Lecture 10: Pharmaceutical Emulsions PDF

1 Coarse dispersion, Emulsion 12/29/2020  Excipients used in pharmaceutical emulsions 2 One major category of excipients for pharmaceutical emulsions, namely surface active agents. However, as in other pharmaceutical formulation...

1 Coarse dispersion, Emulsion 12/29/2020  Excipients used in pharmaceutical emulsions 2 One major category of excipients for pharmaceutical emulsions, namely surface active agents. However, as in other pharmaceutical formulations, other excipients are required to enhance the physical and chemical stability and to render the formulation aesthetically pleasing to the patient. 12/29/2020  Excipients used in pharmaceutical emulsions 3 Vehicle There are two liquid phases in pharmaceutical emulsions: an aqueous phase and an oil phase. The vehicle in the aqueous phase for pharmaceutical emulsions designed for oral or topical administration is usually purified water. When formulated for intravenous administration, sterile water for injections is used as the external aqueous phase. If control of the pH of the aqueous external phase is required, buffers, e.g. citrate, phosphate, may be included in the aqueous vehicle. In light of the ability of electrolytes to compromise the emulsifying properties of surface-active agents, the concentration and type of buffer should be carefully chosen. Emulsion type is determined by the solubility of the emulsifying agent; if it is more soluble in water than in oil the former will be the continuous phase, and vice versa. Consequently, addition of a substance that alters the solubility of the emulsifying agent may cause reversal of the phases (phase inversion). An o/w emulsion stabilized with sodium stearate can be inverted to the w/o type 12/29/2020 by adding calcium chloride to form calcium stearate.  Emulsion, Emulsifying agents 4 Emulsifying agents Emulsifying agents help the production of a stable dispersion by reducing interfacial tension and then maintaining the separation of the droplets by forming a barrier at the interface. Effective emulsifying agents are surface-active agents. These have hydrophilic polar groups which are orientated towards the water and lipophilic non-polar groups that are orientated towards the oil. Emulsion type is determined by the solubility of the emulsifying agent. If the emulsifying agent is more soluble in water, i.e. hydrophilic, then water will be the continuous phase and an o/w emulsion will be formed. If the emulsifying agent is more soluble in oil, i.e. lipophilic, then oil will be the continuous phase and a w/o emulsion will be formed. Emulsifying agents can be classed into three groups: naturally occurring, surfactants and finely divided solids. 12/29/2020  Emulsion, Emulsifying agents 5 1) Naturally occurring emulsifying agents These agents come from animal or vegetable sources. Therefore the quality may vary from batch to batch and they are susceptible to microbial contamination. 1- Polysaccharides: Acacia is the best emulsifying agent for extemporaneously prepared oral emulsions as it forms a thick film at the oil-water interface to act as a barrier to coalescence. It is used for internal and external use. Tragacanth is used to increase the viscosity of an emulsion and prevent creaming. Other polysaccharides, such as starch, pectin and carageenan, are use to stabilize an emulsion. 2- Semi-synthetic polysaccharides: Low viscosity grades of methylcellulose and carboxymethylcellulose will form o/w emulsions. 3- Sterol-containing substances: These agents act as w/o emulsifying agents. Examples include beeswax, wool fat and wool alcohols. 4- Proteins: Example gelatin, which produces o/w emulsions. 12/29/2020 5- Phospholipids: Example lecithin, which produces o/w emulsions. It is the chief emulsifier in egg yolk.  Emulsion, Emulsifying agents 6 2) Surfactants These agents contain both hydrophilic and lipophilic regions in the molecule. They are classified according to their ionic characteristics as anionic, cationic, nonionic and ampholytic. The latter are used in detergents and soaps but are not widely used in pharmacy. 1- Anionic surfactants: These are organic salts which, in water, have a surface-active anion. They are incompatible with some inorganic cations and with large organic cations such as cetrimide. This category are inexpensive, they are comparatively more toxic than for other categories of surface active agent. This limits their use to external formulations as o/w emulsifying agents. They must be in their ionized form to be effective and emulsions made with anionic surfactants are generally stable at alkaline pH. Many different ones are used pharmaceutically. Some examples include: a) alkali metal and ammonium soaps such as sodium stearate (o/w). b) soaps of divalent and trivalent metals such as calcium oleate (w/o). c) amine soaps such as triethanolamine oleate (o/w). 12/29/2020 d) alkyl sulphates such as sodium lauryl sulphate, cetyl, stearic alcohol (o/w).  Emulsion, Emulsifying agents 7 2- Cationic surfactants: These are usually quaternary ammonium compounds which have a surface-active cation and so are sensitive to anionic surfactants such as the soaps. They are used in the preparation of o/w emulsions for external use and must be in their ionized form to be effective. Emulsions formed by a cationic surfactant are generally stable at acidic pH. The cationic surfactants also have antimicrobial activity. Examples include cetrimide and bezalkonium chloride. 3- Non-ionic surfactants: These are synthetic materials and make up the largest group of surfactants. They are used to produce either o/w or w/o emulsions for both external and internal use. Generally the hydrophobic portion of the molecule is composed of a fatty acid or fatty alcohol whereas the hydrophilic portion is composed of an alcohol or ethylene glycol moieties. ex. Span series (form w/o except span 20 form o/w ) tween(o/w) brij and merj. The non-ionic surfactants are more stable than ionic surfactants in the presence of electrolyte (compatible with both anionic and cationic substances) and are highly resistant to pH change. The type of emulsion formed depends on the balance between hydrophilic and lipophilic groups which is given by the HLB (hydrophilic lipophilic balance) number. High HLB numbers (8-18) indicate a hydrophilic molecule, and produce an o/w emulsion. Low HLB numbers (3-6) indicate a lipophilic molecule and produce a w/o emulsion. Examples include Tween 80, has HLB number of 15 and is more soluble in water to give o/w emulsion and Span 80, has HLB number of 12/29/2020 4.3 and is more soluble in oil to give w/o emulsion.  Excipients used in pharmaceutical emulsions 4-Amphoteric surfactants These are compounds that possess both positively and negatively charged groups (cationic at low pH values and anionic at high pH values). The emulsifying properties are reduced as the pH approaches the isoelectric point of the surface-active agent. The most commonly used amphoteric surface-active agent is lecithin Lecithin is used in emulsions (for intravenous and intramuscular administration) and creams, in which it acts as an o/w emulsifying agent. 8 12/29/2020  Emulsion, Emulsifying agents 9 3) Finely divided solids Finely divided solids can be adsorbed at the oil-water interface to form a coherent film that prevents coalescence of the dispersed globules. If the particles are preferentially wetted by oil, a w/o emulsion is formed. Conversely, if the particles are preferentially wetted by water, an o/w emulsion is formed. They form emulsions with good stability which are less prone to microbial contamination than those formed with other naturally derived agents. Examples are bentonite, aluminium magnesium silicate. Colloidal aluminium and magnesium hydroxides are used for internal preparations. 4) Auxiliary emulsifying agents Included under this heading are those compounds which are normally incapable themselves of forming stable emulsions. Their main valued lies in their ability to function as thickening agents and thereby help stabilize the emulsion. Thus, tragacanth or agar is sometimes combined with acacia to increase the consistency of the aqueous phase of an o/w emulsion. 12/29/2020  Emulsion, Emulsifying agents 10 Mechanism of action of emulsifying agents 1- Monomolecular films Examples, potassium laurate and polyoxyethylene sorbitan monooleate (Tween80). These are surface-active agents which form a monolayer of adsorbed molecules or ions at the oil/water interface and are capable of stabilizing the emulsion. The droplets are surrounded now by a coherent monolayer of flexible film formed by surface-active agents, which prevents coalescence between approaching droplets. These agents also lower interfacial tension markedly, and this contributes to stability of emulsion. Non-ionic surface- active agents are widely used to give o/w or w/o emulsions depending on the particular agent(s) chosen. 12/29/2020  Emulsion, Emulsifying agents 11 2- Multimolecular films Examples, acacia and gelatin. Hydrated lyophilic colloids form multimolecular films around droplets of dispersed oil. It forms strong rigid film which produce o/w emulsion. While these hydrophilic colloids are adsorbed at an interface (and can be regarded therefore as “surface-active”), they do not cause an appreciable lowering in surface tension. Rather, their efficiency depends on their ability to form strong, coherent multimolecular films. These act as a coating around the droplets and render them highly resistant to coalescence, even in the absence of a well-developed surface potential. Furthermore, any hydrocolloid not adsorbed at the interface serves to increase the viscosity of the continuous aqueous phase; this enhances emulsion stability. 12/29/2020  Emulsion, Emulsifying agents 12 3- Solid particle films Examples, bentonite, graphite, and magnesium hydroxide. They form film of solid particles that are small in size compared to the droplet of dispersed phase, Particles must be wetted by both phases to some extent in order to remain at the interface and form a stable film. They can form either o/w or w/o emulsions, depending on method of preparation. 12/29/2020  Emulsion, Emulsifying agents 13 1- Formulation by the method of HLB (Hydrophile /Lipophile Balance) As the emulsifier becomes more hydrophilic, its solubility in water increases and the more likely is the formation of an o/w emulsion. Conversely, w/o emulsions are favored with the more lipophilic emulsifiers. This led to the concept that the type of emulsion is related to the balance between hydrophilic and lipophilic solution tendencies of the surface-active emulsifying agent. If an o/w emulsion is required, the formulator should use emulsifiers with an HLB in the range of 8-18. Emulsifiers with HLB values in the range of 3-6 are given consideration when a w/o emulsion is desired. Relationship between HLB range and surfactant application HLB range Use 0–3 Antifoaming agents 3– 6 w/o emulsifying agent 7–9 wetting agents 8 – 18 o/w emulsifying agents 13 – 15 Detergent 10 – 18 Solubilizing agents 12/29/2020  Emulsion, formulation 14 Some typical examples are given in the following table. “HLB values for some pharmaceutical surfactants” Surfactants HLB Sorbitan tri-oleate (Span 85) 1.8 Oleic acid 4.3 Sorbitan mono-oleate (Span 80) 4.3 Sorbitan mono-stearate (Span 60) 4.7 Sorbitan mono-laurate (Span 20) 8.6 Polysorbate 60; Tween 60 (polyoxyethylene sorbitan mono-stearate) 14.9 Polysorbate 80; Tween 80 (polyoxyethylene sorbitan mono-oleate) 15.0 Polysorbate 20; Tween 20 (Polyoxyethylene sorbitan mono-laurate) 16.7 Potassium oleate 20.0 Sodium dodecyl (lauryl) Sulphate 40.0 12/29/2020  Emulsion, formulation 15 Griffin evolved a series of “required HLB” values; i.e., the HLB value required by a particular material if it is to be emulsified effectively. Some values for oils and related materials are contained in the following table: “Required HLB values for a range of oil and waxes” For a For an w/o emulsion o/w emulsion Beeswax 5 12 Cetyl alcohol - 15 Liquid paraffin 4 12 Soft paraffin 4 12 Wool fat 8 10 Stearic acid - 17 Lanolin anhydrous 8 15 Cottonseed oil - 7.5 12/29/2020  Emulsion, formulation 16 If the HLB of the oil phase is known and the type of emulsion desired is known (o/w or w/o), the formulator chooses two emulsifying agents, one with an HLB value above and the second with an HLB value below that required by the oil. These are blended to give a mixture of the correct HLB. The following formula should serve as an example. R Liquid petrolatum (HLB 10.5) 50 g Emulsifying agent 5g Span 80 (HLB 4.3) Tween 80 (HLB 15) Water, q.s. 100 g Prepare o/w emulsion 12/29/2020  Emulsion, formulation 17 Calculation and preparation Let A be the percentage concentration of the hydrophilic (Tween 80) and B the percentage of the hydrophobic surfactants (Span 80) required to give a blend having an HLB value of x. Then: 100 (x – HLB of B) 100 ( 10.5 – 4.3 ) 100 ( 6.2) A = --------------------------------- = ---------------------- = --------------- = 58 % ( HLB of A – HLB of B) ( 15 – 4.3) 10.7 B = 100 – 58 = 42 % Because the total percentage of emulgent blend in the formulation is 5, the percentage of each emulsifier will be: The required weight of Span 80 = 5  42 / 100 = 2.1 g The required weight of Tween 80 = 5  58 / 100 = 2.9 g The oil-soluble Span is dissolved in the oil and heated to 75°C; the water-soluble Tween is added to the aqueous phase, which is heated to 70°C. At this point the oil phase12/29/2020 is mixed  Emulsion, formulation 18 with aqueous phase and the whole stirred continuously until cool. The formulator is not restricted to Span 80 and Tween 80 to produce a blend with an HLB of 10.5. The following table shows the various proportions required using other surface-active agents. “Nonionic blends having HLB values of 10.5” Required amounts (%) Surfactant blend HLB to give HLB = 10.5 Span 65 2.1 34.4 Tween 60 14.9 65.6 Arlacel 60 4.7 43.2 Tween 60 14.9 56.8 Span 40 6.7 57.3 Tween 40 15.6 42.7 Arlacel C 3.7 48.5 Brij 35 16.9 51.5 12/29/2020  Emulsion, formulation 19 Example (2): If a formulation contains a mixture of oils, fats or waxes, the total HLB required can be calculated. The following example of an o/w emulsion will show this. R Liquid paraffin (HLB 12) 35 % Wool fat (HLB 10) 1 % Cetyl alcohol (HLB 15) 1 % Emulsifying agent 5 % Span 80 (HLB 4.3) Tween 80 (HLB 15 ) Water to 100 % Prepare o/w emulsion 12/29/2020  Emulsion, formulation 20 At this point the oil phase is mixed with aqueous phase and the whole stirred continuously until cool. Calculation and preparation The total percentage of oil phase is 37 and the proportion of each is: Liquid paraffin = 35 / 37  100 = 94.6  Wool fat = 1 / 37  100 = 2.7  Cetyl alcohol = 1 / 37  100 = 2.7  The total required HLB number is obtained as follows: Liquid paraffin (HLB 12) = 94.6 / 100  12 = 11.4 Wool fat (HLB 10) = 2.7 / 100  10 = 0.3 Cetyl alcohol (HLB 15) = 2.7 / 100  15 = 0.4 ⎯⎯⎯ Total required HLB 12.1 12/29/2020  Emulsion, formulation 21 The proportions of Span 80 (HLB 4.3) and Tween 80 (HLB 15) to be used to provide an HLB of 12.1, are calculated as follows: Let A be the percentage concentration of the hydrophilic (Tween 80) and B the percentage of the hydrophobic surfactants (Span 80) required to give a blend having an HLB value of x. Then: 100 (x – HLB of B) 100 ( 12.1 – 4.3 ) 100 ( 7.8) A = --------------------------------- = ---------------------- = --------------- = 72.9 % ( HLB of A – HLB of B) ( 15 – 4.3) 10.7 B = 100 – 72.9 = 27.1 % Because the total percentage of emulgent blend in the formulation is 5, the percentage of each emulsifier will be: Tween 80 = 5  72.9/ 100 = 3.6 % Span 80 = 5  27.1 / 100 = 1.4 % 12/29/2020  Excipients used in pharmaceutical emulsions 22 The oil phase of pharmaceutical emulsions is typically composed of vegetable oils, e.g. cottonseed oil, arachis oil, almond oil (mono-, di- and triglycerides of mixtures of unsaturated and saturated fatty acids). Alternative non-aqueous phases used in the formulation of emulsion include: (1) petrolatum and mineral oil; (2) isopropyl myristate. 12/29/2020  Excipients used in pharmaceutical emulsions 23 Petrolatum and mineral oil Petrolatum and mineral oil are hydrophobic excipients that are derived from petrolatum. The former is a complex mixture of hydrocarbons (e.g. aliphatic, cyclic, saturated, unsaturated, branched hydrocarbons) that results in a wide range of chemical and physical specifications in the USP monograph. Mineral oil is a more purified fraction of petrolatum and is a mixture of aliphatic (C14–C18) and cyclic hydrocarbons. Both materials are employed as the internal phase in o/w emulsions and as the external phase in w/o emulsions (usually in combination with a fatty alcohol as the emulsifying agent). 12/29/2020  Excipients used in pharmaceutical emulsions 24 Isopropyl myristate Isopropyl myristate is used as a non-aqueous component of cream formulations, either as the internal phase of o/w creams or as the external phase of w/o creams. More recently isopropyl myristate has been reported to enhance the permeation of drugs through the skin when applied topically. 12/29/2020  Excipients used in pharmaceutical emulsions 25 Antioxidants Antioxidants are included within pharmaceutical formulations to enhance the stability of drugs/components to oxidation. In emulsions and creams the two major components that may be liable to oxidize are the therapeutic agent and the oil selected for the oil phase, vegetable oils. Therefore the inclusion of lipophilic antioxidants within the oil phase may be required, e.g. butylated hydroxyanisole (circa 0.02–0.5% w/w), butylated hydroxytoluene (circa 0.02–0.5% w/w) and propyl gallate ( 0.1% w/v). If the antioxidant is required in the aqueous phase of an emulsion or cream then a water-soluble example should be used, e.g. sodium metabisulphite (0.01–1.0% w/v) or sodium sulphite (0.1% w/v). 12/29/2020  Excipients used in pharmaceutical emulsions 26 Flavours and sweeteners Flavours and sweeteners are commonly included in emulsions for oral administration to mask the unpalatable taste of the therapeutic agent or the internal oil phase. Viscosity modifiers The viscosity of emulsions and creams has been previously described to influence the physical stability of emulsions by decreasing the rate of creaming and therefore viscosity control within a formulation is an important attribute. The inclusion of hydrophilic polymers, e.g. MC, HEC, polyacrylic acid and sodium CMC, to increase the viscosity of aqueous systems. It must be remembered that, as the viscosity of formulations increases, so does the difficulty in administration and, therefore, this must be borne in mind when the final viscosity of the o/w emulsion is selected. Furthermore, the ability of hydrophilic polymers to form a multimolecular layer around the surface of the dispersed-oil droplet is an important function of polymers within emulsion formulations. 12/29/2020  Excipients used in pharmaceutical emulsions 27 Preservatives for emulsions and creams The concept of preservation of pharmaceutical systems, i.e. solutions and suspensions, has been discussed. In particular the effects of pH and the presence of hydrophilic polymers, dispersed particles and surfactant micelles on the available preservative concentration were highlighted. The preservation of o/w emulsions and creams becomes a challenging task to the pharmaceutical scientist due to the possible corequirement for pH control of the external phase and the inclusion of hydrophilic polymers. However, the complexity of this issue is enhanced due to the presence of a dispersed-oil phase into which the antimicrobial active form of the preservative may partition and hence be unavailable to exert its antimicrobial effect. An equilibrium is therefore established 12/29/2020 Excipients used in pharmaceutical emulsions 28 Emulsions contain water, which will support microbial growth. Microbes produce unpleasant odors, color changes and gases and may have an effect on the emulsifying agent, possibly causing breakdown of the emulsion. Other ingredients of emulsions can provide a growth medium for microbes. Examples include Arachis oil, which supports Aspergillus species and liquid paraffin which supports Penicillium species. Microbial growth normally occurs in the aqueous phase of an emulsion, therefore it is important that a sufficient concentration of preservative is present in the aqueous phase. Some preservatives in use are listed below: The most widely use preservatives are mixture of Methyl parahydroxybenzoate in 0.2% & Propyl parahydroxybenzoate in 0.02%. They are suitable for both external and internal use. Benzoic acid, which is effective at a concentration of 0.1% at a pH below 5. Chloroform, as chloroform water (0.25% v/v). Chlorocresol (0.1%). Organic mercurial compounds such as phenyl mercuric nitrate (0.01%). Phenoxyethanol (1%). 12/29/2020  Excipients used in pharmaceutical emulsions 29 The figure Illustrates the partitioning of the unionized form of a weak acid preservative into micelles and oil droplets. The term HA may be replaced by a non-ionisable (or minimally ionizable) preservative, e.g. chlorocresol. As may be observed in the figure, the available (active) concentration is decreased by these various partitioning phenomena and therefore the concentration of preservative must be increased to ensure that required concentration of free preservative is obtained. 12/29/2020