Pharmaceutical emulsions/creams are commonly used pharmaceutical products that are primarily prescribed for the treatment of external disorders. In addition to this use emulsions are clinically used for total parenteral nutrition, for the oral administration of therapeutic agents and for the rectal administration of antiepileptic agents. The terms emulsions and creams refer to disperse systems in which one insoluble phase is dispersed as droplets within a second liquid phase.
The rheological properties (and hence the structure of the network within the formulation) of the two systems differ considerably. Creams are pseudoplastic systems with a greater consistency than, for example, oral or parenteral emulsions.
Emulsions like suspensions, belong to the group of heterogeneous systems. They are coarse dispersion of two immiscible liquids, one of which is uniformly distributed in form of small droplets (diameter greater than 0.1um) throughout the other one. The droplets are called the dispersed or internal phase and the surrounding liquid is named as the continuous phase, external phase or dispersion medium. Emulsions are stabilized by a third component the emulsifying agent, emulgent or emulsifier.
There are two types of emulsions: oil-in-water (o/w) and water-in-oil (w/o) emulsions and they be liquid or semi-solid. In pharmaceutical practice the term “emulsion” is usually applied only to the emulsions that are intended for internal use. Liquid emulsions for external use are commonly referred to as lotions or liniments; if they are more viscous they are called applications. Semi-solid emulsions are called creams, which are applied to the skin.
The physical stability of emulsions may be increased mainly by preventing coalescence and creaming as much as possible
Coalescence is the process where the dispersed droplets re-unite due to the high surface energy of the dispersed phase, which may lead to the cracking of the emulsion. A cracked emulsion cannot be re-dispersed permanently by shaking. Coalescence is reduced by the addition of an emulsifying agent, which decreases the surface tension at the oil-water interface
Emulgent usually consist of larger molecules with a lipophilic and a hydrophilic part; one part of the molecule tends to associate with the oily phase and the other one with the aqueous phase, thus being able to form an interfacial film at the oil-water border. Forexample, with an oil-in-water emulsion the emulgent molecules will form a film around the oil globules with the lipophilic end of the molecule directed towards the oil drops and the hydrophilic end towards the aqueous phase. Which type of emulsion is formed, o/w or w/o, is determined mainly by the solubility of the emulgent; the phase in which the emulgent is more soluble will form the continuous phase.
Creaming occurs when globules aggregates and concentrates in one specific part of the emulsion. The aggregated globules can move upward through the continuous phase and form a layer of concentrated globules at the surface of an emulsion. e.g. when fresh milk stands for some time a layer of cream appears at its surface. A creamed emulsion can be redispersed by shaking or stirring. The rate of creaming depends on the factors indicated in Stoke’s law and can be reduced by decreasing the globule size and by increasing the viscosity of the preparation.
Under certain conditions an o/w emulsion can be turn into (‘invert’ to) a w/o emulsion or vice versa, which means the continuous phase of the original emulsion becomes the dispersed phase and the dispersed phase becomes the continuous phase. Phase inversion may be caused by changing the solubility of the emulgent e.g. addition of calcium ions to an o/w emulsion, which is stabilized by a sodium soap, results in the formation of w/o emulsion, which is stabilized by the formed calcium soap. Phase inversion may also occur when the volume of dispersed phase becomes very large.
This involves coalescence of the dispersed globules and separation of the disperse phase as a separate layer (cracking), and re-dispersion cannot be achieved by shaking. Cracking can be caused by
- Additional of an emulsifying agent of opposite type
- Decomposition or precipitation of emulsifying agent
- Microbial action on the emulsifying agent
- Addition of a common solvent
- Incorporation of excess disperse phase
Advantages of pharmaceutical emulsions
Pharmaceutical emulsions may be used to deliver drugs that exhibit a low aqueous solubility. For example, in o/w emulsions the therapeutic agent is dissolved in the internal oil phase. Following oral administration the oil droplets (and hence the drug) may then be absorbed using the normal absorption mechanism for oils. Some drugs are more readily absorbed when administered as an emulsion than as other oral compactor formulations.
Pharmaceutical emulsions may be used to mask the taste of therapeutic agents, in which the drug is dissolved in the internal phase of an o/w emulsion. The external phase may then be formulated to contain the appropriate sweetening and flavouring agents. Emulsions may be commonly used to administer oils that may have a therapeutic effect. For example, the cathartic effect of oils, e.g. liquid paraffin, is enhanced following administration to the patient as droplets within an o/w emulsion. The taste of the oil may be masked using sweetening and flavoring agents. If the therapeutic agent is irritant when applied topically, the irritancy may be reduced by formulation of the drug within the internal phase of an o/w emulsion. Pharmaceutical emulsions may be employed to administer drugs to patients who have difficulty swallowing solid-dosage forms. Emulsions are employed for total parenteral nutrition.
Pharmaceutical emulsions are thermodynamically unstable and therefore must be formulated to stabilize the emulsion from separation of the two phases. This is by no means straightforward.
Pharmaceutical emulsions may be difficult to manufacture.
Emulsion dosage forms are designed to meet the following quality attributes:
1. Uniformity of content (dose-to-dose within the same bottle and bottle-to-bottle): All the doses dispensed from a given multidose container should have acceptable uniformity of drug content. In addition, the drug content must be uniform between different bottles of a given batch of emulsion.
2. Separation volume or creaming: Once an emulsion has been left undisturbed for some time, it may show some degree of separation of the dispersed phase from the dispersion medium. For example, in the case of an o/w emulsion, creaming of an emulsion is sometimes observed, which indicates a higher concentration of the dispersed oil phase in the top layer of the emulsion. This top phase is visually distinguishable from the bottom layer due to greater light obscuration and diffraction by a higher concentration of the dispersed phase globules.
More the concentration of the dispersed phase, more the light obscuration in a smaller thickness of the creamed layer and greater the instability. Thus, the proportion of the volume occupied by the separated phase is an indicator of physical instability of the emulsion. Higher this volume, more stable is the emulsion.
3. Dispersed phase size distribution: Size distribution of dispersed phase should remain fairly constant during the shelf life of the emulsion. Brownian motion, agitation during handling, and gravitational motion of the dispersed phase lead to collisions of globules with each other, which can cause coalescence or agglomeration resulting in an increase in the size of the dispersed phase. A change in the dispersed phase globule size on storage is indicative of inherently low physical stability of the emulsion.
4. Drug concentration: In cases where drug concentration in the emulsion is close to the drug solubility, crystallization can sometimes occur due to temperature fluctuations during storage, preferential evaporative loss of one phase, incompatibility with packaging components, or unintended nucleation. Crystal growth can be inhibited by the use of appropriate solubilizers and surfactants, and by formulating an emulsion at a lower concentration than the drug’s thermodynamic solubility. Changes such as drug crystallization or evaporative loss of the continuous phase can reflect changes in the drug concentration during storage stability or shelf life.
5. Palatability: Use of an emulsion dosage form can improve the palatability of particularly bitter drugs by dissolving them in the dispersed phase. However, incorporation of the drug in the dispersed phase may not be adequate because some drug would inadvertently partition into the continuous phase depending on the partition coefficient (logP) of the compound.
Palatability of the emulsion can be increased by the use of sweeteners, flavors, and colorants. In certain cases, specialized taste-masking approaches, such as complexation, may be needed. These considerations, of course, are not pertinent for parenteral emulsions. In the case of parenteral emulsions, tissue irritability and osmotic pressure are important considerations.
6. Redispersability: A separated or creamed emulsion should readily redisperse upon gentle shaking of the container.
7. Absence of phase separation: Coalescence leading to phase separation is irreversible. Although creaming of an emulsion is, to some extent, unavoidable, the dispersed phase should not coalesce and separate from the dispersion medium. This needs to be designed into the formulation by the use of right surfactants in an appropriate concentration.
8. Deliverability: The labeled number of doses and the labeled amount of emulsion should be deliverable from a bottle under the normal dispensing conditions by a patient. This is usually ensured by pouring out the labeled number of doses from the container and ensuring that the remaining dose can be poured completely within a reasonable period of time.
9. Flow: The emulsion must not be too viscous to pour freely from a bottle or to flow through a needle syringe or an IV infusion set (for parenteral emulsions).
10. Lack of microbial growth: Use of antimicrobial preservatives could be sufficient for oral and topical emulsions, whereas parenteral, nasal, and ophthalmic suspensions must be sterile.
11. Physical integrity: The dosage form should not show any unexpected change in color, or any other change in physical appearance or perception of the dosage form, such as odor, that may alarm the patient and/or the health-care provider with respect to the physical integrity of the emulsion.
12. Adhesion to the package: Preferential adsorption or adhesion of one phase or component of the emulsion, such as the drug, the chelating agent, or the emulsifier, can adversely affect the uniformity and stability of an emulsion.
13. Leachables and extractables: Primary packaging components of the emulsion can leach out small amounts of chemical components used in the manufacturing of those components. This behavior can be exacerbated at certain pH values of the formulation. The packaging components must be selected appropriately, and their compatibility with the emulsion determined to make sure no chemical compounds leach into or are extracted by the emulsion from the container on storage.
14. Chemical stability: There should not be any unacceptable chemical degradation of the drug during the shelf life of the product under recommended packaging and storage conditions. The drug product must meet the predetermined requirements of maximum levels of known and unknown impurities.
15. Drug release: Since an emulsion contains the drug in the dispersed phase, the release of drug from the dispersed phase into an aqueous solution in an appropriate dissolution vessel is quantified and controlled as an indicator of its bioavailability. This could be particularly important for semisolid emulsions.