These consists of undefined & variable chemical composition, variable emulsifying capabilities, rapidly spoils due to microbial contamination & even gets hydrolysed during storage.
Natural emulsifying products act as surfactants by increasing the viscosity of two phases & are frequently used as stabilizers along with primary emulsifying agents.
Polysaccharides:
Examples: Acacia, Tragacanth & Agar
When used alone, Tragacanth forms less stable emulsion.
Acacia yields stable emulsion of low viscosity, which is thickened by addition of other gums such as tragacanth or agar.
Agar is a poor emulsifying agent, it is used in gels and viscous preparations.
Pectin is also used as emulsion stabilizer.
An effective viscosity enhancing agent- carrageenan is obtained from seaweed. Other seaweed obtained products include salts of alginic acid (sodium alginate).
Some commonly used emulsifiers and viscosity enhancing agents are sodium carboxymethyl cellulose (anionic), hydroxypropyl cellulose (non-ionic) & methyl cellulose (non-ionic).
Steroidal materials:
Derived from animals. These form w/o emulsions.
Examples: wool fat, wool alcohols, beeswax, cholesterol, sodium glycocholate (bile salt), sodium taurocholate (bile salt).
Cholesterol: e.g. lecithin yields o/w emulsions.
Proteins: e.g. Gelatin & Casein
Type A: Cationic gelatin:acidic emulsions (pH 3) are prepared.
Type B: basic emulsions (above pH 8).
Finely divided solids
Colloidal particles accumulate at oil/water interface to yield solid interfacial films. Emulsions prepared with colloidal particles are more stable than prepared with natural emulsifying agents.
Examples:
Bentonite (widely used)
Aluminium magnesium silicate, colloidal anhydrous silica, etc.
For o/w emulsions: 2 to 5% w/v clays are used.
Bentonite can stabilize o/w as well as w/o emulsions.
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