PHT 312: Pharmaceutics II

1. King Saud University College of Pharmacy Department of Pharmaceutics PHT 312: Pharmaceutics II Pharmaceutical Emulsions

2. Outlines • Introduction • Theoretical Aspects • Types and Applications • Emulsion Stability • Formulation of Emulsion • Properties of Emulsion and Emulsifiers

3. Introduction • It consists of a two-phase system prepared by combining two immiscible liquids, one of which is dispersed uniformly throughout the other. • Internal phase = the dispersed phase, • External phase or dispersion medium = continuous phase.

4. The liquid that is dispersed into small droplets is called the dispersed phase or internal phase or discontinuous phase • The other liquid is the dispersion medium external phase continuous phase

5. Two immiscible liquids, not emulsified. An emulsion of Phase B dispersed in Phase A. The unstable emulsion regressively separates. The surfactant positions itself on the interfaces between Phase A and Phase B, stabilizing the emulsion.

6. Emulsions are unstablebecause: the globules of the dispersed liquid tend to coalesce to form large globules until all of the dispersed globules have coalesced. • An emulsifying agentis usually added to the system toprevent the coalescence of the globules and maintain the integrity of the individual globules of the dispersed phase.

7. Emulsions tend to have a cloudy appearance, because the many phase interfaces (the boundary between the phases is called the interface) scatter light that passes through the emulsion. Emulsions are unstable and thus do not form spontaneously. Energy input through shaking, stirring, homogenizers, or spray processes are needed to form an emulsion. • Over time, emulsions tend to revert to the stable state of oil separated from water. Surface active substances (surfactants) can increase the kinetic stability of emulsions greatly so that, once formed, the emulsion does not change significantly over years of storage.

8. A phenomenon is called coalescence, and happens when small droplets recombine to form bigger ones. Fluid emulsions can also suffer from creaming, the migration of one of the substances to the top of the emulsion. • Emulsions are part of a more general class of two-phase systems of matter called colloids. Although the terms colloid and emulsion are sometimes used interchangeably, emulsion tends to imply that both the dispersed and the continuous phase are liquid.

9. There are three types of emulsion instability: • Flocculation, where the particles form clumps; • Creaming, where the particles concentrate towards the surface of the mixture while staying separated; and • Breaking, where the particles coalesce and form a layer of liquid.

10. Emulsifier: • An emulsifier (or surfactant) is a substance which stabilizes an emulsion. • Detergents are another class of surfactant, and will chemically interact with both oil and water, thus stabilizing the interface between oil or water droplets in suspension. • This principle is exploited in soap to remove grease for the purpose of cleaning. • A wide variety of emulsifiers are used in pharmacy to prepare emulsions such as creams and lotions.

11. 20 ml ampule of 1% propofol emulsion suitable for intravenous injection.

12. When oil is the dispersed phase and an aqueous solution is the continuous phase, the system is designated as an oil-in-water (O/W) emulsion. • Conversely, where water or an aqueous solution is the dispersed phase and oil or oleaginous material is the continuous phase, the system is designated as water-in-oil (W/O) emulsion.

13. Oil-in-water (O/W) emulsion used for oral and intravenous administration . • Water-in-oil (W/O) emulsion used for intramuscular injections for a depot effect (extended release or long acting effect).

14. Oil-in-water (O/W) emulsion: • Water-in-oil (W/O) emulsion:

15. Multiple Emulsion Method: multiphase emulsions are prepared by the solvent evaporation technique by a three-step emulsification process. • Aqueous drug solution and oil phase containing emulsion stabilizers are combined to give a water-in-oil emulsion (step 1). Later the w/o emulsion is dispersed in the polymer solution (step 2). The solvent is evaporated under reduced pressure. • In other way: preparation of a primary o/w emulsion in which the ‘oily dispersed phase’ in an organic solution of the drug and the ‘aqueous continuous phase’ is an aqueous solution containing chitosan and an emulsifier (step 1); multiple emulsion formation with a ‘oily outer phase’ (step 2); and finally, cross-linkage adding a cross-linking agent.

16. Hint: Hydrophobic drugs are prepared using o/w/o multiple emulsion method. Hydrophilic drugs are prepared using w/o/w multiple emulsion method.

17. Why would you want an o/w emulsion instead of a w/o emulsion for an oral dosage form? • The continuous water phase would be more palatable to the mouth and the liquid consistency would be easier to flow through the mouth and down the throat. • By dispersing a foul tasting orsmelling drug in the oil phase, your taste buds and your sense of smell will be unaware of the agent passing by. • In addition, in the o/w emulsionthe manufacturer can add sweeteners and flavors to the continuous phase which will be experienced by thetaste buds as the medication passes over them.

18. Advantages of emulsions over other liquid forms: 1- The unpleasant taste or odor of an oil can be masked partially or wholly, by emulsification 2- The solubility of many drugs is increased when they are incorporated into emulsions 3- The stability of many drugs which are unstable in aqueous solutions is increased when incorporated into an emulsion

19. 4-Prolonged drug action and increased bioavailability are often obtained when drugs are incorporated into emulsions 5- The appearance of oleaginous materials intended for topical applications is usually improved when formulated in an emulsified form

20. Emulsion Stability • Flocculation and Coalescence: if no protective barrier is present at the interface, or if very low surface coverage by emulsifier exists, emulsion droplets rapidly aggregate and coalesce. Even though coverage sufficient to prevent coalescence may exist, however, a relatively weak particle-particle interaction known as flocculation may occur. Flocculation is differentiated from coalescence primarily by the fact that the interfacial film remains intact and that aggregation may be reserved.

21. Emulsion Stability • Flocculation and Coalescence (…cont.): While flocculation (aggregation) is the clumping together of particles, coalescence is the fusing of the agglomerates into a large drop, or drops. Coalescence is usually rapid when two Immiscible liquids are shaken together, since there is no large energy barrier to prevent fusion of drops or reformation of the original bulk phases.

22. Emulsion Stability • Flocculation and Coalescence (…cont.): When an emulsifying agent is added to the system, flocculation still may occur but coalescence is reduced to an extent depending on the efficacy of the emulsifying agent to form a stable, coherent interfacial film. It is therefore possible to prepare emulsions that are flocculated, yet which do not coalesce.

23. Emulsion Stability • An emulsion is considered unstable if: • The internal phase tends to form globule aggregates b. Large globules rise to the top (cream) or fall to the bottom to form a concentrated layer of emulsified internal phase globules c. If the emulsion breaks (coalescence of the internal phase globules into a distinct phase). In other words, the separation of the internal phase from the emulsion, and the emulsion is described being cracked or broken.

24. Emulsion Stability • What causes an emulsion to break? The globules coalesce due to too little emulsifying agent in the first place or possibly due to degradation of the emulsifying agents by chemical or enzymatic (from microbes or other sources) means. Sterility isn't necessary with oral emulsions, but destruction of the microbes can improve the physical stability of emulsion formulations. Fungistatic preservatives are generally included because fungi (molds and yeasts) are more likely to contaminate emulsions than are bacteria.

25. Emulsion Stability • What causes an emulsion to break? Methylparaben and propylparaben are frequently used to serve this function. Alcohol at 12-15%, based on the aqueous volume, is frequently added to oral o/w emulsions for preservation. Care must be taken to protect emulsions against extremes of cold and heat. Freezing and thawing causes a coarsening of an emulsion and sometimes causes breaking. Excessive heat has the same effect. Light-resistant containers which can seal tightly should be used to protect the emulsion from photolysis and oxidation. Chemical antioxidants are usually employed.

26. Emulsion Stability • In light of these considerations, the instability of pharmaceutical emulsions may be classified as follows: • Flocculation and creaming • Coalescence and breaking • Miscellaneous physical and chemical changes • Phase inversion

27. Emulsion Stability • Creaming and Stokes’ Law: • Those factors that find importance in the creaming of an emulsion are related by Stokes’ Law. The limitations of this equation to actual systems have been discussed previously for pharmaceutical suspensions, and these apply equally to emulsified systems.

28. Emulsion Stability • Creaming and Stokes’ Law(…cont.) • Analysis of the equation shows that if the dispersed phase is less dense than the continuous phase, which is generally the case in the o/w emulsions, the velocity of sedimentation becomes negative, that is, an upward creaming results. If the internal phase is heavier than the external phase, the globules settle, a phenomenon customarily noted in w/o emulsions in which the internal aqueous phase is more dense than the continuous oil phase. This effect may be referred to as creaming in a downward direction. The diameter of globules is seen to be a major factor in determining the rate of creaming.

29. Formulation of Emulsion • It is difficult to designate a general approach and set of rules for selecting the materials, and their amounts, required to formulate a desired product. • Although there are obvious situations in which certain oils, emulsifiers, and other ingredients must be avoided or used exclusively, decisions of such a specific nature are made ultimately on the basis of the experience and personal tastes of the emulsion formulator, and considerable trial and error.

30. Properties of emulsions • A). Oil Phase and Water Phase: the materials making up the oil portion of an emulsion and their relative amounts are determined primarily by the ultimate use of the product, the optional toxicity of the oil, consistency desired, and the possible chemical incompatibilities with other ingredients. • For pharmaceutical and cosmetics products, the oil phase is restricted to various grades of mineral oil; a number of edible vegetable oils, such as those derived from corn, peanuts, sesame, and olives; and semi-solid and solid substances such as petroleum, lanolin, beeswax, and long chain acids and alcohols.

31. Properties of emulsions • A). Oil Phase and Water Phase: • Isopropyl and myristate, a clear viscous liquid, is also a popular ingredient used in dermatological and cosmetic formulations. • Chemical decomposition of vegetable oils and mineral oil by means of oxidation is common problem that has to be considered, particularly for those systems that must be subjected to heat.

32. Properties of emulsions • B). Phase Volume Ratio: • For fluid emulsions it has been suggested that a 40 to 60 percent internal phase volume produces acceptable emulsions with minimal difficulty. • The use of lower percentages makes it difficult to avoid creaming and sedimentation unless the external phase viscosity is increased by the addition of suitable substances, e.g. hydrophilic colloids.

33. Properties of emulsions • C). Emulsifying agent: • an emulsifier functions and operationally defined as a stabilizer of the droplet form (globules) of the internal phase. • On the basis of their structure, emulsifiers (wetting agents or surfactants) may be described as molecules comprising both hydrophilic (oleophobic) and hydrophobic (oleophilic) portions. • For this reason, this group of compounds is frequently called amphiphilic (i.e. water- and oil-loving).

34. Desired features of emulsifier • It must be compatible with the other components in the formulation, which means it must not interfere with the chemical stability of each of the components or with the therapeutic efficacy of the drug. • It must be stable in the preparation itself. If it decomposes or degrades, what good is it? • The agent must be nontoxic. • It should not possess an unacceptable odor, taste or color. • It must assist in the formation of and continue to support the emulsified system throughout the shelf-life of the product. • 6. The cost of emulsifiers

35. Desired features of emulsifier Emulsifying agents, in general, assist in the formation of emulsion by three mechanisms: • A. Reduction of interfacial tension (thermodynamic stabilization). • B. Formation of a rigid interfacial film (mechanical barrier to coalescence). • C. Formation of an electrical double layer (electrical barrier to approach of particles).

36. Types of emulsifier Carbohydrates: naturally occurring agents such as acacia, tragacanth, agar, and pectin. • These agents generally help to produce o/w emulsions. • Acacia is probably the most common emulsifier for extemporaneous preparations. It is an acidic polysaccharide. • These agents are also called hydrophilic colloids. They influence an emulsion by increasing the viscosity of the aqueous phase.

37. Types of emulsifier Macromolecules such as proteins: • Naturally occurring agents such as gelatin, egg white and casein, which also help to produce o/w emulsions. • They are not very popular since they form thin emulsions, but more importantly because they decompose rapidly which results in a broken emulsion.

38. Types of emulsifier High molecular weight alcohols: such as stearyl alcohol (18 carbons) and cetyl alcohol (16 carbons). Finely divided solids: such as bentonite, magnesium hydroxide or aluminum hydroxide. They have shown to be good emulsifiers alone and in combination with surfactants and/or macromolecules.

39. Types of emulsifier Important Note: All these emulsifiers have in common the ability to accumulate at the oil-water interface, as well as the tendency to influence the degree of particle flocculation, and hence the viscosity of the emulsion.

40. Types of emulsifier Important Note: The major requirement of a potential emulsifying agent is that it readily form a film a round each droplet of dispersed material. The main purpose of this film, which can be a monolayer, a multilayer, or a collection of small particles adsorbed around the interface, is to form a barrier which prevents the coalescence of droplets that come into contact with one another. For the film to be an efficient barrier, it should possess some degree of surface elasticity and should not thin out and rupture when sandwiched between two droplets. If broken, the film should have the capacity to reform rapidly.

41. Hydrophilic-Lipophilic Balance (HLB) System • A convenient way to choosing emulsifiers involves the use of a numerical scale for characterization. • One such approach assigns to an emulsifier a hydrophile-lipophile balance value (HLB), which is characteristic of its relative polarity. • This approach is empirical and essentially no different from choosing a series of any type of emulsifiers. The advantage of HLB system is that to a first approximation one can compare any chemical type when both polar and nonpolar groups are different. With regard to the specific choice of an emulsifier, • it has been suggested that surfactants having an HLB value of 3 to 6 should be used for obtaining w/o emulsions, whereas values of 8 to 18 are suitable for forming o/w emulsions.

42. Hydrophilic-Lipophilic Balance (HLB) System • Surfactants are characterized according to the "balance" between the hydrophilic ("water-loving") and lipophilic ("oil-loving") portions of their molecules. • The hydrophilic-lipophilic balance (HLB) number indicates the polarity of the molecules in an arbitrary range of 1-40, with the most commonly used emulsifiers having a value between 1 and 20. • The HLB number increases with increasing hydrophilicity.

43. Hydrophilic-Lipophilic Balance (HLB) System • According to the HLB number, surfactants may be utilized for different purposes:

44. Hydrophilic-Lipophilic Balance (HLB) System • The desired HLB numbers can also be achieved by mixing lipophilic and hydrophilic surfactants. The overall HLB value of the mixture is calculated as the sum of the fraction * individual HLB. • Example: A mixture of 30% Span 80 (HLB=4.3) and 70% Tween 80 (HLB=15) has an overall HLB value of: HLB=(0.3 * 4.3) + (0.7 * 15)=11.8.

45. Methods of Preparation • A mortar and pestle is employed frequently in the extemporaneous preparation of emulsions. It is not a very efficient technique and is not used on a large scale. The types of equipment available for preparing emulsions can be divided into four categories: • (1) mechanical stirring • (2) homogenizers • (3) colloid mills • (4) ultrasonifiers

46. Methods of Preparation Mechanical Stirring: • An emulsion may be stirred by means of various impellers mounted on shafts, which are placed directly into the system to be emulsified. • The degree of agitation is controlled by the speed of impeller rotation, but the patterns of liquid flow and the resultant efficiency of mixing are controlled by the type of impeller, its position in the container, the presence of baffler, and the general shape of the container.

49. Methods of Preparation Homogenization: • A homogenizer can be used to produce fine droplets by first compressing the liquids to high pressure and then allowing them to escape gradually past a flat disc held by a strong spring. • The high shearing stresses produced at pressure ranging from 500-5000 p.s.i. can produce extremely fine particles, the size depending on the viscosity and the interfacial tension of a system.