Pharmaceutical Emulsions
Pharmaceutical Emulsions
It is a preparation which consist of 2 immiscible liquids in which one is dispersed as globules in the other phase known as the continuous phase. The dispersed phase is usually immiscible or partly miscible in the continuous phase.
Emulsification process requires energy input (usually in form of agitation) to produce an emulsion. Emulsion produced is usually thermodynamically unstable and will require an emulsifier to stabilize it
Type Of Emulsions
·?????? Water-in-oil > dispersed phase is water and continuous phase is oil.
·?????? Oil-in-water> dispersed phase is oil and continuous phase is water
·?????? Multiple emulsions> can be made from an already existing emulsion for example o/w emulsion can be used t form oil-in-water-in-oil(o/w/o) emulsions
Emulsion Formation and Surface-free Energy
Emulsions consist of at least 2 immiscible liquids and are thermodynamically unstable. The oil phase usually exhibits Van der Waals forces between molecules and the water phase exhibits hydrogen bonding. Formation of dispersion droplets is thermodynamically unfavorable and thus will require introduction of energy. This energy is mainly introduced in the form of agitation or shear mixing.
After the formation of the emulsion, molecules from both phases must be stabilized to prevent coalescing or phase separation. This is achieved by using emulsifying agents
Emulsifying Agents
Emulsifying agents achieve emulsification by following ways:
Types Of Emulsifiers
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Surfactants
These are amphiphilic molecules, which means they contain both polar group and non-polar group to their structure. These surfactants get adsorbed at the water-oil interface, which then decrease the interfacial tension. Some charged surfactants can be used to alter the zeta potential of dispersed phase as well
Type of Surfactants
They include ionic surfactants, nonionic surfactants and polymeric surfactants. Ionic surfactants are further grouped into anionic and cationic surfactants. Ionic surfactants have a strong affinity to variety of molecules due to their charge and are highly toxic hence their limited use in oral/i.m/i.v. formulations. Many of the ionic surfactants are used in topical preparations at low concentrations. Nonionic are less toxic and some are used in oral and i.v/i.m preparations. They are less affected by changes in pH or electrolytes when compared to ionic agents
Anionic Surfactant
These contain an anionic or acidic functional group which becomes negatively charged at pH higher than their pKa. Anionic surfactants lose their potency under acidic conditions or to electrolytes and polyvalent ions. Examples include Triethanolamine stearate, Sodium lauryl sulfate and Calcium oleate
Cationic Surfactant
They contain a basic functional group which becomes positively charged at pH higher their pKa. Cationic agents are less effective and unstable at high pH or to electrolytes and polyvalent ions. Examples include Quaternary ammonium compounds.?
Nonionic Surfactant
They do not contain any charge. Examples include Polyoxyethylene sorbitan oleate, Polyethylene glycol 40 stearate
Polymeric Surfactants
These are neutral synthetic emulsifiers. They are less toxic as compared to ionic surfactants and can be used for parenteral preparations. Examples include Poloxomers.
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Naturally Occurring Emulsifying Agents
These are derived from plants or animals. Their concentration varies and are prone to microbial contamination. Use of these emulsifiers is not economically viable since the resource in which they are obtained maybe limited and also requires extraction and purification. Examples include acacia, wool fat, bentonite lecithin.
Finely Divided Solid Particles
The solid particles used as emulsifiers must be wetted by both the oil and water phases. The solid particles accumulate at the oil-water interface where they form a film around dispersed droplets. This film acts as a physical barrier which prevents coalescing of droplets. The solid particles used must be smaller than the dispersed droplet size. Solid particles which are wetted more by water form oil-in-water emulsions whilst those wetted more by oil form water-in-oil emulsions. Examples include Aluminum hydroxide, bentonite.
The hydrophile-lipophile balance (HLB)
HLB is based on the relative strength and size of the hydrophilic portion to the hydrophobic portion of the emulsifier. The HLB scale ranges from 0-20 and the greater the number, the more water soluble the emulsifier is. For o/w emulsions, emulsifiers with HLB range 8-15 are used and for w/o emulsions, emulsifiers with HLB scale 4-8 are used.
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Emulsion Manufacturing Process
The process of mixing 2 immiscible liquids together requires high shear mixing in order to produce droplets of required size. Emulsifiers help in mixing by making droplets break up easily into desired size.
Before mixing, excipients and API are added in the phase which they are most soluble. The phases are combined by slowly adding the dispersed phase into the continuous phase whilst continuously mixing. Continuous agitation (mixing) should be maintained for an optimum period of time to ensure that emulsion is formed with the right droplet size distribution.
Some oils will require certain high temperatures to melt before mixing, thus the water phase should also be heated to the same temperature prior mixing to avoid formation of granules/precipitates. Volatile or thermosensitive excipients are added lastly once the emulsion has cooled down.
As for multiple emulsions, the primary emulsion either o/w or w/o is prepared. After its preparation, it is re-emulsified to produce w/o/w or o/w/o emulsions
In Pharmaceutical preparation of emulsion, a mixture of emulsifiers are used instead of one emulsifier. In most cases, an emulsifier with a low HLB is mixed with that with a high HLB. The resulting emulsion from mixture of emulsifiers is more stable when compared to emulsions with individual emulsifiers.
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Emulsion Stability
3 main stabilities of importance in emulsions are physical, chemical and microbial stability
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Physical Instability
The 4 main types of physical instability which affects emulsions are, coalescence, flocculation, Ostwald ripening and creaming. Creaming and flocculation tend to be reversible upon agitation or shaking. Ostwald ripening and coalescence are irreversible and ultimately affect product integrity to a greater extent.
Flocculation
It is formed when droplets come close together to form clusters or floccules which are separated by the entrapped continuous phase. The floccule behaves as a droplet, although each droplet within the floccule will remain separated from the other. Flocculation occurs due to attractive force (Van der Waals) which attracts droplets to come together but weak enough to overcome the repulsive force thus keeping the droplets from merging with one another. Flocculation is reversible and can be achieved by mild shaking/ agitation of emulsion. Illustration of flocculation is shown below
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Creaming
It is a process which is facilitated by gravity where the dispersed droplets having different density with continuous phase come close together to form a more concentrated layer of droplets which forms a cream. Since oil is less dense than water, in an o/w emulsion, the droplets rise to the top of emulsion and in a w/o the droplets will be at the bottom of emulsion forming a sediment. Creaming increases likelihood of coalescing because of close packing of droplets and is undesirable. Creaming is reversed by mild agitation of the emulsion
Coalescence
It is an irreversible by which dispersed droplets merge together to form larger drops. Coalescence occurs when droplets come together and the attractive forces are greater than the repulsive forces such that droplets reach primary minimum well. At the primary minimum, there is drainage of continuous phase between droplets, once droplets are close together, there follows the rupture of the film surrounding the droplets, merging the droplets to produce a much bigger droplet. Coalescence can be avoided by use of emulsifier that forms a strong film surrounding the droplets which does not rupture and increasing viscosity of emulsion such that droplets do not come close together.
Ostwald Ripening
It is an irreversible process which occurs when droplets are slightly miscible in continuous phase. The droplets dissolve in continuous phase and redeposit on larger droplets forming a bigger droplet size. This process can be prevented by having an emulsifier which forms a strong film that does not rupture easily. It can also be prevented by adding an oil which is immiscible in the continuous phase
Phase Inversion
This is where the dispersed phase becomes the continuous phase and continuous phase becomes dispersed phase. For phase inversion to occur, specific conditions must be met first. In most cases, higher temperatures contribute to phase inversion where a Phase Inversion Temperature must be reached (PIT). Within the PIT range, the HLB value of emulsifier changes, in most cases it becomes more lipophilic, which increases the chances of turning an o/w emulsion into a w/o emulsion. Storage condition for emulsions should be kept within 25?C to 60?C. Phase Inversion may occur due interaction of emulsion with certain ions such as Calcium ions.
Quality Attributes of A Good Emulsion
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Palatability
This is important for oral emulsions. Drugs with unpleasant taste can be masked by dissolving them in dispersed phase. In some cases the drug may be miscible in continuous phase, and in such cases, sweeteners or flavors maybe added to the emulsion to mask the taste
Uniformity Drug Concentration
There should be a constant uniform dose on each dosage within a bottle and across a whole batch on each individual package
Redispersability
In the event of creaming or flocculation, the emulsion should be re-dispersed easily by a mild shaking of emulsion
Flow
For i.m. or i.v. the emulsion should not be too viscous so that it can run through a needle easily. For oral emulsion, optimum viscous should be attained so that drug concentration on each dose remains the same
Chemical stability
Emulsion should be able to withstand chemical degradation such as oxidation or hydrolysis during its shelf life. This can be achieved by adding antioxidants to the emulsion
Microbial Stability
This can be achieved by use of preservatives which prevents microbial growth during product shelf life
Physical Stability
Coalescence of emulsion is unacceptable as this is irreversible and affects uniform drug concentration and should be prevented by specific emulsifiers. Processes such as creaming or flocculation may occur and if they do occur, they should easily be reversed by mild shaking of emulsion. The emulsion also should be able to maintain its color and smell.
?Uniform droplet size distribution
There should be a fairly constant droplet size distribution within the emulsion as this helps with constant drug concentration per dose. Processes which affect droplet size such as coalescence or Ostwald ripening should be prevented